Christina Lindén

Prostaglandin Analogues in the Treatment of Glaucoma

Prostaglandin (PG) analogues are a new class of ocular hypotensive drugs that have been developed for the treatment of open angle glaucoma. Two of these drugs, latanoprost and unoprostone, are presently commercially available.Latanoprost was introduced in 1996 in the US and Europe. Presently it enjoys the most widespread use and is the most well documented drug of this group. It reduces the intraocular pressure (IOP) by a mechanism of action different from other drugs; namely by increasing the uveoscleral outflow. The aqueous inflow is not affected. The optimal dose regimen is one drop of 50 μg/ml once daily, which reduces the IOP by approximately 30% in patients with glaucoma. A more pronounced ocular hypotensive effect is demonstrated when latanoprost is combined with other glaucoma therapies, including β-blockers, adrenergic and cholinergic agonists or carbonic anhydrase inhibitors. Latanoprost is well tolerated. The drug reaches a plasma concentration below that needed for stimulation of the FP-receptor, which may explain its favourable systemic tolerability profile. The major ocular adverse effect is increased iris pigmentation, which is due to increased synthesis of melanin in the melanocytes of the iris stroma. It is most frequently seen in green-brown eyes and it is probably permanent. A low frequency of cystoid macular oedema has also been reported, predominantly in predisposed eyes.Unoprostone was launched in Japan in 1994, but there is little experience with this drug outside the Japanese market and the documentation is more limited. Its main mechanism of action is on outflow, but this is not yet fully elucidated. The recommended dosage regimen is 1 drop of 1.2 mg/ml twice daily. No comparative studies in humans between the 2 drugs have yet been published.

Pascal, ICare and Goldmann applanation tonometry - a comparative study

Purpose:  To compare intraocular pressure (IOP) measurements by Pascal, ICare and Goldmann applanation tonometry (GAT), to evaluate the effects of central corneal thickness (CCT) and curvature on IOP measurement and to estimate the intra‐observer variability.

Aqueous humor lidocaine concentrations in topical and intracameral anesthesia

Purpose: To assess aqueous humor lidocaine concentrations in 2 common regimens of topical anesthesia and after intracameral injection of the anesthetic agent. Setting: University hospital eye clinic. Methods: Twenty patients having routine cataract surgery were randomized into 3 groups: 1 given 3 drops of lidocaine 4% before surgery; 1 given 6 drops; 1 given 3 drops plus an intracameral injection of 0.1 mL lidocaine 1%. Lidocaine concentration was measured in aqueous humor samples taken before surgery. Results: With 3 drops, aqueous lidocaine concentration was 1.4 Pg/mL ± 0.5 (SD) and with 6 drops, 4.3 ± 1.5 &mgr;g/mL (P = .0015). With an intracameral injection, it was 341.8 ± 152.6 &mgr;g/mL. Conclusion: Measurable amounts of lidocaine entered the anterior chamber in topical anesthesia, and more entered when more drops were given. It is likely that concentrations in this range could anesthetize the iris, but they are far lower than concentrations after an intracameral injection.

Central nervous system and ophthalmic involvement in nephropathia epidemica (European type of haemorrhagic fever with renal syndrome)

Central nervous system (CNS) - related symptoms occur in haemorrhagic fever with renal syndrome (HFRS). To study the CNS and ophthalmic involvement in nephropathia epidemica (NE), the European type of HFRS, we included 26 patients in a prospective study. Most common CNS-related symptoms were headache (96%), insomnia (83%), vertigo (79%), nausea (79%), and vomiting (71%). Ophthalmic symptoms were reported by 82% of patients; 41% had photophobia and 50% had impaired vision. A transient loss of vision was recorded in one patient, who also had a generalized seizure. Minor white matter lesions were found in about half of the patients investigated with brain magnetic resonance imaging (MRI). Electroencephalography (EEG) showed severe alterations in only one patient, and slight and reversible patterns in another two patients. Neopterin, interleukin-6 and interferon-gamma levels in the cerebrospinal fluid (CSF) were elevated, which may indicate immune activation. However, we found no evidence of intrathecal NE virus replication. We conclude that CNS-related symptoms are common in NE, and transient ophthalmic involvement can be demonstrated in about half of the patients.

