Experimental observation of a torus doubling of a metal/ferroelectric film/semiconductor capacitor.

A metal-ferroelectric-semiconductor (MFS) structure was used as a nonlinear capacitor in a series resonance circuit. The following materials were used as components of the MFS structure: aluminium as the metal electrode, Bi4Ti3O12 film as the ferroelectric, and p-type silicon as the semiconductor. The system was driven by a single frequency at suitably chosen amplitudes. Besides the sequences of period-doubling bifurcations which were already observed in the series resonance circuit with a pure ferroelectric capacitor, we found regions with torus-doubling bifurcations by varying the frequency of the driving voltage at suitably high amplitudes. Comparing the behaviour of the series resonance circuit with a pure ferroelectric capacitor and with the MFS structure, we attribute the reason for the new effect of torus doubling to the properties of the ferroelectric-semiconductor boundary layer.

Microprocessor controlled compliance monitor for eye drop medication.

BACKGROUND/AIMS: The effectiveness of a self administered eye drop medication can only be assessed if the compliance is known. The authors studied the specificity and sensitivity of a new microprocessor controlled monitoring device. METHODS: The monitoring system was conducted by an 8 bit microcontroller for data acquisition and storage with sensors measuring applied pressure to the bottle, temperature, and vertical position. 10 devices were mounted under commercial 10 ml eye drops. Test subjects had to note down each application manually. A total of 15 applications each within 3 days was intended. RESULTS: Manual reports confirmed 15 applications for each of the 10 bottles. The monitoring devices detected a total of 149 events; one was missed; comprising a sensitivity of 99%. Two devices registered three applications, which did not appear in the manual protocols, indicating a specificity of about 98%. Refrigerated bottles were correctly identified. The battery lifetime exceeded 60 days. CONCLUSION: The new monitoring device demonstrated a high reliability of the collected compliance data. The important, yet often unknown, influence of compliance in patient care and clinical trials shall be illuminated by the new device. This may lead to a better adapted patient care. Studies will profit from a higher credibility and results will be less influenced by non-compliance.

[Three conventional eye drops versus a single lyophilisate. A comparative bioavailability study]. / Comparaison de deux formes d'application de médicaments: collyre versus lyophilisat.

PURPOSE: The ocular bioavailability of a single application of a triple dose of sodium fluorescein to the human anterior segment of the eye was studied as a novel drug delivery device. METHODS: The lyophilisate contained a fluorescein dose of 204 microg corresponding to three conventional, preservative-free eye drops of 40 microl Fluorescein SE Thilo 0.17% (68microg each) (Alcon). A single lyophilisate was applied to one eye of 22 healthy volunteers (+1 min) and three conventional eye drops (+1, 16, 31 min) were applied to their fellow eye. In this randomized, open label study, fluorophotometry was performed (Fluorotron Master IItrade mark, Ocumetrics, Mountain View, California, USA) before and +15, 30, 45, 60, 120, 180, 240, 300, 360, 420 min after application. The fluorescein concentrations of the corneal stroma (C), mid-anterior chamber (AC) were analyzed by paired t-test. RESULTS: Cornea and AC mean values (ng/ml) were significantly higher (p < 0.018, paired t-test) in the lyophilisate group up to 7 h after application, with the exception of +45 min. The mean fluorescein bioavailability from the lyophilisate was up to 11 times higher in the C and up to 8.7 times higher in the AC compared with the three preservative-free eye drops. DISCUSSION: For the first time a triple dose was delivered to the human eye with a single lyophilisate application. Significantly better bioavailability was achieved in the C and AC for up to 7 h using this new device. The treatment of glaucoma, bacterial, viral, and fungal infections, as well as dry eye syndrome, for example, will be improved using lyophilisate.

[The effect of brimonidine on the pupillary reflex. A pupillographic study in healthy volunteers]. / Beeinflussung der Pupillenreaktion durch Brimonidin. Eine pupillographische Studie an Normalpersonen.

PURPOSE: The effect of brimonidine in comparison with acetazolamide on pupillary reflex was investigated in 18 volunteers. METHODS: Infrared pupillography was performed with white diode light of 200 ms duration to measure pupil diameter, constriction latency, reaction time, constriction amplitude, and relative constriction amplitude. The measurements were performed according to a fixed schedule including a phase without medication to determine the baseline level. Data were analyzed by Student's paired t-test. RESULTS: Application of brimonidine and acetazolamide led to a significantly reduced intraocular pressure as well as static and dynamic differences in the pupillary reflex. The pupil diameter measurements were significantly smaller after both medications in comparison to baseline. The reduction of pupil diameter after brimonidine led to significantly reduced contraction amplitude and prolonged latency. CONCLUSION: Application of brimonidine leads to significant miosis, which might due to the affinity to alpha(2)-receptors with reduction of noradrenaline release in the synapse. This effect may play a role in a higher decrease of intraocular pressure by increasing aqueous humor outflow in comparison to clonidine and apraclonidine, but further investigations are required.

