Pharmacokinetic-pharmacodynamic relationship of levodopa with and without tolcapone in patients with Parkinson's disease.

OBJECTIVE: To investigate the effect of administration of the catechol-Omethyltransferase (COMT) inhibitor tolcapone on the concentration-effect relationship of levodopa in patients with advanced Parkinson's disease and on-off fluctuations. DESIGN: Nonblind single-group 2-period pharmacokinetic-pharmacodynamic study. PATIENTS AND PARTICIPANTS: 12 patients, mean age 59 years, with idiopathic Parkinson's disease and response fluctuations. METHODS: The pharmacokinetics [plasma concentrations of levodopa and 3-O-methyldopa (3-OMD)] and motor effects [global score of the Columbia University Rating Scale (CURSsigma)] of levodopa (plus the peripheral decarboxylase inhibitor benserazide 1:4) were determined for 4 consecutive dosage intervals (4 hours each, starting at 8.00am) in 12 patients before (day 1) and during (day 8) coadministration of tolcapone 100 mg 3 times daily for 7 days. RESULTS: Under tolcapone, exposure to levodopa [area under the plasma concentration-time for the dosage interval (AUCt)] observed for the separate doses increased by 1.6- to 2.2-fold, and peak plasma drug concentrations (Cmax) increased by 1.1 - to 2.1 -fold. 3-OMD concentrations at day 8 were reduced to about 20% of the values at day 1. At baseline (day 1, before the first levodopa dose), CURSsigma averaged 40 +/- 10 points. After the first levodopa dose. CURSsigma declined to 20 +/- 9 points. At day 8. the predose CURSsigma decreased to a final score of 31 +/-13 points, and the maximal decline after the first levodopa dose was to a final score of 16 +/- 8 points. Population analysis (NONMEM) of the concentration-effect relationship of levodopa according to a sigmoidal Emax model and over all dosage intervals did not show differences in levodopa responsiveness with or without tolcapone. The population mean of the 50% effective concentration (EC50) of levodopa was 1350 microg/L with an standard error of the population parameter estimate of 18%: adding tolcapone treatment as a covariate did not significantly change the population fit. Circadian influences on levodopa respon- siveness were not evaluable by the NONMEM model due to overparametrisation, but visual inspection of plotted data did not suggest differences in the concentration-effect relationship between the 4 consecutive dosage intervals on days 1 and 8. CONCLUSIONS: The gain in clinical improvement with levodopa under tolcapone can be fully explained by tolcapone-induced changes of peripheral levodopa pharmacokinetics. We suggest that this interaction study, performed in patients and using clinical data, excludes any central effects of tolcapone or any inhibiting effect of 3-OMD on levodopa permeation through the blood-brain barrier, which otherwise would have led to a decrease in the EC50 of levodopa.     

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Factors affecting the change in lower-order and higher-order aberrations after wavefront-guided laser in situ keratomileusis for myopia with the Zyoptix 3.1 system

PURPOSE: To identify factors that affect the change in lower- and higher-order wavefront aberrations after myopic wavefront-guided laser in situ keratomileusis (wg-LASIK). SETTING: Department of Ophthalmology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany. METHODS: Sixty myopic eyes of 32 patients were treated with wg-LASIK (Zyoptix version 3.1, Bausch & Lomb) and had an uneventful follow-up of 12 months. Wavefront errors were measured preoperatively and 12 months after LASIK and were computed for pupil diameters (PDs) of 3.5 mm and 6.0 mm. Multiple stepwise regression analysis was performed to assess the influence of patient age, spherical equivalent (SE), sphere, cylinder, optical zone (OZ) diameter, and the preoperative individual Zernike coefficients on lower- and higher-order aberration (HOA) change. RESULTS: The mean preoperative SE was -5.59 diopters (D) +/- 2.20 (SD) (range -1.00 to -9.50 D); the mean OZ diameter was 6.70 +/- 0.68 mm (range 5.6 to 8.1 mm). Reduction in almost all Zernike coefficients was influenced significantly by the preoperative amount of the individual coefficient. The effect varied among the coefficients and was lower with the 6.0 mm PD. With the 3.5 mm PD, age, SE, sphere, cylinder, and OZ diameter did not have a significant effect on individual Zernike coefficients. With the 6.0 mm PD, SE and OZ diameter had a significant effect on the induction of Z4(0); the OZ diameter also had an effect on the induction of coma root mean square. CONCLUSIONS: Three groups of factors influenced the change in HOAs: The negative correlation with the magnitude of preoperative HOA values reflected the effect of the wavefront-guided algorithm. The SE and OZ diameter affected the inadvertent induction of spherical aberrations. Randomly acting effects such as decentration or flap creation, which were not included in the model, affected the induction of HOAs, particularly coma-like terms.     

