Open-Label, Dose-Escalation, Phase 1 Study of Safety and Single and Multiple-Dose Pharmacokinetics of Dichlorphenamide in Healthy Volunteers.

Single-and multiple-dose pharmacokinetics and safety were investigated in this phase 1 study of dichlorphenamide, a carbonic anhydrase inhibitor approved in the United States for treatment of primary periodic paralysis. Dichlorphenamide was administered to 6 cohorts (n = 6 each) of healthy adults. Cohorts A through E received single doses of 25-400 mg followed by 50-800 mg/day in divided doses for 10 total doses. Cohort F (safety analysis only) received up to 28 titrated doses from 100-800 mg/day. Plasma for pharmacokinetics sampling was obtained predose and up to 48 hours postdose. Twenty-five of 36 enrolled subjects completed. Median time to maximum plasma concentration ranged from 1.5-3 hours, and mean half-life from 32-68 hours. Mean area under the concentration-time curve from time 0 to tau (length of the dosing interval estimated using the trapezoidal method) and maximum observed plasma concentration increased dose-proportionally after multiple doses. The incidence and severity of adverse events (AEs) were dose-related, with at least one mild AE reported among 17%, 17%, and 67% of patients in cohorts A, B, and C, respectively; and at least one mild-to-moderate AE among 100% of subjects in cohorts D, E, and F. One serious AE of rash was reported in cohort F. Eleven subjects discontinued; 10 due to AEs at 400 or 800 mg/day (cohorts E and F), including 100% of cohort F. Hypokalemia contributed to 5 of 6 discontinuations in cohort F (all 800 mg/day).

Biodegradable fumarate-based drug-delivery systems for ophthalmic applications.

The function of a photocrosslinked poly(propylene fumarate) (PPF)/poly(N-vinyl pyrrolidone) (PVP) matrix for the sustained release of three ophthalmic model drugs, acetazolamide (AZ), dichlorphenamide (DP), and timolol maleate (TM), was investigated. The drugs differ in molecular weight and degree of dissociation in aqueous environments; both are parameters that significantly influence drug diffusivity. AZ, DP, and TM-loaded cylindrical rods (10 mm length, 0.6 mm diameter) were fabricated by photoinduced cross-copolymerization of PPF and N-vinyl pyrrolidone (NVP) in molds. The released amounts of AZ, DP, TM, and NVP were determined by high-performance liquid chromatography (HPLC). The effects of drug properties and loading on the release kinetics were investigated. The in vitro release of AZ, DP, and TM was well sustained from the polymer matrices over a period of approximately 210, 270, and 250 days, respectively. The release kinetics correlated with the HPLC retention profiles of the different drugs. Following a small initial burst release (<10%), a dual modality release controlled by diffusion and bulk erosion was found for all drugs. Drug release rates of up to 4 microg/day were reached. Matrix drug loading generally affected the extent of the burst release, release kinetics, as well as the matrix water content and matrix degradation that were determined gravimetrically. Microcomputed tomography was used to image structural and dimensional changes of the devices. A preliminary rabbit implantation study revealed promising ocular biocompatibility of drug-free PPF/PVP matrices. All results indicate the potential of photocrosslinked PPF-based matrices as polymeric carriers for long-term ophthalmic drug delivery.

[Minimally inflammatory cataract surgery]. / Minimal inflammatorische Kataraktchirurgie (MIK).

