Intestinal absorption of dietary fat in patients with multiple sclerosis.

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.

Recent developments in chemotherapy of ocular diseases.

The profile of organisms responsible for ocular infections has changed over the past few decades. Although nonresistant and resistant staphylococci still lead the list, gram-negative, mixed infections and anaerobic organisms have become more evident. In spite of more potent and broader spectra antibiotics, resistant organisms still emerge. The therapy of intraocular infections requires an awareness of the latest antibiotics, particularly their advantages, limitations, toxicities, and administration. Iontophoresis through the sclera overlying the pars planum area with small diameter applicators may offer another route of administration which may reduce or eliminate the value of direct intravitreal injections of antibiotics. Reduction of the harmful effects of endotoxins of organismal origin might minimize the adverse effects of intraocular infection, particularly after gram-negative invasion. The choice of antibiotic may influence the quantities of endotoxins released.

Update on antibiotics in ocular infections.

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.

Alpha-adrenergic receptors in rabbit eyes.

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.

Clinical evaluation of the Humphrey automatic refractor.

A new automatic objective refractor was used on healthy adults. In the absence of cycloplegic drugs, spherocylindrical objective refractions performed with the instrument provided 20/20 acuity 96% as often as with standard subjective techniques. No instrument-induced accommodations effects were seen. One hundred percent of instrument spherical findings were repeatable within 0.50 diopters; all cylindrical findings were repeatable within 0.37 D. This result represents a higher level of repeatability than that reported for standard subjective refraction under clinical conditions. In the absence of cycloplegic drugs, the correlation coefficient between the instrument's findings and standard subjective spherical findings was .97 v .98 between two practitioners' subjective refractions. The average difference between cylindrical findings of the instrument and those of an experienced practitioner was 0.04 D larger than the average difference seen between two practitioners using subjective techniques.

Forskolin, a potent adenylate cyclase activator, lowers rabbit intraocular pressure.

To our knowledge, this is the first report of a topically applied, specific adenylate cyclase activator that reduces intraocular pressure. Forskolin, a novel adenylate cyclase activator, is reported to increase cyclic adenosine monophosphate (AMP) in intact cells. Cyclic AMP levels are increased with various antiglaucoma agents. Intraocular pressure in rabbits was significantly reduced with two concentrations of forskolin, 0.1% and 0.05%. Ocular hypertension was noted with 0.05% and 0.2%. No change in IOP was noted with 0.01% forskolin. The IOP lowering with 0.1% and 0.05% forskolin lasted approximately six hours. Mild, transient conjunctival chemosis was noted in the doses that decreased IOP. The contralateral control eye showed decreases in IOP, but the differences between control and tested eyes were significant by the Student's paired t test.

Topically applied oxymetazoline. Ocular vasoconstrictive activity, pharmacokinetics, and metabolism.

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.

Erythrocyte membrane 2', 3'-cyclic nucleotide 3'-phosphodiesterase activity in multiple sclerosis.

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.

[A hypothesis: multiple sclerosis a systemic disease]. / Une hypothèse: la sclérose en plaques, une maladie systémique.

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.

A clinical evaluation of the effects of topically applied levobunolol and timolol on increased intraocular pressure.

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.

Intraocular penetration of rosoxacin in rabbits.

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.

Preclinical ocular evaluation of noncorticosteroidal antiinflammatory agents.

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.

Calcium and protein in tears: diurnal variation.

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.

Angiotensin-converting enzyme activity in ocular fluids.

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.

Antiproteolytic activities found in human tears.

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.