Use of an indirect pharmacodynamic stimulation model of MX protein induction to compare in vivo activity of interferon alfa-2a and a polyethylene glycol-modified derivative in healthy subjects.

Interferon alfa-2a was chemically modified by the covalent attachment of a polyethylene glycol (PEG) moiety to enhance its circulating half-life and to reduce its immunogenicity. A comparative evaluation of the pharmacokinetics of the PEG-modified interferon alfa-2a showed a greater than twofold increase in the circulating half-life as a result of this chemical modification. An indirect physiologic response model was developed to characterize the time course of the MX protein response after subcutaneous administration of single ascending doses of either interferon alfa-2a or PEG-interferon alfa-2a in healthy volunteers. Analysis of the pharmacokinetic-pharmacodynamic relationship suggested that the PEG-modified interferon alfa-2a could not be administered less than twice weekly and therefore offered little therapeutic advantage over its unmodified counterpart, which is administered three times weekly. These results were consistent with findings in phase II trials. This study substantiates the usefulness of pharmacodynamic modeling as a tool for the development of dose recommendations and for the early selection of drug candidates in the drug development process.

Retrospective study of drug response in 87 patients with progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease that responds poorly to pharmacologic intervention despite its clinical, neurochemical, and pathologic similarity to Parkinson's disease. We reviewed our experience with drugs used in the treatment of patients with PSP who were followed in the Department of Neurology, University of Medicine and Dentistry of New Jersey--Robert Wood Johnson Medical School. Of 136 patients identified, adequate drug-response data were available for 87 (64%). Benefit and adverse effects of therapy were graded on a 4-point scale: 0, none; 1, minimal; 2, moderate; 3, marked. The three most frequently used drugs were amitriptyline (32% of patients benefited), imipramine (28% of patients benefited) and levodopa/carbidopa (Sinemet) (38% of patients benefited). Levodopa/carbidopa, amantadine, selegiline, and amitriptyline gave the best risk/benefit ratios. Monotherapy tended to show more benefit and fewer adverse effects than polypharmacy.

Stability of cyclosporine with magnesium sulfate in 5% dextrose injection.

The compatibility and stability of cyclosporine with magnesium sulfate in 5% dextrose injection was studied. Cyclosporine solution 50 mg/mL was added to each of three glass bottles containing magnesium sulfate injection and 5% dextrose injection; final theoretical concentrations of cyclosporine and magnesium sulfate were 2.0 mg/mL and 30 mg/mL, respectively. The samples were stored under fluorescent lighting at controlled room temperature (24 +/- 2.4 degrees C). At 6, 12, 24, and 36 hours each solution was visually inspected under normal lighting against a white and black background for color change, haze, or precipitation. Samples were assayed in duplicate for cyclosporine concentration by using a stability-indicating high-performance liquid chromatographic method. Turbidity occurred immediately after mixing but resolved in approximately 30 seconds. No other changes in clarity or color were noted. The admixtures retained > 90% of initial cyclosporine concentration for six hours, and there were no significant differences in mean cyclosporine concentrations among the individual samples. Cyclosporine 2.0 mg/mL added to magnesium sulfate 30 mg/mL in 5% dextrose injection was stable for six hours when stored in glass bottles at 24 degrees C under fluorescent lighting.

Synthesis and biological activity of cocaine analogues. 2. 6H-[2]Benzopyrano[4,3-c]pyridin-6-ones.

1,2,3,4-Tetrahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (20) and cis- and trans-1,2,3,4,4a,10b-hexahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (3a and 3b) were synthesized. The design of 3b was based on the proposal that the active conformation of cocaine is one in which the phenyl and amino groups are arranged in a manner that will superimpose upon a beta-phenethylamine in a trans-staggered conformation. The compounds were compared with cocaine and tropacocaine for their ability to inhibit uptake of [3H]norepinephrine by rat brain synaptosomal preparations. The test compounds (IC50 = 3.2 X 10(-4) M, 20; 6.5 X 10(-4) M, 3a; and 3.2 X 10(-4) M, 3b; respectively) were considerably weaker than cocaine (IC50 = 5.8 X 10(-7) M) and tropacocaine (IC50 = 5.6 X 10(-6) M). Compound 3b showed selectivity at 1 X 10(-5) M for inhibiting the uptake of norepinephrine (36%). It inhibited dopamine (3%) and serotonin (0%) uptake to a much lesser extent, if at all, at this concentration.

Synthesis and biological activity of cocaine analogs I: N-alkylated norcocaine derivatives.

N-Allylnorcocaine, N-dimethylallylnorcocaine, and N-cyclopropylmethylnorcocaine were prepared and examined for cocaine-like activity. The compounds were prepared by alkylation of norcocaine, which was obtained by demethylation of cocaine with 2,2,2-trichloroethyl chloroformate followed by zinc--acetic acid reduction. The compounds were evaluated by comparison with cocaine in causing disruption of milk intake in rats, behavioral modification in squirrel monkeys, and inhibition of 3H-serotonin uptake by rat synaptosomes. The compounds showed cocaine-like activity less potent than cocaine in the latter two tests and were inactive in the milk intake test.

Synthesis of potential mescaline antagonists.

1-[2-(3,4,5-Trimethoxyphenyl)ethyl]-3-pyrroline, 2-(3,4,5-trimethoxybenzyl)-1,2,3,6-tetrahydropyridine, N-n-propylmescaline, N-cyclopropylmethylmescaline, and N-allylmescaline were synthesized as potential mescaline antagonists. The ability of these compounds to antagonize mescaline-induced disruption of swim behavior is also given.

Substituted thiadiazolines as inhibitors of central nervous system carbonic anhydrase.

A series (24-30) of substituted thiadiazolines was synthesized and tested for in vitro carbonic anhydrase inhibition and for protective ability against pentylenetetrazole-induced convulsions. ED50 (pentylenetetrazole protection), TD50, and LD50 values are reported for each compound. With the exception of 30, all compounds approximated the model compound methazolamide as in vitro carbonic anhydrase inhibitors. Several of the compounds produced extended protection against pentylenetetrazole-induced convulsions. Ring methoxy substitution in the ortho position appeared to produce maximum activity.