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Fat absorption was studied in 24 patients with clinically definite multiple sclerosis and in 36 healthy control subjects. Beta-carotene and vitamin A in their plasma were also measured. This double-blind and randomized study showed no differences between these two populations with regard to the three parameters. We did not find evidence for fat malabsorption in multiple sclerosis.

The ocular effects in rabbits of topically applied labetalol hydrochloride, a new alpha- and beta-adrenergic receptor blocking agent, were studied. A dose-related reduction in intraocular pressure (IOP) followed treatment with 0.01% to 1% solutions. Labetalol at a 1% concentration had no effect on pupil diameter. The same dose blocked an increase in IOP after water loading but did not significantly alter the coefficient of aqueous outflow facility. Mydriasis induced by phenylephrine hydrochloride was competitively inhibited.

With the use of an automatic titrator for calcium and a microcolorimetric assay for protein, diurnal variations in tear calcium and total protein values were studied in nine subjects during a ten-day period. Tear calcium and total protein concentrations were found to be individualized functions that were dependent on the sampling time and sampling day. Prolonged eye closure resulted in an approximate twofold increase in both tear calcium and total protein concentrations. The concentrations of both species remained relatively constant during the day between 8 AM and 5 PM, exhibiting few substantive variations. Diurnal changes in tear calcium and protein values closely paralleled one another. It was found that the tear concentrations of these two species could be related with a simple linear function, which suggests that calcium binding and transport by tear protein may be occurring.

To minimize the risk of visual loss in diabetic patients, recognition of early signs of oculopathy is essential. Diabetes-associated third-nerve palsy is manifested by unilateral ptosis and exotropia. Symptoms of closed-angle glaucoma are intense pain, halos around lights, and blurred vision. Open-angle glaucoma does not necessarily produce symptoms and is treated medically. A gradual decrease in visual acuity, sometimes associated with photophobia and difficulty in night driving, and monocular diplopia, are manifestations of cataract. The patient with "background" retinopathy usually complains of blurred or distorted central vision. Once the macula is involved, vision progressively decreases. Although the relationship of metabolic control to retinopathy has not been settled, evidence indicates that good medical control of the disease may delay onset of vascular complications.

We have obtained comparative data for the intraocular absorption of topically administered clindamycin hydrochloride hydrate and clindamycin phosphate, made feasible with a new gas chromatographic method of analysis. Results indicated that clindamycin phosphate underwent hydrolysis in the eye, liberating the biologically active clindamycin. However, topical clindamycin hydrochloride produced higher levels (two to six times more) of the antibiotic than those achievable with the phosphates ester in the uvea, aqueous humor, and cornea, presumably due to clindamycin hydrochloride's higher lipid solubility. Based on this data, clindamycin hydrochloride appears to be the preferred form of the antibiotic for topical ocular applications.

The nature of inflammation in general and the special aspects of ocular inflammation are discussed. Causes of inflammation, the cellular and tissue response to noxious stimuli and the biochemical mediation of the inflammatory response are described. Prostaglandins and their relatives the thromboxanes and prostacyclins are shown to play an important role in the mediation of ocular inflammation. Inhibitors of the biochemical synthesis of prostaglandins show strong potential for use in topical ocular antiinflammatory therapy, however their preclinical evaluation requires the choice of a suitable animal model. A review of animals of both specific and general ocular inflammation is presented.

Human tears were found to inhibit the thiol-dependent protease, papain. Inhibitory activity in normal tears was compared with that in patients with blepharitis, infectious and allergic conjunctivitis, and herpes simplex. Activities lower than normal were found in some patients with infectious conjunctivitis and blepharitis. Higher than normal activities were found in patients with herpes simplex and allergic conjunctivitis. Differences from normal values were found to be statistically significant in allergic conjunctivitis and blepharitis by analyses of sample medians, means, and geometric means. A function of this inhibitor in external ocular inflammations is suggested.

Following the suggestion that prostaglandins are involved in corneal neovascularization, two inhibitors of prostaglandin formation, prednisolone acetate and flurbiprofen sodium, have been evaluated in two experimental models of corneal neovascularization. The fatty acid cyclooxygenase inhibitor, flurbiprofen, at concentrations of 0.01% and 0.1%, significantly decreased the rate of vessel growth compared with vehicle controls in both silver nitrate cauterization and anterior chamber alloxan models of corneal neovascularization. Prednisolone, at a concentration of 1%, was used as a positive control. It did inhibit neovascularization in the latter model, but was ineffective in the former. It is concluded that 0.1% flurbiprofen is equipotent to 1% prednisolone as an inhibitor of corneal neovascularization. The mechanism is unknown but is likely to be via inhibition of prostaglandin formation and/or inhibition of leukocytic infiltration.