Optic nerve head morphometry in healthy adults using confocal laser scanning tomography.

BACKGROUND/AIMS: To study the optic nerve head (ONH) characteristics in a cross sectional study with confocal laser scanning tomography using the Heidelberg retina tomograph (HRT I) and thereby to obtain a new HRT database for comparison of healthy and glaucomatous eyes. METHODS: White adults with no history of ocular pathology were eligible for the study. The examination comprised: assessment of visual acuity; slit lamp examination of the anterior and posterior segment; Goldmann applanation tonometry; computerised perimetry, and optic nerve head tomography with HRT. Eyes with ocular pathology were excluded. Mean (standard deviation, SD) and difference between right and left eye (RE-LE) were calculated for HRT I measurements. Differences in mean topographic parameters between male and female participants and between the age quartiles were analysed. The study included 1764 eyes of 882 healthy adults (154 females and 728 males, mean age of 46.8 (SD 8.6) years). The population investigated was larger and older in comparison with similar studies using confocal laser scanning tomography. RESULTS: With HRT I, a mean disc area of 1.82 (SD 0.39) mm(2), a mean cup area of 0.44 (SD 0.32) mm(2) and a mean cup:disc area ratio of 0.22 (SD 0.13) was observed. Right eyes showed a larger mean retinal nerve fibre layer thickness (RNFLT) (0.263 (SD 0.066) mm) compared with left eyes (0.252 (SD 0.065) mm, p<0.001). Higher values in younger volunteers (mean age 35.7 years) in comparison with elderly participants (mean age 59.1 years) were noted for disc area (1.84 mm(2)v 1.78 mm2) and mean RNFLT (0.263 (SD 0.06) mm v 0.249 (SD 0.07) mm) but were not significant (p>0.01). The presented results differ from published data on ONH measurements of healthy volunteers with different techniques. CONCLUSION: The observed differences in ONH measurements between left and right eyes seem not to be of clinical importance. This is also true for age or sex dependent changes in ONH topographies. The presented data provide a new basis for comparison of optic disc characteristics between healthy eyes and glaucomatous eyes.

A 12 week study comparing the fixed combination of latanoprost and timolol with the concomitant use of the individual components in patients with open angle glaucoma and ocular hypertension.

BACKGROUND: To compare the intraocular pressure (IOP) lowering effect and safety of the fixed combination of latanoprost and timolol with that of the concomitant use of the individual components. METHODS: A 12 week, double masked, randomised, crossover, multicentre study of patients with open angle glaucoma or ocular hypertension and IOP controlled on ocular hypotensive treatment (mean < or =21 mmHg). Patients received either a once daily morning dose of the fixed combination of latanoprost 0.005% and timolol 0.5% or once daily evening latanoprost 0.005% and twice daily timolol 0.5% for six weeks and then switched to the other combination. The primary efficacy endpoint was the within-patient difference in diurnal IOP between fixed and unfixed treatment combinations after six weeks of treatment; a one sided 97.5% confidence interval (CI) for the mean difference in IOP <1.0 mmHg indicated the fixed combination was not inferior to the unfixed combination. Adverse events were recorded at each visit. RESULTS: In all, 190 patients were included in observed cases analyses (93 fixed to unfixed combination; 97 unfixed to fixed combination). Mean IOP at baseline was 16.9 mmHg in both groups. The mean diurnal IOP was 17.0 mmHg after fixed combination treatment and 15.9 mmHg after unfixed combination therapy (p<0.0001). The difference in mean within-patient diurnal IOP was 1.1 mmHg favouring the unfixed combination (95% CI 0.8 to 1.4 mmHg). Both treatments were tolerated well. CONCLUSIONS: Although the primary efficacy endpoint was not met, once daily administration of the fixed combination of latanoprost and timolol was found to be safe and effective. The fixed combination provides a convenient alternative to the three instillations required with the individual components.

Bioavailability of fluorescein from a new drug delivery system in human eyes.

