Publications by authors named "Maren T"

The accession to cornea, aqueous humor and ultimately ciliary process was studied for a series of 6 sulfonamides which differed in their free acid lipophilicities. The drugs were applied as 5 mM solutions at pH 5 in unionized form or in chiefly ionized form at pH 8.4-9.

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We compared the effect on intraocular pressure (IOP) of maximal doses of a topical carbonic anhydrase inhibitor (CAI) at acidic and alkaline pH where it is maximally effective with full systemic CA inhibition in ocular normotensive New Zealand Albino rabbits. Tonometric IOP levels were measured hourly during 3 hour control period. Topical MK-417 (pKa 5.

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Though chemical assays indicate that carbonic anhydrase (CA) activity is present in marine teleost nephrons, CA inhibitors have no effect on urine pH or bicarbonate excretion, parameters typically CA dependent in almost all vertebrate groups. Because marine teleost renal sulfate secretion is associated with bicarbonate anion exchange, we investigated the effect of CA inhibition on transepithelial sulfate transport by flounder renal tubule primary monolayer cultures (PTC) and on renal sulfate secretion (QSO4) by intact flounder. Both methazolamide and ethoxzolamide (10 microM) inhibited PTC secretory flux by approximately 50%; reabsorptive sulfate flux, Na-dependent glucose transport, and transepithelial electrical resistance were unaffected.

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The accession of methazolamide in ionized and unionized form to cornea, sclera, aqueous humor and ciliary process was studied 10 minutes following separate application to either sclera or cornea of a 1 mM solution. Cornea and ciliary process concentrations were 27.3 and 14.

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The connection between carbonic anhydrase and the formation of aqueous humor arose in the decade 1950-1960 when a number of experiments of differing types showed that HCO3- ion catalytically formed in the ciliary process from CO2 was a principal element in the production of the aqueous. It was soon shown that inhibitors of the enzyme, given systemically, slowed HCO3- formation and sodium and fluid transport and thereby lowered intraocular flow and pressure in normal vertebrates and in patients with glaucoma. In the past 15 years successful efforts have been made to produce sulfonamide inhibitors that reach the ciliary process after local application to the cornea.

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Purpose: To determine whether the well-known effect of timolol in reducing ocular pressure and aqueous humor (AH) flow is a function of reduced Na+ movement from plasma to aqueous. Previously, the authors have shown this to be the case for carbonic anhydrase inhibitors.

Methods: The rate of appearance of 22Na in rabbit posterior aqueous was measured 1 to 3 minutes after the intravenous injection (time T) of the isotope.

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A study was undertaken to investigate whether diverse carbonic anhydrase (CA) isozymes (both native Zn as well as cobalt-substituted) are able to catalyze the hydrolysis of anions such as cyanide, cyanate, and thiocyanate. A controversy exists between the crystallographic and spectroscopic data of CA II-anion adducts. In the former case it has been shown that "metal poisons" such as CN- and CNO- are not directly coordinated to the active site Zn(II) ion whereas spectroscopic studies indicate otherwise.

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Dorzolamide is a powerful inhibitor of carbonic anhydrase (CA) II that penetrates the sclera and cornea to reach the ciliary process and lowers formation of HCO3 and aqueous humor. The usual dose applied to the eye in treatment of glaucoma is 1 drop (30 microL of 2% solution) every 8 hr to each eye, or a total daily dose of 4 mg. On this regime, the red cells accumulated drug over a period of 8 days, reaching a value of 20-25 microM, which corresponds to the concentration of CA II in human red cells.

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To achieve selective inhibition of cytosolic and membrane-bound carbonic anhydrase (CA II and CA IV, respectively), we synthesized a polymer of molecular weight 3500 from polyoxyethylene bis acetic acid and aminobenzolamide. The new compound, designated F (for Florida) 3500, is stable, water soluble and nontoxic. It is excreted largely unchanged by glomerular filtration.

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Carbonic anhydrase inhibitors (CAIs) lower intraocular pressure by reducing aqueous flow. It has been thought that this pharmacologic reduction of aqueous flow is mediated by the ciliary epithelium, but it is not known whether this cellular action is effected by inhibition of the membranal (CA IV) and/or cytosolic (CA II) carbonic anhydrases of the ciliary epithelium. The isolated ciliary epithelial bilayer maintains its anatomic and functional polarity and generates a transepithelial potential difference (TEP) in an Ussing type chamber.

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Systemically administered carbonic anhydrase inhibitors have been in clinical use since the 1950's. Their use and side effects have been reviewed extensively. Our review summarizes the development of topically administered carbonic anhydrase inhibitors in patients with glaucoma.

