OBJECTIVE:

To report the 12-month outcomes of the dexamethasone intravitreal implant in retinal vein occlusion (RVO), using an as-needed repeat injection protocol.

DESIGN:

Retrospective consecutive case series of 51 eyes of 49 patients with macular oedema as a result of RVO that received an intravitreal dexamethasone implant and were followed up for at least 12 months.

RESULTS:

70% of patients responded to dexamethasone implant injection with an improvement in visual acuity (VA) and macular oedema within 3 months of injection, but only 30% of eyes gained ≥15 letters. The mean change in VA letter score at 12 months compared with baseline for branch RVO (BRVO) and central RVO (CRVO) was 5.7±2.3 and 11.5±11.0 EDTRS letters, respectively. 56% of patients relapsed, with the median time to relapse being 17 weeks for patients with branch RVO and 18 weeks for patients with CRVO. Repeat injections achieved similar VA gains, but the duration of effect of repeat dexamethasone implants was much shorter at 10 weeks. 14 eyes (27%) developed a significant rise in intraocular pressure, and three of these required treatment with oral acetazolamide. Four eyes with CRVO developed neovascular glaucoma during the study.

CONCLUSIONS:

The intravitreal dexamethasone implant does not last the 6 months implied by the retreatment protocol in the GENEVA trial, and improved results can be achieved with an as-needed retreatment protocol, particularly in CRVO. However, visual outcomes remain similar to those previously seen with triamcinolone in the SCORE study and neovascular complications remain a feature of CRVO.

Purpose.

To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of acetazolamide (ACTZ) in peritoneal dialysis patients, ACTZ 500 mg was administered intravenously to 7 healthy subjects (HV) and 8 peritoneal dialysis patients (CAPD). Methods. Population PK/PD modeling was performed with ACTZ serum (total and unbound), urine and dialysate concentrations, intra-ocular pressure (IOP) and covariates. A multi-compartment PK model (accounting for non-linear protein binding) and an inhibitory Emax (maximal change in IOP) PD model were selected.

Results.

As expected, renal clearance (which almost equals total body clearance) was severely decreased in CAPD (1.2 vs 80.3 L/h) and the elimination half-life of total ACTZ was prolonged (20.6 vs 3.4 hours). The protein binding was significantly altered with a mean free fraction 4.2% in HV and 8.6% in CAPD. Moreover protein binding of ACTZ was concentration dependent in both HV and CAPD. Despite a higher free fraction of ACTZ, the Emax was lower in CAPD: 4.4±1.4 vs 7.4±2.8 mmHg.

Conclusion.

Both PK and PD are significantly altered in dialysis patients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on

ABSTRACT

on the issue's contents page.

Acetazolamide-responsive ataxia represents a unique collection of genetically distinct episodic ataxia (EA) disorders associated with paroxysmal cerebellar symptoms many of which are responsive to medical treatment with acetazolamide, a carbonic anhydrase inhibitor. Among all of the subtypes of episodic ataxia, types 2 (EA2), 3 (EA3), and 5 (EA5) are thought be the most medication responsive. Some patients with episodic ataxia type 1 (EA1) will also describe improvement with acetazolamide. Each of these individual genetic syndromes is characterized by its own unique mechanism and clinical presentation. In this review, the author provides an overview of the pathophysiology of acetazolamide-responsive ataxia, its natural history, and its clinical management.

Protein X-ray crystallography has seen a progressive shift from data collection at cool/room temperature (277-298 K) to data collection at cryotemperature (100 K) because of its ease of crystal preparation and the lessening of the detrimental effects of radiation-induced crystal damage, with 20-25%(v/v) glycerol (GOL) being the preferred choice of cryoprotectant. Here, a case study of the effects of cryoprotectants on the kinetics of carbonic anhydrase II (CA II) and its inhibition by the clinically used inhibitor acetazolamide (AZM) is presented. Comparative studies of crystal structure, kinetics, inhibition and thermostability were performed on CA II and its complex with AZM in the presence of either GOL or sucrose. These results suggest that even though the cryoprotectant GOL was previously shown to be directly bound in the active site and to interact with AZM, it affects neither the thermostability of CA II nor the binding of AZM in the crystal structure or in solution. However, addition of GOL does affect the kinetics of CA II, presumably as it displaces the water proton-transfer network in the active site.

Here, we provide an alternative synthesis of the natural bromophenol 3,4-dibromo-5-(2,3-dibromo-4,5-dihydroxybenzyl)-6-(ethoxymethyl)benzene-1,2-diol (3) and the first synthesis of (4,5-dihydroxy-2-methylphenyl)(3,4-dihydroxyphenyl)methanone (18) and its brominated derivatives 19-21. The compounds were characterized and tested against the two most studied members of the pH regulatory enzyme family, carbonic anhydrase (CA). The inhibitory potencies of the novel compounds and two natural bromophenols 2, 3 were analyzed at the human isoforms hCA I and hCA II as targets and the KI values were calculated. The KI values of the novel compounds were measured in the range of 13.7-32.7 µM for the hCA I isozyme and 0.65-1.26 µM for the hCA II isozyme. The structurally related compound 14 was also tested in order to understand the structure-activity relationship, and the clinically used sulfonamide acetazolamide (AZA) was tested for comparison reasons. All of the compounds exhibited competitive inhibition with 4-nitrophenylacetate as substrate. The compounds showed strong inhibitory activity against hCA I, being more effective as compared to the clinically used AZA (KI : 36.2 µM), but rather less activity against hCA II.