AIM: To assess the ocular bioavailability of fluorescein from a novel drug delivery system compared with one single preservative free eye drop. METHODS: Part A: In a randomised study 10 volunteers applied the lyophilisate to one eye and a conventional fluorescein eye drop to the fellow eye. Fluorophotometry was performed before and every 2 minutes up to 30 minutes after application in the cornea and anterior chamber. Part B: Another 10 volunteers applied each form of the application. Fluorophotometry was performed before, +2 minutes, and at +8, +10, +12 hours. The dose corresponding to a single fluorescein dose of the lyophilisate was 68 l microg fluorescein SE 0.17%. RESULTS: Part A: During the first 30 minutes after administration of the preservative free eye drop of 40 microg the corneal and anterior chamber concentration means were up to 16 times higher in eyes treated with the lyophilisate. Part B: 8-12 hours after application the mean fluorescein concentration in the cornea of the lyophilisate group was two times higher than at baseline. Eyes treated with eye drops had baseline values at +8, +10 and +12 hours. CONCLUSION: A significantly better bioavailability was achieved in human eyes by using lyophilisate compared with the same dose from a conventional eye drop. Lyophilisates are a favourable alternative to conventional eye drops since they have no preservatives, higher long term stability, no pH adjustment, and easy handling.

Persistency and clinical outcomes associated with latanoprost and beta-blocker monotherapy: evidence from a European retrospective cohort study.

PURPOSE: To evaluate persistency (time on initial therapy) and the clinical impact of latanoprost versus beta-blocker monotherapy in treating glaucoma. METHODS: This observational, multicenter, retrospective medical chart review study conducted in four European countries included patients with primary open-angle glaucoma or ocular hypertension who began their first glaucoma treatment with latanoprost or a beta-blocker between November 1996 and November 1998. Persistency and glaucoma-related clinical outcomes data were abstracted for the 2 years following treatment initiation. RESULTS: In all, 260 patient charts were analyzed (94 latanoprost, 166 beta-blocker). Patients in the latanoprost group stayed on therapy twice as long as those who received a beta-blocker (p < 0.0001). After adjusting for baseline characteristics, patients receiving a beta-blocker as initial therapy were 3.8 times more likely to change therapy than those initially treated with latanoprost (p < 0.0001). Patients in the latanoprost group also experienced greater mean decreases in intraocular pressure (IOP) than those receiving a beta-blocker (7.4 mmHg versus 4.6 mmHg, respectively; p < 0.0001), and fewer had worsened optic nerve head excavation (1.7% versus 14.2%, respectively; p < 0.05) by the time of their first therapy change or last study visit, whichever came first. CONCLUSIONS: Over a 2-year period, latanoprost was associated with significantly greater persistency and better clinical IOP outcomes compared with beta-blocker therapy.

Photodynamic modulation of wound healing in glaucoma filtration surgery.

AIM: To report a clinical pilot study investigating photodynamic therapy (PDT) in combination with glaucoma filtration surgery. BCECF-AM was used as the photosensitising substance. The clinical safety and tolerability of BCECF-AM, and its efficacy in controlling postoperative intraocular pressure (IOP) were assessed. METHODS: Before trabeculectomy (TE), 42 consecutive eyes of 36 glaucoma patients received one subconjunctival injection of 80 micro g BCECF-AM (2,7,-bis- (2-carboxyethyl) -5- (and-6) -carboxy-fluorescein, acetoxymethyl-ester) followed by an intraoperative illumination with blue light (lambda = 450-490 nm) for 8 minutes. Antifibrotic efficacy was established as postoperative IOP reduction of >20% and/or an IOP constantly < 21 mm Hg without antiglaucomatous medication. Follow up of the filtering bleb was documented by slit lamp examination. RESULTS: Eyes had mean 1.1 preoperative surgical interventions (filtration and non-filtration glaucoma surgery). Mean preoperative IOP was 31.6 (SD 9.7) mm Hg. Patients were followed for mean 496 days (range 3.5-31.8 months). Of the 42 eyes, 25 eyes had an IOP decreased to 15.8 (3.4) mm Hg without medication (complete success: 59.5%; p<0.001; t test). Seven eyes showed good IOP reduction < 21 mm Hg under topical antiglaucomatous medication (qualified success: 16.7%). 10 eyes failed because of scarring within 2-67 weeks (23.8%). Clinical follow up examinations revealed no local toxicity, no uveitis, and no endophthalmitis. CONCLUSIONS: This method is a new approach in modulating postoperative wound healing in human eyes undergoing glaucoma filtration surgery. The data of the first human eyes combining TE with PDT underline the clinical safety of this method and its possible potential to prolong bleb survival.

A comparative bioavailability study of three conventional eye drops versus a single lyophilisate.