Labetalol has a unique and profound effect on the IOP of rabbits, in contrast to pure beta-adrenergic blockers which have little or no effect in this animal. Its action cannot be satisfactorily explained by simple alpha and beta-adrenergic blocking activity. In the concentrations used, it failed to block the action of a beta-adrenergic agonist (isoproterenol), the action of an alpha-adrenegic agonist (norepinephrine), and its own hypotensive action was neither blocked nor potentiated by the alpha-adrenergic blocker phenoxybenzamine. However, the beta blocker, timolol, did reduce the action of labetalol. These observations and the reduced response to labetalol after cervical sympathectomy, suggest that labetalol's ocular hypotensive effect may occur through some mechanism other than alpha or beta blockade.

Prazosin hydrochloride, an oral antihypertensive, is reported to inhibit phosphodiesterase and block postsynaptic alpha-adrenergic receptors, intraocular pressure (IOP) in rabbits was reduced in a dose-related manner following topical ocular application of concentrations of 0.0001% to 0.1%. The ocular hypotensive response lasted six to eight hours with a maximum effect at approximately two hours. The IOP of unilaterally sympathectomized rabbits treated in both eyes with prazosin decreased more in the normal eyes than in the sympathectomized eyes. Treatment of only the unsympathectomized eyes of these rabbits elicited a similar response. Normal rabbits elicited a similar response. Normal rabbits treated in only one eye also showed a slight response in the contralateral eye. Preliminary experiments did not support the hypothesis that these effects were due to a decrease of systemic blood pressure. No substantial ocular toxicity or pupillary changes were observed.

Efforts have been made to develop noncorticosteroidal anti-inflammatory therapy. The goals of such therapy have been to eradicate the primary cause, prevent the initial tissue injury, moderate inflammatory response, and enhance tissue repair while minimizing and eliminating the undesirable aspects of the therapy.

Angiotensin II is a biological active octapeptide that is formed by the action of angiotensin-converting enzyme (ACE) on the inactive precursor, angiotensin I. ACE activity was found in tears and aqueous humor from both rabbit and human eyes. The activity was higher in tears than aqueous humor. Enzyme activity was determined fluorimetrically from the rate of breakdown of the substrate, hippuryl-L-histidyl-L-leucine. The enzyme activity was further characterized by determining the effects of inhibitors. There was a significant difference in ACE levels in human tears when eye color was considered. People with either green or brown eyes had a higher ACE level than did blue-eyed individuals. The presence of this enzyme activity in ocular fluids suggests that angiotensin II may play a role in normal ocular physiology.

Leucocyte-migration inhibition was to determine the state of hypersensitivity in 65 diabetic patients with different stages of retinopathy and 21 nondiabetic controls. About one third of the patients with simple or proliferative retinopathy exhibited significant leucocyte-migration inhibition of 0.2 mg/ml. protein concentration of uvreoretinal antigen. In contrast, only one of 15 patients with minimal retinopathy and none of the controls showed significant leucocyte-migration inhibition. Corneal and lenticular antigens did not evoke a cellular immune response in any of the tested individuals. These findings suggest that cell-mediated hypersensitivity to uveoretinal antigen may develop in diabetic patients with prolonged, progressive, simple or proliferative retinopathy.

This case report describes a chronic medically-refractory corneal ulcer which eventually yielded Herellea vaginicola from resected corneal tissue. A review of the literature cites the occurrence of this organism as an inhabitant of normal conjunctiva, as an infrequent cause of conjunctivitis, and as the causative agent in two previous cases of corneal ulcers. This case illustrates the difficulty in the isolation of the organism and indicates the need for diagnostic and therapeutic keratectomy in conjunction with a conjunctival flap.

The enucleated eyes of New Zealand albino rabbits were injected with 50, 100, 250, and 500 mg/kg of amoxicillin to determine the drug penetration into the aqueous humor, vitreous humor, serum, and other ocular tissues after oral administration. Detectable levels were achieved after each specific dose for at least five hours. In the aqueous humor, drug levels were present at 15 minutes, peaked at 1.5 and two hours, and were present at leave five hours after oral administration.

Tear film breakup time (BUT) was measured in 25 normal subjects on 8 different occasions over a period of one month. Reproducibility of the BUT test and factors involved in interpretation of tear film breakup were studied. It was found that of 50 eyes, the average BUT ranged from five to 100 seconds, and that there were noticeable variations (P less than or equal to .05) in an individual eye from one patient visit to the next. The BUT is not a closely reproducible phenomenon in an individual eye.