Heparin Surface-Modified Poly(methylmethacrylate) and Foldable Hydrophobic Acrylic Intraocular Lenses in Cataract Patients with Acquired Immune Deficiency Syndrome and CMV-Retinitis

BACKGROUND: In HIV-positive patients with necrotising retinitis, well-tolerated lens material as well as minimal invasive surgery to avoid postoperative complications are imperative. Heparin surface-modified PMMA-IOLs as well as acrylic IOLs are associated with less postoperative inflammation than conventional intraocular lenses. METHODS: In this randomised prospective clinical trial 18 patients received 7 HSM-IOLs through a self-sealing scleral tunnel and 11 foldable Acrysof-IOLs through a self-sealing limbal tunnel incision by the same surgeon. 7 of the 18 eyes were silicone oil-filled before cataract surgery, one eye received oil after the IOL implantation. Visual acuity, intraocular pressure, contrast sensitivity, intraocular inflammation and posterior capsule opacification were assessed. The follow-up period was 1 year. RESULTS: Eyes with Acrysof-IOLs were associated with lower, but not statistically significant, laser flare photometry values (photon counts/ms) than those with HSM-IOLs pre- (90.18 +/- 54.7 vs. 73.92 +/- 6.44) and 3 months post-surgery (69.06 +/- 8.27 vs. 55.03 +/- 7.75). 6 of the 7 eyes with HSM-IOL and 3 eyes of the Acrysof-group developed a dense posterior capsule opacification (PCO), 2 eyes had no and 6 eyes only a distinct PCO. YAG capsulotomy did not improve visual acuity in any case but retinal examination was again possible. Eyes with Acryl-IOL showed pre- and postoperatively a better visual acuity than eyes with HSM-IOL ("hand movement" - 0.4 vs. "no light perception" - 0.1 pre- and 0.05 - 0.6 vs. "no light perception" - 0.1 3 months postoperatively. Contrast sensitivity testing (Vistech method) could be performed in the PMMA-group preoperatively only in 1 eye (A1), in the Acryl-group in 2 eyes (A4, B4, C2, D2) and revealed postoperatively "no contrast vision" - A1, B2, C1 vs. "no contrast vision" - A2, B2, C3, D1, E1. The intraocular pressure was preoperatively 13.86 mm Hg (PMMA) vs. 14.82 mm Hg (Acrysof) and 14.4 mm Hg vs. 12.89 mm Hg 3 months post surgery. CONCLUSION: In the parameters we observed there was no statistical significant difference between heparin-surface modified (Pharmacia 811 C) and hydrophobic acrylic IOLs (Alcon Acrysof MA60BM) in patients with AIDS. As foldable Acrysof-IOLs can be implanted through a self-sealing bloodless tunnel incision and are associated with less posterior capsule opacification we prefer this IOL type in cataract surgery of AIDS patients.     

Aberrationen höherer Ordnung nach Implantation einer irisgestützten Vorderkammerlinse (Ophtec Artisan®) in das phake Auge

BACKGROUND: The purpose of the present study is to demonstrate the change of higher order wavefront aberrations (HOA) after implantation of an iris claw pIOL. METHODS: Thirteen eyes of seven patients were examined preoperatively and 1 month after implantation of an Artisan lens. The mean preoperative spherical equivalent was -10.69+/-1.92 D (-7.63 to -14.88 D). The diameter of the IOL optic was 6 mm and the lens was inserted though a tunnel incision at 12 o'clock. The root mean square (RMS) wavefront error was computed for all aberrations of the third to fifth order for pupil diameters of 3.5 and 6 mm. RESULTS: On average, HOA RMS changed for a 3.5 mm pupil by 0.037+/-0.089 microm (6 mm pupil: 0.405+/-0.245 microm). Third-order aberrations changed by 0.031+/-0.098 microm (0.320+/-0.269 microm). For both pupil diameters, a notable increase of Z 3,-3 of 0.117+/-0.085 microm (0.596+/-0.350 microm) could be observed depending on the distance between the limbus and incision. Fourth-order aberrations changed on average by 0.018+/-0.037 microm (0.280+/-0.143 microm), namely Z 4,0 increased by 0.025+/-0.034 microm (0.296+/-0.164 microm). CONCLUSION: After implantation of the Artisan lens HOA increased slightly. Particularly induction of Z 3,-3 and Z 4,0 contribute to the increase of HOA. The induction of trefoil ( Z 3,-3) is a result of the incision, whereas the increase of spherical aberration is due to the implant.     