AIM: To study the ocular bioavailability of a triple dose, single application of sodium fluorescein to the human anterior segment from a novel drug delivery device. METHODS: In a randomised, open label study 22 healthy volunteers applied a single lyophilisate to one eye (+1 minute) and three conventional eye drops (+1, 16, 31 minutes) of fluorescein ophthalmic solution to the fellow eye. The fluorescein dose of the lyophilisate was 204 mg corresponding to three conventional, preservative-free eye drops of 40 ml fluorescein SE Thilo 0.17% (68 micro g each) (Alcon). Fluorophotometry was performed (Fluorotron Master II Ocumetrics, USA) before and +15, 30, 45, 60, 120, 180, 240, 300, 360, 420 minutes after application. The fluorescein concentrations of the corneal stroma and mid-anterior chamber were analysed by paired t test. RESULTS: Cornea and anterior chamber mean values (ng/ml) were significantly higher (p<0.018, paired t test) in the lyophilisate group up to 7 hours after application with the exception of +45 minutes. The mean fluorescein bioavailability from the lyophilisate was up to 11 times higher in the cornea and up to 8.7 times higher in the anterior chamber compared with the three preservative-free eye drops. CONCLUSION: A triple dose was delivered to the human eye with a single lyophilisate application for the first time. A significantly better bioavailability was achieved in the cornea and anterior chamber for up to 7 hours by means of drug application with lyophilisates. The application of medications by means of the lyophilisate will improve the treatment of, for example, glaucoma, bacterial, viral and fungal infections, as well as dry eye syndrome.

Lyophilisates for drug delivery in ophthalmology: pharmacokinetics of fluorescein in the human anterior segment.

AIMS: To assess the ocular bioavailability of fluorescein from a novel water free, freeze dried ophthalmic drug delivery system compared to conventional preservative-free fluorescein eye drops. METHODS: Sodium fluorescein 0.17% was dissolved in an aqueous solution of hydroxypropylmethyl cellulose 1.0% (HPMC), deposited on sterilised flexible hydrophobic poly(tetrafluoroethylene) (PTFE) carrier strips and freeze dried under aseptic conditions. The fluorescein dose of the lyophilisate was 68 micro g, corresponding to a single conventional drop of 40 micro l fluorescein 0.17% solution. In a randomised, open label study 12 healthy volunteers applied the lyophilised fluorescein to one eye and one drop of conventional fluorescein ophthalmic solution to the fellow eye. Fluorophotometry measurements of fluorescein concentrations in the anterior segment were performed with the Fluorotron Master II (Ocumetrics, USA) before and +15, 30, 45, 60, 120, and 180 minutes after application. RESULTS: At all times anterior chamber fluorescein concentration was greater in the lyophysilate treated eye than the solution treated eye. The magnitude of this difference ranged from 2-5.3 times and was statistically significant. CONCLUSION: The greater intraocular bioavailability of fluorescein from the lyophilisate relative to the solution suggests that it may be a useful method for delivering substances to the eye.

The efficacy and safety of unfixed and fixed combinations of latanoprost and other antiglaucoma medications.

Adjunctive therapy for the management of glaucoma is commonly used. Unfixed combinations of the prostaglandin analog latanoprost and other glaucoma medications have been demonstrated to effectively lower intraocular pressure (IOP). The range of reported additional reductions in IOP compared to a monotherapy baseline are as follows: latanoprost-timolol (13-37%), latanoprost-pilocarpine 2% (7-14%), latanoprost and carbonic anhydrase inhibitors (15-24.1%), and latanoprost and dipivefrin (15-28%). There is a fixed combination of latanoprost (0.005%) and timolol (0.5%) that has been investigated in Phase III trials in Europe and the United States. In these trials, it was noted that the efficacy of the fixed combination was superior to either of the monotherapy components. After 12 months of follow-up of patients on fixed combination, there was no evidence of long-term drift. The new formulation appears to be safe and does not demonstrate any more side effects than either of the components. The convenience of a fixed combination may enhance patient compliance. Unfixed combination therapy with latanoprost and other antiglaucoma medications and the fixed combination formulation of latanoprost and timolol provide an effective and safe option for lowering IOP in glaucoma patients.

Development of a completely encapsulated intraocular pressure sensor.

A completely encapsulated intraocular pressure (IOP) sensor equipped with telemetric signal and energy transfer is introduced integrated into a silicone disc for implantation into the eye. After implantation into enucleated pig eyes and into rabbit eyes in vivo, the IOP was recorded and compared to established techniques of IOP measurement. Pressure chamber tests showed that the sensor functioned correctly after biocompatible encapsulation in polydimethylsiloxane. In vivo and in vitro tests in rabbit and pig eyes demonstrated that the implanted system worked with the same precision as established techniques for IOP determination. The correlation between the measurements with the implanted device and pneumotonometry in several experiments was between 0.9 and 0.99. This device serves as a functioning model for the realization of a telemetric IOP sensor for integration into an artificial intraocular lens. Such a device will open new perspectives, not only in the management of glaucoma, but also in basic research for mechanisms of glaucoma.