Therapeutic potential of prostaglandin analogues in glaucoma.

One of the most recent contributions to the therapeutic arsenal available for the treatment of glaucoma is the prostaglandin (PG) analogues. They represent a new class of ocular hypotensive drugs, targeting the uveoscleral outflow of ocular aqueous humour. Two drugs, latanoprost and unoprostone, are presently commercially available. In terms of intraocular pressure (IOP) reduction, latanoprost is the most powerful drug in clinical use today. The once daily dosing promotes compliance. Additional effect is achieved in combination with other hypotensive drugs, including those that increase trabecular outflow facility. The most frequent side effect is increased iris pigmentation that seems to be irreversible. A low frequency of cystoid macular oedema has been reported, predominantly in patients whose blood-retinal barrier (BRB) is compromised. Systemic side effects are rare. The experience with unoprostone is still much less than that with latanoprost. The ocular hypotensive mechanism of action of unoprostone is not well documented but an increase in uveoscleral outflow may be at least a part of its mode of action. Systemic side effects are rare and the ocular side effects seem to be mild. The ocular hypotensive effect is less than that of latanoprost and may not be suitable for monotherapy. It is widely accepted that the IOP alone is not responsible for the development of glaucomatous visual defects. It remains to be seen if this class of drugs will preserve vision in glaucoma patients better than other classes. More PG analogues are under development for potential clinical use.

Latanoprost twice daily is less effective than once daily: indication of receptor subsensitivity?

PURPOSE It is known that twice daily dosing of latanoprost is less effective in reducing intraocular pressure (IOP) than once daily applications. The aim of the present study was to investigate this phenomenon further in order to see if the results could be compatible with a subsensitivity of the FP-receptor. METHODS Latanoprost, 50 microg/ml, was instilled once daily (8 PM) in one eye of 40 healthy volunteers and twice daily (8 AM and 8 PM) in the fellow eye in a randomized, masked fashion for 2 weeks, with the last drop on the evening of Day 15. IOP was determined at 8 AM, noon and 4 PM on Days 0, 2, 15 and 16. Also, the effect of a single dose of latanoprost was measured 6-11 months after cessation of treatment. RESULTS There was a significant reduction of mean diurnal IOP from Day 2 (p < 0.001), with both dose regimens. Once-daily dosing resulted in a significantly lower IOP compared with twice-daily dosing on Day 15 (p < 0.001) but not on Day 2. The difference remained (p < 0.001) on Day 16 when no morning dose had been given, but was not present after a single application 6-11 months later. CONCLUSIONS The results of the present study are compatible with development of subsensitivity, at the level of the FP-receptor or its associated intracellular signaling pathways, with twice- but not with once-daily dosing of latanoprost. This effect is reversible.

Applanation resonance tonometry for intraocular pressure in humans

Glaucoma is a group of diseases associated with optic nerve damage and loss of visual field. The aetiology is not completely understood, but one of the major risk factors is elevated intraocular pressure (IOP). Reliable methods for measuring the IOP are therefore important. The aim of the study was to investigate the ability of the applanation resonance tonometry (ART) system, based on continuous force and area recording, to measure IOP in humans. Both the phase of initial indentation (IOPIndentation) and the phase when the sensor was removed (IOPRemoval) from the cornea were analysed. The Goldmann applanation tonometry (GAT) was used as reference method. The study included 24 healthy volunteers with normal IOP and 24 patients with elevated IOP. The correlation and standard deviation (SD) between IOPIndentation and IOPGAT was R = 0.92 (p < 0.001), SD = 3.6 mmHg, n = 104, and between IOPRemoval and IOPGAT R = 0.94 (p < 0.001), SD = 3.1 mmHg, n = 104. In conclusion, resonance sensor technology has made it possible to introduce a new multi-point method for measuring IOP, and the method is relevant for measuring IOP in humans. The study indicates that with further development towards elimination of position dependence, the ART has the potential to become a useful clinical instrument for IOP measurement.

Clinical evaluation of applanation resonance tonometry: a comparison with Goldmann applanation tonometry.

