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An ultrafiltration technique or equilibrium dialysis has been used to study the in vitro human plasma protein binding of racemic zileuton, its individual enantiomers, and its pharmacologically inactive metabolite N-dehydroxyzileuton. The plasma protein binding of zileuton and N-dehydroxyzileuton over the concentration range of 0.1 to 100 mg/L averaged 93.1 +/- 0.22 and 92.0 +/- 0.12%, respectively. However, there appeared to be a stereoselective effect, with the R(+) enantiomer of zileuton demonstrating greater binding to plasma proteins than the S(-) enantiomer (96 vs 88%, respectively). Zileuton was bound to both human serum albumin (40 g/L) and alpha 1-acid glycoprotein (1 g/L), although binding affinity to albumin was approximately 3-fold greater. Displacement interactions of zileuton with warfarin, salicylate, theophylline, naproxen, ibuprofen, prednisone, and terfenadine were minimal. The blood to plasma concentration ratio for zileuton and N-dehydroxyzileuton ranged from 0.65 to 0.68, indicating that these compounds were mainly distributed in the plasma. Thus, zileuton is approximately 93% bound to plasma proteins at expected therapeutic concentrations in vitro, and this figure is largely unaffected by several commonly prescribed agents with which the drug may be coadministered.

Incorporation of nonreactive polar functionalities at the C- and N-termini of renin inhibitors led to the development of a subnanomolar compound (21) with millimolar solubility. This inhibitor demonstrated excellent efficacy and a long duration of action upon intravenous administration to monkeys. While activity was also observed intraduodenally, a comparison of the blood pressure responses indicated low bioavailability. Subsequent experiments in rats showed that, although the compound was absorbed from the gastrointestinal tract, extensive liver extraction severely limited bioavailability.

Twelve adult beagle dogs received both an oral and intravenous dose (12 mg/kg) of fostedil in a cross-over design. The plasma levels and urinary excretion of intact fostedil were measured, and the pharmacokinetic parameters of the drug were defined. The results indicate that fostedil was at least 68% bioavailable after an oral dose given as a suspension or solution. The terminal half-life was about 7-8 h. The in vitro protein binding, at concentrations of 0.1-100 micrograms/mL, ranged from 95 to 97%. The binding was not concentration dependent, and saturation of the binding sites was not apparent at concentrations up to 100 micrograms/mL. Excretion of unchanged drug from the kidneys accounted for only a small percentage of drug clearance.

In the late 1960s the artificial sweetener cyclamate was implicated as a bladder carcinogen in rats. This finding and other concerns about its safety ultimately led to a ban on cyclamate in the U.S. and restrictions on its use in many other countries. Since that time, the carcinogenic potential of cyclamate and cyclohexylamine, its principal metabolite, has been reevaluated in a group of well-controlled, well-designed bioassays that have failed to substantiate the earlier findings. This review of the published and unpublished literature on cyclamate attempts to evaluate the carcinogenicity question and other important aspects of the toxicity of cyclamate and cyclohexylamine, including their effects on various organ systems, their genotoxic potential, and their effects on reproduction. In addition, the physiological disposition of cyclamate is reviewed, with particular attention directed toward the site and extent of its conversion to cyclohexylamine.

The intraocular penetration of [14C]fosfonet was studied following topical application of 25 mg of an ointment containing 5% [14C]fosfonet sodium onto the intact and abraded eyes of New Zealand white rabbits. Radioactivity penetrated rapidly through the abraded cornea and entered the anterior chamber. The concentration of fosfonet in the aqueous humor peaked at 7.2 microgram/ml by 90 min. Assuming an aqueous humor volume of 300 microliter, this level would correspond to approximately 0.2% of the applied dose. The highest concentration of fosfonet found in the abraded cornea was 0.3 microgram/mg, or 0.4% of the applied dose. The half-lives for the elimination of fosfonet from the aqueous humor and cornea were about 2.5 and 2.7 hr, respectively. The fosfonet levels in the iris were extremely low throughout the 6-hr period. The penetration of [14C]fosfonet through the intact cornea was considerably less than that found in the abraded eye. The peak concentrations of fosfonet in the aqueous humor and cornea of the intact eye were 0.26 microgram/ml and 0.02 microgram/mg, respectively, and occurred within 10 min of application of ointment.

