Oral magnesium therapy improves endothelial function in patients with coronary artery disease.

BACKGROUND: Magnesium blocks many of the physiological actions of calcium. Nevertheless, the impact of magnesium supplementation on endothelial function and exercise tolerance in stable coronary artery disease (CAD) patients has not been assessed. METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled trial, 50 stable CAD patients (41 men and 9 women, mean+/-SD age 67+/-11 years, age range 42 to 82 years) were randomized to receive either magnesium (n=25) (30 mmol/d Magnosolv-Granulat; Asta Medica Company, Inc) or placebo (n=25) for 6 months. Before and after 6 months, endothelium-dependent brachial artery flow-mediated vasodilation (FMD) and endothelium-independent NTG-mediated vasodilation were assessed with high-resolution (10-MHz) ultrasound. Exercise stress testing was performed with use of the Bruce protocol. Intracellular magnesium concentrations ([Mg(2+)](i)) were assessed from sublingual cells through x-ray dispersion (EXA) (normal mean+/-SD values 37. 9+/-4.0 mEq/L). The magnesium therapy significantly increased postintervention ([Mg(2+)](i) versus placebo (36.2+/-5.0 versus 32.7+/-2.7 mEq/L, P<0.02). There was a significant correlation in the total population between baseline [Mg(2+)](i) and baseline FMD (r=0. 48, P<0.01). The magnesium intervention resulted in a significant improvement in postintervention FMD (15.5+/-12.0%, P=0.02 compared with baseline), which was not evident with placebo (4.4+/-2.5%, P=0.78 compared with baseline). There was better exercise tolerance (9.3+/-2.0 versus 7.3+/-3.1 minutes, P=0.05) and less ischemic ST-segment changes (4 versus 10 patients, P=0.05) in the magnesium versus placebo groups, respectively. CONCLUSIONS: Oral magnesium therapy in CAD patients is associated with significant improvement in brachial artery endothelial function and exercise tolerance, suggesting a potential mechanism by which magnesium could beneficially alter outcomes in CAD patients.

Improvement in endothelium-dependent brachial artery flow-mediated vasodilation with low-density lipoprotein cholesterol levels <100 mg/dl.

To determine whether the current National Cholesterol Education Program cholesterol recommendations are consistent with beneficial endothelium-dependent vasodilation, we prospectively assessed endothelium-dependent brachial artery vasoreactivity in 50 patients with stable coronary artery disease. Our results showed that endothelial-dependent vasoreactivity was greater when low-density lipoprotein cholesterol was <100 mg/dl, suggesting that it may be beneficial to reach the National Cholesterol Education Program Adult Treatment Panel II target of low-density lipoprotein cholesterol of <100 mg/dl.

Topical minoxidil for glaucoma filtration surgery in the rabbit.

Studies evaluated the effect of topical minoxidil on the proliferation of limbal fibroblasts in rabbits following filtration surgery. New Zealand white rabbits underwent unguarded trabeculectomies in a masked, randomized, paired-design prospective study. Rabbits were treated topically every 3 hr around the clock for 1, 2 or 4 days post-operatively, with one drop of a 50-microliters solution containing either 20, 40 or 120 nM minoxidil or the vehicle alone. Another group of animals continued to receive 120 nM minoxidil topically every 8 hr for up to 10 days. Intraocular pressure (IOP), bleb appearance, signs of ocular toxicity and anterior chamber reaction were monitored. Animals were killed and tissues immediately surrounding the trabeculectomy ostium were removed and processed for vimentin detection by immunohistochemistry. Minoxidil, in 20 and 40 nM concentrations, did not induce a significant IOP reduction, nor prolonged bleb survival at any time point, and the changes in fibroblast counts between treated and control eyes were insignificant (P > 0.05). Fibroblast counts in the 120 mM minoxidil-treated eyes were significantly reduced by 42.6% within 24 hr compared to control (P < 0.001). This inhibitory effect remained for at least 2 days after surgery (P < 0.05), the critical period for scar formation. The blebs in this group remained consistently higher than in any other group, and some blebs survived for up to 8 days after surgery. IOP remained below preoperative level for at least 6 days in 50% of the eyes treated with 120 mM minoxidil (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Nasolacrimal occlusion improves the therapeutic index of antiglaucoma medications.

The purpose of this study was to assess whether nasolacrimal occlusion improves the therapeutic index of various antiglaucoma medications. Use of nasolacrimal occlusion resulted in better efficacy and safer usage. Nasolacrimal occlusion used with 2% pilocarpine, 1.5% carbachol, 0.25% timolol maleate, or 1% epinephrine every 12 hours gave the maximal response for these drugs. Applying 0.25% timolol and 1.5% carbachol every 12 hours gave the maximal response for this combination. Nasolacrimal occlusion did not alter the effect of 0.1% dipivefrin, and since the corneal penetration of this prodrug is 17 times that of epinephrine, 0.05% dipivefrin every 12 hours might be an adequate dosage for maximal effect. Our findings suggest that most of the commercially used antiglaucoma agents can achieve the same maximal effect with lower concentrations and less frequent administration (never exceeding every 12 hours). Nasolacrimal occlusion should markedly decrease systemic absorption and side effects following topical treatment.