PurposeThe purpose of this study was to calibrate and evaluate the precision of the new applanation resonance tonometry (ART) in a clinical study designed in accordance with the International Standard Organizations requirements. MethodsThis was a prospective, randomized, single-center study, where healthy volunteers and patients participated. A total of 153 eyes were divided into 3 groups with respect to their intraocular pressure (IOP) at screening: <16 mm Hg, 16 to 23 mm Hg, and >23 mm Hg. IOP was measured with Goldmann applanation tonometry (GAT) as reference method and by ART in both a biomicroscope (ARTBiom) and a handheld (ARTHand) setup with a 10-minutes pause between methods. The mean of 6 readings was regarded as one measurement value. ResultsMean age of the subjects was 59 years (range 20 to 87 y). GAT showed a mean IOP of 20.0 mm Hg (range 8.5 to 43.5 mm Hg, n=153). The precision was 2.07 mm Hg for ARTBiom and 2.50 mm Hg for ARTHand, with a significant dependency for age as compared with GAT. Measurement order produced a decreasing IOP with a mean of 2.3 mm Hg between the first and last method. ConclusionsThe precision obtained in both ARTBiom and ARTHand was within the limits set by the International Standard Organization standards for tonometers. The standardized procedure and the stability of the biomicroscope setup resulted in a slightly better precision as compared with the handheld setup. Despite a 10-minutes pause between measurements, the order was a significant factor, possibly because the patients were more apprehensive at the first measurement.

The effect on intraocular pressure of latanoprost once or four times daily

AIMS To compare the effect on intraocular pressure (IOP) of latanoprost applied once daily with four times daily and to study if the difference persisted when treatment changed to once daily. METHODS IOP was followed in 28 healthy volunteers in a double masked randomised 52 day study. Latanoprost 50 μg/ml was administered once daily in one eye and four times daily in the other during 2 weeks. Subsequently both eyes received one daily drop for 2 weeks. After another 3 weeks without treatment, a single drop was instilled in each eye. RESULTS The IOP reduction on days 2 and 3 was greater in the eyes treated with four daily doses (p<0.01). During the following period there were no statistically significant differences between the eyes. After 3 weeks without treatment the IOP was lower than pretreatment (p<0.001). A single dose of latanoprost on day 50 resulted in a similar decrease in IOP in both eyes. Transient photophobia, mild flare, and/or a few cells occurred in 15 subjects. Two subjects were withdrawn because of photophobia and/or signs of anterior uveitis. CONCLUSION Latanoprost four times daily caused an IOP reducing effect which was similar to once daily dosing, except for the first 2 days of treatment when it was more effective. Transient photophobia, cells, and flare were common during the four dose regimen, but resolved spontaneously without cessation of treatment.

Spatial distribution of corneal light scattering after corneal collagen crosslinking

PURPOSE: To assess the spatial distribution and time course of increased corneal light scattering after corneal collagen crosslinking (CXL) with riboflavin and ultraviolet‐A irradiation. SETTING: Umeå University Hospital Eye Clinic, Umeå, Sweden. DESIGN: Case series. METHODS: Eyes with keratoconus were examined with Scheimpflug photography before and 1 and 6 months after CXL. Corneal light scattering was quantified throughout the corneal thickness at 8 measurement points 0.0 to 3.0 mm from the central cornea. RESULTS: The study comprised 11 eyes of 11 patients. Central corneal light scattering increased significantly 1 month after CXL (P<.001). At 6 months, it decreased (P=.002); however, it was still higher than pretreatment values (P<.001). Light scattering at 1 month was more pronounced in the superficial stroma, gradually diminishing to zero at 240 μm depth. It was greater at the corneal center than 1.0 to 3.0 mm from the center. At 6 months, a second peak of light scattering occurred between 240 μm and 340 μm depth. No increased light scattering deeper than 340 μm was seen at either time point. CONCLUSIONS: Corneal light scattering after CXL showed distinctive spatial and temporal profiles. Analysis of corneal light scattering may give an impression of tissue changes, the depth of the CXL treatment effect, and the corneal response to the treatment. Scheimpflug photography appears to be useful for this purpose. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.