Rosoxacin, a new synthetic antimicrobial agent, has a wide spectrum of activity that may prove beneficial in the treatment of ocular infections. To determine the penetration of rosoxacin into ocular tissues and serum of the rabbit after topical, subconjunctival, and intravenous (IV) administration, rosoxacin levels were measured using a microbiological assay after enzymatic digestion of the ocular tissues. Quantities of rosoxacin that should prove to be of therapeutic value were detectable in the anterior segment of the eye after topical or subconjunctival administration. Subconjunctival administration also resulted in high levels in the retina and choroid area and in the optic nerve. Low levels were detected in the retina and choroid 15 minutes following IV injection; however, no detectable levels were found in the ocular tissues after this period.

Progress is painful. This is certainly true in drug therapy. No drug in clinical use is devoid of toxicity, and all ophthalmologists are aware that no human being should be exposed to needless risk. On the other hand, the potential harm done to present and future generations by lack of adequate therapy for many diseases makes it imperative that new drugs, despite their associated hazards,continue to be introduced into research and practice. If an ophthalmologist accepts these thoughts, he also must accept a commitment to understand the effect of drugs in disease, the predisposing factors leading to drug reactions and interactions, the effect of disease on drugs, before he uses them.

Each year, new antimicrobials are found or synthesized in an effort to improve the chance of overcoming infections. In the early 1950s, the only antibiotic available for ocular use was penicillin. Today, ophthalmologists can make a choice from a large selection of antibiotics for ocular infections. The majority of antibiotics have been literally unearthed, since worldwide soil surveys may have been the means of their discovery. In addition, synthetic derivatives of penicillin, cephalosporins, aminoglycosides, and tetracyclines, as well as drugs against tuberculosis and fungi, have become available, and new names have been added to the already bewildering list of less frequently used sulfonamides. However, it takes several years to appreciate the impact of new agents and the continued contribution of older ones. Constant reevaluation is mandatory. The real benefits as well as the untoward effects of a new antimicrobial agent may not be known until several years after the clinical introduction. In addition to approaching infection from the viewpoint of the offending organism and a specific antibiotic to address this organism, one may also approach this problem from the host's immunity. Until now, we have relied largely on the corticosteroids, but one must also consider various nonsteroidal anti-inflammatory agents and, even more importantly, the development of drugs to enhance the host's natural immunity.

To assess the association between open-angle glaucoma and HL-A antigens, the frequencies of 25 HL-A antigens were determined in 49 patients with OAG, and 22 patients with increased intraocular pressure, due to causes other than OAG, using the microcytotoxicity method. The results were compared to 250 individuals from the general population who were tested in the same laboratory at the same period of time. Using rigid statistical analysis, the incidence of the Bw35 antigen was found to be significantly (less than 0.012) higher among OAG patients. In a group of 27 first relatives of OAG patients who were tested at the same time, the frequency of Bw35 antigen was increased compared to the general population. The biological importance of the association between Bw35 and OAG, which may still be a chance deviation, is not yet fully understood. It may indicate that the Bw35 antigen or the HLA loci are among the genetic factors which produce susceptibility to open-angle glaucoma.

Tear calcium levels were measured in 27 normal subjects. An instrumental technique that required only 5- to 10-microL tear samples was used for this purpose. A mean of 2.11 +/- 49 (SD) mg/dl of calcium with a range of 1.05 to 3.49 mg/dl was determined for 67 tear samples from 27 subjects. This is in excellent agreement with more elaborate and previous methods. Various factors involved in tear calcium levels were also studied. Tear calcium levels were not significantly affected by the normal walking-hour wear of either hard or soft contact lenses among 22 women aged 19 to 35 years. Tear calcium day-to-day and diurnal variations were found for five of five subjects in a three-day study. Further studies of these variable phenomena are indicated.

Tears of patients and laboratory animals on systemic medications have been analyzed for the presence and influence of these agents on tear constituents. Antibiotic penetration into tears, drugs stimulating or retarding lacrimation, and effects on tear electrolytes, lysozyme, and immunoglobulins are reviewed from the literature. Important applications to clinical practice such as contact lens wear, general anesthesia, eye infections, and epiphora or dry eye symptoms are discussed.