A comparison of the efficacy of various metipranolol-pilocarpine combinations in patients with ocular hypertension and primary open-angle glaucoma.

We compared the ocular hypotensive effects of four fixed-dose metipranolol-pilocarpine combinations in nineteen ocular hypertensive subjects and glaucoma patients. Each patient was tested with all of the study medications: vehicle alone, 0.1% metipranolol HCl + 2% pilocarpine HCl, 0.1% metipranolol HCl + 4% pilocarpine HCl, 0.3% metipranolol HCl + 2% pilocarpine HCl, and 0.3% metipranolol HCl + 4% pilocarpine HCl, in a single dose, randomized, double-masked, cross-over placebo-controlled trial. In addition, another eight age and baseline intraocular pressure (IOP)-matched subjects received 0.1% or 0.3% metipranolol HCl, while a similar group of 14 volunteers received 2% or 4% pilocarpine HCl. A two week washout period was instituted between the various groups of treatments. All four metipranolol-pilocarpine combinations were more effective than placebo or either medication alone in reducing the average IOP for up to 8 hours (p < 0.05 for each treatment group). Metipranolol HCl 0.3%, regardless of the pilocarpine concentration, demonstrated the most significant IOP lowering effect, reducing the IOP by 4.9 mm Hg or about 20% from baseline. However, 0.1% metipranolol HCl in combination with 4% pilocarpine HCl was found almost as effective with a 18.5% reduction in IOP from baseline, but a shorter duration of action. In conclusion, all metipranolol-pilocarpine combinations were more efficacious than either medication alone in a single-dose trial. Additional multiple-dose studies are needed to determine the long-term effectiveness and tolerance of combining 0.3% metipranolol HCl with either 2% or 4% pilocarpine HCl.

Pharmacokinetics, acid-base balance and intraocular pressure effects of ethyloxaloylazolamide--a novel topically active carbonic anhydrase inhibitor.

Studies evaluated a novel series of biscarbonylamides of 2-amino-1,3,4-thiadiazole-5-sulfonamide (2-ATS) for topical use as ocular hypotensive carbonic anhydrase inhibitors (CAI). Transcorneal accession rate constants (k(in)) for ethyloxaloylazolamide (EtOxAz), ethylsuccinylazolamide (EtSuxAz) and ethyladipoylazolamide (EtAdipAz), and activity against carbonic anhydrase (CA) were determined in vitro by an enzymatic assay and High Performance Liquid Chromatography (HPLC). The ocular hypotensive effect was measured by pneumatonometry on conscious normotensive New Zealand White (NZW) rabbits, using masked, randomly assigned paired-eye design for treatment vs. control. At various time points following treatment, aqueous humor, ciliary processes and corneal buttons were collected and assayed for drug concentrations using enzymatic assay and HPLC. Transcorneal accession rates for the novel compounds were 1.5 to 18 times that of the parent compound, acetazolamide (Actz). The activity factor for EtOxAz was 72.8 x 10(3) hr-1 of 23 times that of Actz. The activity factors for EtSuxAz and EtAdipAz were 6.8 and 1.1 x 10(3) hr-1, respectively. Subcutaneous administration of EtOxAz. EtSuxAz, and EtAdipAz, in 225 mumol kg-1 concentrations, induced a significant decrease in the intraocular pressure (IOP) at 1 hr post injection of 4, 5.8 and 6 mmHg for EtOxAz, EtSuxAz and EtAdipAz, respectively (P < 0.05 for each). Topical application of 75 mM EtOxAz lowered the IOP by 3.0 mmHg (P < 0.05). This effect was maximal after 60 min and persisted for at least 5 hr. EtSuxAz and EtAdipAz did not alter the IOP significantly when given topically. Subcutaneous administration of the three compounds was associated with acidosis (pH as low as 7.21). Topical application did not cause any changes in the acid-base balance. There was a direct correlation between the amount of drug delivered to the ciliary process and the magnitude of ocular hypotensive effect. Following topical application EtOxAz reached the ciliary epithelium in concentrations sufficient to inhibit more than 99.95% of the ciliary carbonic anhydrase (> 8 microM), while plasma drug concentrations were below the limit of detection by the assay (< 0.2 microM). Within the first hour after topical application, half of the EtOxAz was eliminated from the anterior uvea. In summary, EtOxAz is a topically effective CAI. Structural modifications of thiadiazole sulfonamides, with the increase of both water and lipid solubilities, improved the transcorneal accession while preserving sufficient CA inhibitory activity, resulting in a significant IOP decrease following topical application of EtOxAz.(ABSTRACT TRUNCATED AT 250 WORDS)

Topically active ocular carbonic anhydrase inhibitors: novel biscarbonylamidothiadiazole sulfonamides as ocular hypotensive agents.