Influence of pupil and optical zone diameter on higher-order aberrations after wavefront-guided myopic LASIK

PURPOSE: To investigate the influence of pupil and optical zone (OZ) diameter on higher-order aberrations (HOAs) after myopic wavefront-guided laser in situ keratomileusis (LASIK). METHODS: Twenty-seven myopic eyes of 19 patients were included. The mean preoperative spherical equivalent was -6.86 diopters (D) +/- 1.24 (SD) (range -4.25 to -9.5 D); the mean planned OZ diameter was 6.26 +/- 0.45 mm (range 5.7 to 7.1 mm). All patients had uneventful wavefront-guided LASIK (Zyoptix version 3.1, Bausch & Lomb) and an uncomplicated follow-up of 12 months. Wavefront measurements were performed with a Hartmann-Shack sensor in maximum mydriasis preoperatively and 12 months after LASIK. Wavefront errors were computed for pupil diameters (PDs) of 3.0, 3.5, 4.0, 5.0, 6.0, and 7.0 mm for the individual OZ diameter and for the individual mydriatic PD (7.93 +/- 0.46 mm). The impact of the relationship between pupil diameter and OZ diameter (fractional clearance [FC]) on HOA was described and quantified using curvilinear regression with a 4th-order polynomial fit. RESULTS: There was a reproducible relationship between FC and the amount of induced HOA. The change in HOA root mean square and primary spherical aberration (Z(4)0) was significantly correlated with FC. If the OZ was 16.5% larger than the pupil (FC = 1.17), only half the amount of HOA was expected to be induced than if the OZ equaled the pupil. In contrast, an OZ that was 9% smaller than the pupil (FC = 0.91) resulted in an HOA induction 50% higher than at FC = 1. CONCLUSION: The OZ zone to pupil ratio (fractional clearance) had a significant impact on HOA induction after wavefront-guided LASIK.     

Intraocular lenses for the correction of refraction errors. Part II. Phakic posterior chamber lenses and refractive lens exchange with posterior chamber lens implantation

In this overview, the current status of intraocular lens surgery to correct refractive error is reviewed. The interventions are divided into additive surgery with intraocular lens implantation without extraction of the crystalline lens (phakic intraocular lens, PIOL) or removal of the crystalline lens with implantation of an IOL (refractive lens exchange, RLE). Phakic IOLs are constructed as angle-supported or iris-fixated anterior chamber lenses and posterior chamber lenses which are fixated in the ciliary sulcus. The implantation of phakic IOLs has been demonstrated to be an effective, safe, predictable and stable procedure to correct higher refractive errors. Complications are rare and differ for the three types of PIOL; for posterior chamber lenses these are mainly cataract formation and pigment dispersion. RLE is preferable in cases of high ametropia in which the natural lens has lost its accommodative effect. The main complications for myopic RLA include retinal detachment, while hyperopic refractive lens exchange may be associated with surgical problems in the narrower anterior eye segment.     

Aberrationen höherer Ordnung nach Implantation von asphärischen und sphärischen Intraokularlinsen in Abhängigkeit von der Pupillenweite

BACKGROUND: The implantation of aspherical IOLs with negative spherical aberration should equalize the positive spherical aberration of the cornea. The aim of our study was the intraindividual comparison of higher order aberrations (HOA) after implantation of an aspherical and spherical IOL.PATIENTS AND METHODS: In ten patients we randomly implanted an aspherical IOL in one eye and a spherical IOL in the other. After 3 months, we used a Hartmann-Shack sensor to measure total HOA, 3rd to 5th order as well as spherical aberration Z4.0, in mydriasis. We compared all aberrations intraindividually for pupil diameters of 3.5-6 mm.RESULTS: For both IOLs, all aberrations rose with increasing pupil diameter. However, after implantation of the aspherical IOL total HOA, 4th order and spherical aberration Z4.0 were lower, for 4th order aberration and Z4.0 even significantly. For 3rd and 5th order aberrations, there was no difference between both IOLs.CONCLUSIONS: With implantation of aspherical IOLs, total HOA, 4th order and spherical aberration Z4.0 could be reduced compared to spherical IOLs.