Drug treatment for obstructive sleep apnea (OSA) is desirable because at least 30% of patients do not tolerate continuous positive airway pressure (CPAP) treatment. The negative pressure reflex (NPR) involving superficially located mechanoreceptors in the upper airway (UA) is an important mechanism for UA patency inhibitable by topical UA anesthesia (lidocaine). The NPR may serve as a target for pharmacological intervention for a topical treatment of OSA. The objective was to determine the effect of pharmacological augmentation of the NPR on UA collapsibility.We developed a model of UA collapsibility in which application of negative pressures caused UA collapses in spontaneously breathing α-chloralose-urethane anesthetized pigs as indicated by characteristic tracheal pressure and air flow changes.N/A.N/A.N/A.The potassium channel blocker AVE0118 administered topically to the UA in doses of 1, 3, and 10 mg per nostril sensitized the NPR, shifting the mechanoreceptor response threshold for the genioglossus muscle to more positive pressures (P < 0.001; n = 6 per group) and dose-dependently inhibited UA collapsibility. Ten mg of AVE0118 prevented UA collapses against negative pressures of -150 mbar (P < 0.01) for > 4 h in all pigs, while in control pigs the UA collapsed at -50 mbar or less negative pressures. The effect of AVE0118 was abolished by UA lidocaine anesthesia. Acute intravenous administration of naloxone or acetazolamide was ineffective; paroxetine and mirtazepine were weakly effective and fluoxetine was moderately effective in line with reported clinical efficacy.Topical administration of AVE0118 to the UA is a promising pharmacologic approach for the treatment of OSA. CITATION: Wirth KJ; Steinmeyer K; Ruetten H. Sensitization of upper airway mechanoreceptors as a new pharmacologic principle to treat obstructive sleep apnea: investigations with AVE0118 in anesthetized pigs. SLEEP 2013;36(5):699-708.

PURPOSE:

: To evaluate the effects of oral acetazolamide (ACZ), anterior chamber paracentesis (ACP), or topical brimonidine tartrate (BT) to reduce intraocular pressure (IOP) elevation after intravitreal bevacizumab injection (IVBI).

PATIENTS AND METHODS:

: A total of 56 patients scheduled for IVBI (1.5 mg/0.06 mL) were randomly assigned to a pretreatment with ACZ (14 eyes), BT (14 eyes), as well as an immediately after ACP (14 eyes), or no treatment (control group-CG) (14 eyes). IOP was measured 90 minutes before injection (baseline), just before injection, and at 3, 10, 20, and 30 minutes after the procedure.

RESULTS::

IOP was increased at 3 minutes after injection in CG, 20.9±2.1 (mean±SE intraindividual change in mm Hg); BT, 15.5±2.3; ACZ, 13.7±1.7; but not in ACP, 0.3±1.2 (P<0.0001). At 30 minutes after injections, IOP difference to baseline was not significantly different in groups BT, 0.0±0.7; ACZ, -3.2±0.8; and ACP, -2.5±3.9, but was kept higher in the CG, 4.0±4.3 (P<0.0001).

CONCLUSIONS::

ACP prevents IOP elevation after IVBI, whereas ACZ and BT caused a faster return to baseline than untreated nonglaucomatous eyes. Further studies with larger number of subjects, including glaucomatous patients, and the use of other topical glaucoma medications are warranted to establish a standard recommendation.

Introduction: Glaucoma is one of the major causes of blindness, affecting together with age-related macular degeneration > 70 million people worldwide. One of the therapeutic options for its management is based on the inhibition of the metalloenyme carbonic anhydrase (CA, EC 4.2.1.1). CA inhibitors (CAIs) diminish intraocular pressure (IOP) by reducing the rate of bicarbonate formation and thus secretion of the aqueous humor. Areas covered: The main classes of clinically used antiglaucoma CAIs are the sulfonamides with systemic (acetazolamide, methazolamide, ethoxzolamide and dichlorophenamide) and topical (dorzolamide and brinzolamide) action. A patent literature review covering the period 2007 - 2013 is presented. Expert opinion: This review presents an overview of the patent literature in the CAI antiglaucoma drug design field during the past 6 years. Most of the patents deal with sulfonamide/sulfamide/sulfamate CAIs, sulfonamides incorporating NO-donating moieties, as well as hybrids incorporating sulfonamide and prostaglandin (PG) analogs, were also reported. There is an urgent need for new antiglaucoma CAIs/approaches to treat and diagnose this disease in the very near future, as the last drug which has been discovered in the field (latanoprost) dates back > 10 years ago.