A novel homologous series of bis(carbonyl)amidothiadiazole sulfonamides has been synthesized for structure-activity relationship studies, and initial characterization has been performed. The goal was synthesis of thiadiazole derivatives with appropriate lipid and water solubilities for utility as topically (corneal application) active carbonic anhydrase (CA) inhibitors. This series has solubility properties and pKa which bracket those of acetazolamide--the prototypical CA inhibitor. All of these compounds are active as in vitro CA inhibitors, and are 10-25% as potent as acetazolamide as in vitro enzyme inhibitors. Two of these compounds act as ocular hypotensive agents after topical application of a single dose to the corneas of normotensive New Zealand albino rabbits. The efficacy of the lead compound of this series (in this one model) is approximately equivalent to that of topical CA inhibitors that are presently in clinical trial. None of these novel compounds reacts to an appreciable extent with free sulfhydryl groups (a predictor of toxicity). This family of compounds will be useful for future studies of ocular pharmacokinetics, as well as ocular and systemic effects of topical administration of CA inhibitors. These and future studies may lead to development of thiadiazole sulfonamides useful in the management of glaucoma.

In vitro inhibition of collagen formation by 2,4-pyridine dicarboxylate and minoxidil in rabbit corneal fibroblasts.

Two anti-fibrotic agents were evaluated in vitro for potential application in trabeculectomy. The rate of collagen formation by cultured rabbit corneal fibroblasts was determined by [3H]proline uptake and hydroxylation assay. Incubation of fibroblasts, for 96 hours, with 16 mM 2,4-pyridine dicarboxylic acid (2,4-PDCA), a competitive inhibitor of prolyl 4-hydroxylase, decreased [3H]OH-proline formation from control by 28.2 +/- 3.9%; (average +/- S.E.M), whereas 10 mM minoxidil, an antihypertensive pyrimidine oxide and a lysyl hydroxylase inhibitor, induced a decrease of 17.3 +/- 4.5%. Incubating fibroblasts with a mixture of the two inhibitors, 16 mM 2,4-PDCA and 10 mM minoxidil, resulted in a further decrease in [3H]proline incorporation of 40.7 +/- 5.1%. After 96 hours of incubation with the inhibitors, rabbit corneal fibroblast growth was decreased from control by 17.2 +/- 4.2% and 10.5 +/- 4.5% for 16 mM 2,4-PDCA and 10 mM minoxidil, respectively. These effects were dose dependent. The results suggest that both 2,4-PDCA and minoxidil have an inhibitory effect on collagen formation and may be useful in delaying surgical wound healing.

A comparison of the ocular tolerability of a single dose of timolol and levobunolol in healthy normotensive volunteers.

Subject acceptance of a single dose of timolol and levobunolol was compared in a three-center, double-masked, randomized, crossover study in healthy normal subjects. We tested 115 subjects who received the medications OU, in a random order, separated by a washout period of three to seven days. At the end of the administration, the subjects were asked to report any symptoms and were monitored by ophthalmologic examination. Those receiving levobunolol reported a two- to threefold higher frequency of symptoms than did those receiving timolol (P = .0002, by Mainland-Gart chi-square test). Thirty-five subjects (30.4%) treated with levobunolol complained of burning versus 14 (12.2%) receiving timolol (P = .0021). Similar results were obtained in regard to stinging (31 versus 10 subjects; P = .0011). The duration of these symptoms did not differ between the two groups (P > .05). Timolol induced considerably less burning and stinging on day 1 compared with levobunolol, using a visual analog scale over time (P = .0004). Seventy-nine percent of those stating a preference chose timolol (P < 3 x 10(-9).

Initial treatment of glaucoma: surgery or medications.

Should surgery or medications be the initial therapy for primary open angle glaucoma? In this set of articles, Drs. Sherwood, Migdal, and Hitchings present evidence suggesting that filtration surgery provides better intraocular pressure control than does medical treatment, good (or better) visual field preservation, and visual acuity as good as that in medically treated fellow eyes. They also cite cost effectiveness, quality of life, and possible adverse effects of medical treatment on future surgery. Drs. Sharir and Zimmerman, on the other hand, favor initial medical therapy, questioning the validity of some reports on surgical results, citing the risks of complications, and noting recent and current progress in the development of antiglaucoma medications. Dr. Schultz' editorial evaluates both points of view, concluding that additional prospective randomized tests may be useful and that either approach may be a viable option, as long as it is individualized to each particular patient.