N-Heptyl-1,2,3,4-tetrahydro-6-met,hoxy-1-naphthylamine methanesulfonate (I) is a potent, long lasting local anesthetic. It was as potent as tetracaine and at least 10 times more potent than lidocaine in the rabbit corneal reflex, guinea pig wheal, and mouse sciatic nerve block tests. The threshold anesthetic concentration (TAC), defined as the concentration required to produce anesthesia lasting 5 min, was calculated from each linear regression line fitted to the log dose-duration data, and these values were used to compare the potencies of the local anesthetics. In the rabbit corneal reflex test, the TAC values were 0.04% for I. 0.04% for tetracaine, and 0.66% for lidocaine. In the guinea pig wheal test, I had a TAC of 0.02%, which was equipotent to tetracaine and 11 times more potent than lidocaine; epinephrine (1:100,000) prolonged the duration of action of all three local anesthetics but had the least effect with I. In the mouse sciatic nerve block test, the TAC values were 0.06% for I, 0.10% for tetracaine, and 0.86% for lidocaine. The acute LDm values of I in mice were 138 mg/kg sc and 26 mg/kg iv. By either route, I was less toxic than tetracaine and more toxic than lidocaine. Comparison of the LD50 and TAC values in the mouse sciatic nerve block test indicated that I had a greater therapeutic index than either reference standard.

(1982). Metabolic Fate of Selected Selenium Compounds in Laboratory Animals and Man. Drug Metabolism Reviews: Vol. 13, No. 2, pp. 271-318.

The synthesis of diol-containing renin inhibitors has revealed that a simple vicinal diol functionality corresponding to the scissile Leu-Val bond in human angiotensinogen is capable of imparting inhibitory activity at a comparable or higher level than either the corresponding aldehyde or hydroxymethyl functionality (compare inhibitors 2a-c or 3a-c). This finding has led to the further optimization of a series of small transition-state analogue inhibitors by the inclusion of a second hydroxyl group in the Leu-Val surrogate to give compounds that inhibited human renin in the 200-700-pM range (e.g. 43, 45, 63, 66). The magnitude of effect of the second hydroxyl group on potency is not only dictated by the absolute stereochemistry of the diol but also by the side chain of the P1 residue. Molecular modeling of the diol-containing inhibitors suggests that one of the hydroxyl groups hydrogen bonds to Asp 32 and Asp 215, while the second hydrogen bonds to Asp 215. These diol inhibitors are extremely selective for human renin over the related enzymes cathepsin D, pepsin, and gastricsin. At high concentrations, compounds containing a leucine or phenylalanine rather than a histidine at the P2 position gave only minor amounts of inhibition of the other enzymes. Inhibitor 43 suppressed plasma renin activity completely and lowered mean blood pressure in monkeys after both intravenous and intraduodenal administration, but the blood pressure drop lasted less than 1 h. Monitoring the blood levels of 43 by enzyme inhibition assay after intraduodenal administration to monkeys or oral administration to rats revealed low absorption and rapid clearance. While intratracheal administration to dogs gave approximately 50% bioavailability, rapid clearance was still a problem. After examination of inhibitor 45 in a sensitive primate model in which monkeys were rendered both hypertensive and hyperreninemic, the effects on lowering systolic but not diastolic pressure were apparent even after 22 h postdosing. Details on the synthesis, in vitro structure-activity relationships, molecular modeling, in vivo activity, and metabolism of these inhibitors are described.

Seven N-substituted 1,2,3,4-tetrahydro-1- and three 2-naphthylamines were prepared and tested for local anesthetic activity in the rabbit corneal reflex test and the mouse sciatic nerve block test. At 0.1 and 1%, three 1-alkylamino compounds had durations of action comparable to that of tetracaine in the rabbit corneal reflex test and were considerably more potent than lidocaine. The other four 1-alkylamino derivatives were inactive or at best minimally active. The durations of action of 1% concentrations of the three 2-alkylamino compounds were equivalent to that of 1% lidocaine in the corneal reflex test. In the mouse sciatic nerve block test, the three active 1-alkylamino compounds were considerably longer acting than either tetracaine or lidocaine. Three 1-alkylamino and the three 2-alkylamino compounds showed toxicity equal to or greater than lidocaine, while two 1-alkylamino and two 2-alkylamino compounds showed toxicity equal to or greater than tetracaine by the intraperitoneal route in mice. N-Heptyl-1,2,3,4-tetrahydro-6-methoxy-1-naphthylamine methanesulfonate was the most promising local anesthetic in these series.

Many students wrote family histories for their term papers. They interviewed their grandparents and members of their family and identified German traditions, customs and ways in their background. Needless to say, all of this aided me as a teacher in terms of getting to know the community and students. Students desired more courses on GermanAmericana, such as: who's who in German-American literature; the German-American novella; German-American poetry; GermanAmerican folklore; German-American art; German-American music; recurrent themes in German-American literature; contemporary German-American literature; Pennsylvania German culture; and Cincinnati German history and literature. Perhaps it would be advisable for German departments to introduce and develop new courses on German Americana. There is a definite interest and a wealth of material to draw