Data from two short-term double-masked studies using 24 and 16 subjects suggest that topically applied levobunolol safely and effectively treats open-angle glaucoma and ocular hypertension. The onset of effect of a single drop of 0.5% levobunolol occurred within the first hour, producing a maximal hypotensive effect of more than 8 mm Hg after two hours. An intraocular pressure deceased of greater than or equal to 2 mm Hg was still observed after 24 hours for both concentrations of levobunolol tested (0.5% and 1%). Intraocular pressure decreases of more than 9 mm Hg persisted during a one-month trial in which patients were treated twice daily, confirming the results obtained in the 24-hour study. Systemic effects of both timolol (0.5%) and levobunolol (0.5% and 1%) included a consensual intraocular pressure-decreasing effect in the untreated eye and clinically significant reductions in heart rate. Diastolic blood pressure was decreased at two and four hours after administration of 0.5% levobunolol.

The IOP and pupil response to alpha-adrenergic agonists and blockers was studied in albino rabbits. Topical ocular application of solutions of methoxamine (alpha 1) and oxymetazoline (alpha 2) caused dose-related early rises in IOP which were inhibited by pretreatment with prazosin, an alpha 1-blocker, or with yohimbine, an alpha 2-blocker. Although both prazosin and yohimbine have ocular hypotensive activity, the effect on the early IOP rise did not appear to be related to this action. Prazosin and yohimbine also inhibited the early IOP rise after treatment with clonidine, a second alpha 2-agonist. Surgically sympathectomized rabbits showed little or no hypersensitivity to methoxamine or oxymetazoline when compared to non-operated normal rabbits. However the treated ipsilateral eyes showed a much greater increase in IOP than the treated contralateral eyes. There was little difference in the IOP response between clonidine-treated ipsilateral and contralateral eyes. Methoxamine and oxymetazoline caused dose-related increases in the pupil diameter which were blocked by the nonselective alpha-blocker phentolamine but not by prazosin (alpha 1) or yohimbine (alpha 2). This study suggests: 1) That the early IOP rise after treatment with alpha-agonists is due to stimulation of postsynaptic alpha 1-receptors, possibly located in superficial blood vessels in the anterior segment of the eye; 2) The mydriatic response to alpha-agonists appears to be mediated by alpha-receptors which differ from the classical alpha 1 and alpha 2 subtypes.

Metallochemical and biochemical studies completed in the Department of Ophthalmology at the University of California, Irvine, offer a new perspective in understanding MS. Low plasma zinc levels were observed in MS patients, and this has been confirmed in laboratories elsewhere in the world. Generalized malabsorption could not be demonstrated in MS patients when using a double-blind, randomized study of 72-hours fecal fat. A double-blind, randomized zinc tolerance test confirmed the low plasma zinc levels in fasting MS patients, but once an oral zinc load had been given, the 7-hour post treatment levels were elevated to that of control patients. Intracellular erythrocyte zinc concentration was measured in controls and in MS patients. The controls had no change over 7 hours despite a large zinc load with consequent elevation in plasma levels. However, MS patients demonstrated a gradual elevation of intracellular zinc concentration over the 7-hour period, with P less than 0.01. Thus, the erythrocyte membranes of controls were able to maintain the zinc gradient between the extracellular and the intracellular compartments, while MS patients were not, suggesting a functional abnormality in plasma membranes outside of central nervous system. Erythrocyte membrane-bound CNP was observed to be abnormality low in MS patients when compared to controls. The study has been confirmed by a different laboratory using a different substrate on MS erythrocytes. The rationale for considering MS as a possible systemic disease is presented.

Two double-blind, random-assignment clinical trials demonstrated the effectiveness of topical oxymetazoline hydrochloride in reducing histamine-induced hyperemia. Oxymetazoline hydrochloride at an optimum strength of 0.025% produced a marked and prolonged reduction of hyperemia, with the onset of effect occurring within one to five minutes of instillation. Safety indicators, including BP, heart rate, intraocular pressure, pupil size, and visual acuity, did not change significantly from baseline values. Oxymetazoline was absorbed slowly into the eye: only 0.006% of the original drug concentration was found in the aqueous humors of rabbits 30 minutes after instillation; the balance remained primarily in external ocular tissues. Metabolic studies in rabbits indicated that excreted amounts of unmetabolized radioactive oxymetazoline in urine following drug administration were similar (23%) for the ocular and nasal routes of application. The proportions of oxymetazoline metabolite to unchanged oxymetazoline were constant for all administration routes tested.

The specific activities of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase, EC3.1.4.37) in erythrocyte membranes from five patients with active multiple sclerosis (MS) and five normals were compared. The CNPase assay used 2',3'-cyclic NADP as the substrate in an enzyme coupled reaction to produce fluorometrically detectable NADPH. The specific activity of CNPase in the MS and normal groups were 19.2 +/- 2.3 and 28.7 +/- 1.8 mumol/h/mg protein, respectively. The difference was significant with p less than 0.006, based on a one-tailed t-test.