Novel topical thiadiazoles and benzothiazoles as pharmacological probes of corneal endothelial function.

Corneal transparency is maintained by an active transport system, located at the endothelial cell membranes. This bicarbonate-dependent pump counteracts the tendency of the corneal stroma to absorb water, swell and become opaque. Carbonic anhydrase inhibitors (CAI) are capable of attenuating the bicarbonate efflux, therefore causing thickening of the cornea. Eight novel sulfonamides were evaluated as potential probes for assessing the corneal endothelial functional reserves. Five of the six thiadiazoles and both benzothiazoles have demonstrated carbonic anhydrase inhibitory properties in vitro. Of the eight compounds tested, 2-ethyladipoyl-1,3,4-thiadiazole-5-sulfonamide (compounds III), 2-epoxy-1,3,4-thiadiazole-5-sulfonamide (compound V), and 2-acetamido-1,3,4-thiadiazole-5-N-methylsulfonamide (compound VI) have induced reversible corneal thickening. Although statistically significant (p < 0.05), the magnitude of the pachymetric effect did not exceed 6-10% of the total corneal thickness, probably because carbonic anhydrase (CA) is only one component of the active pump complex. The fact that a non-CAI (compound VI) was capable of inducing a reversible corneal thickening may suggest that other mechanisms are involved. Further studies will be conducted to identify a pharmacological agent capable of reversibly inhibiting the endothelial function in normal and diseased corneas, with a higher magnitude of effect.

Therapeutic index of pilocarpine, carbachol, and timolol with nasolacrimal occlusion.

We assessed the effect of nasolacrimal occlusion on the therapeutic index of various antiglaucoma medications in healthy volunteers and patients with glaucoma. Nasolacrimal occlusion used with pilocarpine 2% every 12 hours gave the maximal ocular hypotensive response. Carbachol 1.5% every 12 hours with nasolacrimal occlusion gave the maximal response for this drug. For timolol, nasolacrimal occlusion collapsed the dose-response curve and extended the duration of action. A final trial of carbachol added to timolol with nasolacrimal occlusion showed that timolol 0.25% and carbachol 1.5% every 12 hours gave the maximal response for this combination. Our findings suggest that most of the commercially used ocular hypotensive agents can achieve the same maximal effect with lower concentrations and less frequent administration (never exceeding every 12 hours) than are currently recommended should nasolacrimal occlusion be performed. Furthermore, nasolacrimal occlusion should markedly decrease the systemic absorption of topical ocular drugs and lessen the chance of systemic side effects.

Therapeutic index of epinephrine and dipivefrin with nasolacrimal occlusion.

We assessed the effect of nasolacrimal occlusion on the therapeutic index of the adrenoreceptor agonists in healthy volunteers and patients with glaucoma. Nasolacrimal occlusion did not significantly alter the response to 2% epinephrine or to 0.1% dipivefrin in healthy subjects, suggesting that both 2% epinephrine and 0.1% dipivefrin are at the top of the dose-response curve. When 0.5% epinephrine with nasolacrimal occlusion was tested in patients with glaucoma, effects were noticeable at four and eight hours (P less than .05), but not at 12 hours. For 2% epinephrine, there was no significant difference at any measurement time. Epinephrine (1%) with and without nasolacrimal occlusion gave results similar to those of 2% epinephrine, suggesting that 1% epinephrine is also at the top of the dose-response curve. Nasolacrimal occlusion did not increase the ocular hypotensive effect of either of these concentrations. Because dipivefrin, the most widely used formulation in this class, is a prodrug of epinephrine that has a corneal penetration approximately 17 times that of epinephrine, 0.05% dipivefrin, every 12 hours, might be an adequate dosage for maximal effect. Although nasolacrimal occlusion did not alter the drug effect of 0.1% dipivefrin, preventing as much drug as possible from reaching the systemic circulation is desirable.

Sneezing as a cause of acute angle-closure glaucoma.

We report the case of a patient who had an attack of acute angle-closure glaucoma precipitated by sneezing, probably as a result of a sudden increase in venous back pressure. This young woman had a history of allergic sinusitis.

Bilateral spontaneous dislocated lenses, retinal vasculitis and progeria-like changes.

Findings are reported for a 70-year-old man with a progeria-like syndrome consisting of premature aging (per history), diffuse wasting, skin atrophy, disseminated skeletal osteoporosis (documented for at least 25 years), especially in the vertebral column and metacarpal joints with short stature, beaked nose and high-pitched voice, The ocular findings include: spontaneous bilateral dislocation of spherophakic mature cataracts into the vitreous together with bilateral retinal vasculitis, characterized by venous congestion, tortuosity and occlusion, To the best of our knowledge, there is no case report with all the above features in one person, Hence, the differential diagnosis will also be discussed.