[The effect of latanoprost 0.005% on pupillary reaction of the human eye]. / Der Einfluss von Latanoprost 0,005% auf die Pupillenreaktion des menschlichen Auges.

PURPOSE: Infrared pupillography was performed to investigate the effect of one week topical treatment with the prostaglandin analogue Latanoprost 0.005% on pupillary reflex to light stimuli in glaucomatous human eyes. METHODS: Infrared pupillography using the compact integrated pupillograph was performed in 20 glaucomatous eyes of 11 patients. After 10 minutes dark adaptation one pupil was stimulated with a blue, yellow and white diode light of 100 ms duration. Measurements of pupil diameter, constriction latency, constriction amplitude and relative constriction amplitude were taken twice for each light source in a time interval of 15 seconds. After a 2 week wash-out period the measurements were performed from 8:00 to 10:00 a.m. before and one week after topical treatment with Latanoprost 0.005% applied as single dose once in the evening. RESULTS: The measurements after 1 week treatment with Latanoprost showed a significantly smaller pupil diameter for blue (p = 0.044) and white stimulus (p = 0.039) and the latency was significantly reduced (p = 0.029) as well. CONCLUSIONS: Although the statistical analysis shows some small significant differences in pupil diameter and constriction latency there were no clinical signs of changes in pupillary response due to Latanoprost. The system turned out as easy to use and showed reliable measurements during the study. How far latanoprost may lead to miosis and a decrease of constriction latency has to be investigated in further studies with larger study populations. Other topics concerning drug influence, diurnal rhythm and glaucomatous damage in pupillary light reaction will be investigated in the near future.

[Long-term follow-up of 700 trabeculectomies]. / Langzeituntersuchung von 700 Trabekulektomien.

BACKGROUND: A major focus of our study was to determine the value of postoperative intraocular pressure (IOP) in predicting the outcome of trabeculectomy (TE). PATIENTS AND METHODS: The medical charts of 547 patients undergoing glaucoma filtering surgery at the Department of Ophthalmology of the University of Cologne from 1987 to 1996 were reviewed. The eyes with congenital glaucoma and those treated with anti-metabolites were excluded. RESULTS: Defining the qualified criteria for success of trabeculectomy as an IOP

The additive intraocular pressure-lowering effect of latanoprost 0.005% daily once and pilocarpine 2% t.i.d. in patients with open-angle glaucoma or ocular hypertension. a 6-month, randomized, multicenter study. German Latanoprost Study Group.

PURPOSE: To compare the additional intraocular pressure-lowering effect of latanoprost 0.005% administered once daily with that of pilocarpine 2% administered three times daily in patients with primary open-angle glaucoma or ocular hypertension currently on monotherapy with timolol 0.5% twice daily. METHODS: In a 6-month, multicenter, randomized, open-label study 242 patients with POAG or OH whose IOP was not controlled with timolol 0.5% b.i.d. were enrolled. Eyes had not been treated with pilocarpine and latanoprost for at least 2 years. An analysis of covariance with diurnal IOP change from baseline to month 6 for study eyes was performed. RESULTS: Four patients on latanoprost 0.005% and 35 on pilocarpine 2% did not complete the study (P<0.001). Two hundred and forty patients were included in the intent-to-treat analysis. For both treatments the diurnal IOP reduction after 6 months was statistically significant (P<0.001). IOP (mean+/-SD) was reduced from 23.3+/-2.8 to 17.8+/-2.8 (-5.6) mmHg in the latanoprost 0.005% group and from 23.0+/-3.2 to 18.5+/-2.4 (-4.8) mmHg in pilocarpine 2% t.i.d.-treated eyes. The mean difference of -0.8 mmHg (per protocol, PP) and -1.6 mmHg (intend-to-treat, ITT) was statistically significant (P<0.04, PP; P<0.001, ITT) in favor of latanoprost 0.005%. Two eyes treated with latanoprost showed an iris color change. Thirty-six patients in the latanoprost group and 106 in the pilocarpine 2% group reported ocular adverse events (P<0.001). CONCLUSION: From the data we conclude that the additivity of latanoprost 0.005% is at least as effective as pilocarpine 2% t.i.d. in reducing IOP when added to eyes currently on monotherapy with timolol 0.5% b.i.d. Latanoprost was better tolerated than pilocarpine 2% eye drops in this study. The increase in iris pigmentation requires further investigation.