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We report the effect of temperature on the equilibrium dissociation constants (Kl) for a series of six sulfonamides binding to three carbonic anhydrase (CA) isoenzymes (I, II, and IV). Kl values obtained at 0 degree, 15 degrees, and 23 degrees under conditions of nearly constant and low substrate (CO2) concentration were used to calculate enthalpy and entropy changes associated with sulfonamide binding as well as to provide estimates of inhibitory potency of sulfonamides at 37 degrees. We studies four classic sulfonamide (methazolamide, benzolamide, ethoxzolamide, and sulfanilamide) and the novel sulfonamides MK-507 (dorzolamide) and CF3SO2NH2.

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Ampholyte carbonic anhydrase inhibitors (including MK-927) have previously been shown to elicit greater intraocular pressure reduction when applied in ionized form at moderately acidic or alkaline pH compared to application of un-ionized drug at neutral pH. Since ionized solutions should be far more membrane-impermeant than un-ionized solutions, we attempted to solve this apparent paradox. We studied the distribution at 0.

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The mechanism of renal acid secretion in marine fish is largely unknown. We explored whether H(+)-K(+)-adenosinetriphosphatase (H(+)-K(+)-ATPase) is present and functional in acid secretion in the kidney of the elasmobranch spiny dogfish shark, Squalus acanthias. In whole animal studies, a specific inhibitor of mammalian H(+)-K(+)-ATPase, Sch-28080, abolished greater than 87% of basal (62 mg/kg) and 75% of imidazole-stimulated titratable acid excretion (5 and 62 mg/kg).

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Aliphatic sulfonamides, as CH3SO2NH2, are very weak inhibitors of the carbonic anhydrases (KI congruent to 10(-4) M) and are extremely weak acids (Ka congruent to 10(-10.5) M). We now find CF3SO2NH2 a very potent inhibitor of carbonic anhydrase II (KI = 2 x 10(-9) M) and a much stronger acid (Ka = 10(-5.

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The carbonic anhydrase (CA) isozyme (IV) in microsomes is thought to have a dominant role in secretory processes. Using microsomes from bovine kidney and lung (which had the same activity), we have measured the Km and kcat for CO2 hydration and compared these numbers with those for CA I (red blood cells and gut), CA II (red blood cells and secretory cells), and CA III (muscle). For kidney CA IV, Km is 10 mM and kcat is 170,000 sec-1 at 0 degree, approaching the rate for CA II but much greater than those for CA I or III.

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We have assessed the onset and duration of decreased intraocular pressure and aqueous humor flow contrasting systemic and topical administration of carbonic anhydrase inhibitors. The relationship between physiological effects and fractional activity of carbonic anhydrase isoenzymes in the eye was also investigated. Experiments were performed in normotensive New Zealand white rabbits.

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Purpose: To evaluate the effect of drug ionization on the ocular hypotensive activity of topical carbonic anhydrase inhibitors.

Methods: Ocular normotensive New Zealand albino and ocular hypertensive Dutch Belted pigmented rabbits were used. Tonometric intraocular pressure levels were taken after topical application of 50 microliters of drug (at various concentrations and pH values) to one eye with the contralateral eye used as an untreated control.

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Organic sulfamates are a new variation to the carbonic anhydrase (CA) inhibitor structure-action relationship. Inhibitory activity is conferred by the classic sulfonamide group, but through linkage to the benzene ring by an oxygen. AHR-16329, a representative sulfamate, has an acidic (sulfonamide, pKa 8.

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Several imidazolylphenyl sulfamate and (imidazolylphenoxy)alkyl sulfamate derivatives were synthesized and evaluated as topically active carbonic anhydrase inhibitors. Water solubility, pKa, carbonic anhydrase inhibition, and partition coefficient for the compounds were measured. Sulfamic acid 2-[4-(1H-imidazol-1-yl)phenoxy]ethyl ester monohydrochloride (16) has the best combination of properties and showed excellent topical activity in lowering the intraocular pressure in New Zealand white rabbits.

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Carbonic anhydrase (CA) activity has been detected and quantified in the corneal epithelia of various mammalian species using a microchemical assay. The highest levels were found in the rabbit, followed by man, dog, sheep, and cat. Enzyme levels in the rabbit epithelium were approximately one-third the amount found in the endothelium, perhaps explaining earlier failures to find CA in the epithelium.

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We have measured sequentially the concentrations of ethoxzolamide (6-ethoxybenzothiazole-2-sulfonamide) in ocular tissues following its intravenous or topical administration to normal albino rabbits. This was done in parallel with determinations of intraocular pressure (IOP) measured by tonometer or direct manometry. Ethoxzolamide was used because of its very high activity against carbonic anhydrase and experience showing that there is little or no other receptor in tissues.

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We have sought to define urinary acid-base excretion in the marine teleost using the long-horned sculpin, Myoxocephalus octodecimspinosus. Urine flow (1.7 ml.

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