BACKGROUND: Cataract surgery leads to a more or less intensive postoperative inflammation due to breakdown of the blood-aqueous barrier. In a prospective, randomized and controlled clinical trial, we examined aqueous flare as well as intraocular pressure and visual acuity after a minimally invasive cataract surgical procedure under different anti-inflammatory treatment. PATIENTS AND METHOD: In 150 patients (39-88 years of age) without glaucoma or pre-existing deficiencies of the blood-aqueous barrier, phacoemulsification through a clear-corneal tunnel incision with implantation of a 5 mm PMMA posterior chamber intraocular lens was performed. Patients were randomly assigned to one of 5 treatment groups, each consisting of 30 patients: 1) preservative-free diclofenac 0.1% eyedrops (DICpf) pre- and postop.; 2) diclofenac 0.1% eyedrops with preservative (DICp) pre- and postop.; 3) DICpf only postop.; 4) DICpf pre- and postop. in combination with dexamethasone-21-dihydrogenphosphate 0.1% eyedrops (DEXA); 5) DEXA postoperatively. For prevention of postoperative intraocular pressure (IOP) elevation, carbachol 0.01% (for intraocular application) was injected into the anterior chamber intraoperatively, and dichlorphenamide (50 mg/d per os) was applied until day 1 postoperatively. - Aqueous flare (laser flare-cell meter FC-1000), IOP (Gold-mann applanation tonometer) and best-corrected visual acuity were determined on the day before surgery as well as 6 hrs (only flare and IOP), 1 day, 3 and 7 days postoperatively. RESULTS: Aqueous flare (photon counts/ms) in treatment group 1 increased from 10.8 +/- 1.7 (means +/- SE) preoperatively to only 14.7 +/- 3.1 in the afternoon of the day of surgery. Already on day 1 postoperatively, the flare decreased to 9.3 +/- 0.9, and remained relatively constant on days 3 and 7 after surgery. The flare in group 3 (DICpf only postop.) was significantly higher (p = 0.03; ANOVA) than in group 1. There were no other significant group differences concerning flare (group 1 vs. 3;1 vs. 4;4 vs. 5). -IOP (mm Hg) dropped from 16.3 +/- 0.2 preoperatively to 15.8 +/- 0.6 already 6 hrs postoperatively (group means). On days 1 and 3, the IOP continued to drop to 13.2 +/- 0.3 and 12.7 +/- 0.3, respectively. Not before day 7, the IOP tended to increase again (14.2 +/- 0.3). The IOP showed no significant group differences. - Visual acuity increased from 0.25 +/- 0.01 preoperatively to 0.73 +/- 0.02 already on day 1 postoperatively (group means). On days 3 and 7, the acuity amounted to 0.83 +/- 0.24 and 0.92 +/- 0.02, respectively. DISCUSSION: Under the conditions of the present study (with specific pharmacological therapy and patient selection), clear-corneal phacoemulsification leads to an extremely low and short-lasting intraocular inflammation, especially under pre- and postoperative treatment with preservative-free diclofenac eyedrops. Thus, the aim of minimally inflammatory cataract surgery (MICS) is realized. As secondary phenomenon, a postoperative IOP increase, often observed in the early postoperative period, is lacking, and the visual acuity rises very fast postoperatively.

Topical ocular hypotensive activity and ocular penetration of dichlorphenamide sodium in rabbits.

A single topical instillation (50 microliter) of the water soluble sodium salt of dichlorphenamide (10%) produced a pronounced and prolonged lowering of intraocular pressure (IOP), compared to suspensions of its free acid, in rabbits with alpha-chymotrypsin-induced ocular hypertension. In normal rabbits, instillation of dichlorphenamide sodium also produced a markedly elevated drug aqueous humor level relative to instillation of its free acid, indicating enhanced penetration into the eye. The IOP response after ocular instillation of dichlorphenamide sodium was equivalent to that produced by oral administration of 6 or 18 mg/kg dichlorphenamide sodium. Serum drug levels were lower and aqueous humor and iris-ciliary body levels were higher after instillation of dichlorphenamide sodium (10%) than after oral administration of 2 or 6 mg/kg. The data indicate that topically instilled dichlorphenamide sodium is capable of lowering IOP by a local action in the eye and provides a rationale for the potential utility of topical carbonic anhydrase inhibitors as a therapy for glaucoma in man.

Effects of timolol and Daranide on elevated intraocular pressure after aphakic keratoplasty.

In a randomized, blind clinical study, we tested the effect of timolol and Daranide against placebo medications among patients who had intraocular pressures greater than 30 mm Hg on the first postoperative day after aphakic keratoplasty. The study failed to show any significant difference in the pressure course. We concluded that because this type of severe secondary glaucoma is extremely difficult to treat, it should be prevented by using a donor cornea larger in size than the recipient bed.

Ocular hypotensive effects of carbonic anhydrase inhibitors in normotensive and glaucomatous Beagles.

Four carbonic anhydrase inhibitors (acetazolamide, dichlorphenamide, ethoxzolamide, and methazolamide) cause ocular hypotony in normotensive and glaucomatous Beagles. Four dosages of acetazolamide and methazolamide and three dosages of dichlorphenamide and ethoxzolamide were evaluated. The extent of ocular hypotony after these carbonic anhydrase inhibitors was usually greater in glaucomatous Beagles than it was in normotensive Beagles.

Diclofenamide in the treatment of therapy-resistant epilepsy.

An average daily dose of 33 mg of diclofenamide, a carbonic-anhydrase inhibitor, was added to the anti-epileptic medication already employed in 105 cases of severe epilepsy which had shown insufficient clinical improvement. A favourable action on seizures, often accompanied by an improvement in the EEG tracing, was observed in 83 cases. The effect was of long duration in 47 cases in that it lasted for more than a year. It persisted for one to twelve months in a further 17 cases, while in 19 patients, who had reacted favourably to the treatment, medication had to be suspended because of intolerance.