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Biomedical subjects

N Bodor

Publications and source records attributed to N Bodor.

At least 73 records · Page 4Linked to original sources
PubMed1995

Efficacy of a 3-substituted versus 17-substituted chemical delivery system for estradiol brain targeting.

Brain-targeted delivery of estrogens has been achieved by a chemical delivery system (CDS) in which a molecular targetor (1-methyl-1,4-dihydronicotinate) was attached to the 17-alcohol of estradiol. Optimization of this effect was attempted with the isomeric 3-phenol ester. Estradiol 3-nicotinate was prepared with nicotinic anhydride, which selectively acylated the phenol position. Methylation and reduction gave estradiol 3-(1-methyl-1,4-dihydronicotinate) of the 3-E2-CDS. Theoretical and electrochemical investigation indicated that the 3-E2-CDS was more stable to oxidation than was the prototype 17-ester (17-E2-CDS). Systemic administration of the 17-E2-CDS produced high levels of the corresponding quaternary salt in the brain of rats, which disappeared with an estimated half-life of > 2 days, but 3-E2-CDS dosing resulted in no significant quaternary salt trapping. Pharmacological activity was potent and sustained after 17-E2-CDS dosing but transient after 3-E2-CDS administration. Thus, the 3-E2-CDS reduced the rate of weight gain in male rats but to a lesser extent and for a shorter duration than did the 17-E2-CDS. Similar effects were seen on pituitary hypertrophy, reduction in serum androgen concentrations, and involution of prostate and seminal vesicles. The results of these studies suggest that placement of the targeting ester at the phenol position increases dihydropyridine stability but, at the same time, reduces brain sequestration.

Animals↗
PubMed1995

Preparation, characterization, and anesthetic properties of 2-hydroxypropyl-beta-cyclodextrin complexes of pregnanolone and pregnenolone in rat and mouse.

Prototype formulations of the progesterone derivatives pregnanolone and pregnenolone were prepared by solubilizing the steroids in 2-hydroxypropyl-beta-cyclodextrin (HP beta CD). The aqueous solubility of the steroids was increased as a function of HP beta CD concentration generating linear (AL) or curvilinear (AP) phase-solubility profiles. While the solubility of pregnanolone could not be increased with the addition of water-soluble pharmaceutical polymers, the concentration of pregnenolone in HP beta CD was increased more than 60% by the addition of small amounts (0.10%) of (hydroxypropyl)methylcellulose. Mice studies found that while pregnanolone was highly potent in an HP beta CD vehicle, pregnenolone was devoid of activity. Since pregnenolone and pregnanolone differ marginally in structure and physicochemical profile, the data suggest that these derivatives interact via a specific receptor and not via nonspecific membrane perturbations. Sex differences in the action of the pregnanolone complex was observed in that parenteral (i.v. and i.p.) drug administration was more effective in males than females. These data are in contrast to observations made in the case of alfaxalone, a related steroid anesthetic, in which the sex difference favored female animals. On the other hand, females appeared to be more sensitive to the effects of the pregnanolone complex when administered orally. Finally, parenteral pregnanolone was more toxic to males than females with LD50 (i.v.) values of 355 and 548 micromol/kg, respectively.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1995

Minimal cardiac electrophysiological activity of alprenoxime, a site-activated ocular beta-blocker, in dogs.

A closed chest catheter technique was used in dogs to examine the potential cardiac effects of alprenoxime, a potent new ocular antihypertensive agent. Alprenoxime was designed to undergo metabolic activation to the beta-blocker, alprenolol, specifically within the eye using hydrolase and reductase enzymes that reside in the iris-ciliary body. Previous studies in rabbits confirmed that intraocular pressure (IOP) significantly decreased after topically instilling ophthalmic drops of alprenoxime, while heart rates remained essentially unchanged after intravenous dosing. To further explore the safety and ocular specificity of this potential antiglaucoma drug, several cardiac electrophysiologic parameters were monitored during alprenoxime infusion in anesthetized dogs. In contrast to the pharmacologically significant increases (33-144%) measured after alprenolol or other previously tested beta antagonist infusion, the identical dose of alprenoxime had no effect on sinus cycle length (SCL), conduction times through the bundle of His and atrium (H and AH), or any other monitored cardiac electrophysiologic parameter. No changes greater than 6% from baseline were detected with alprenoxime infusion. Similarly, no beta-antagonist cardiac activity could be detected in isoproterenol stimulated dogs after alprenoxime. The results demonstrate that alprenoxime has no significant cardiac activity at doses much greater than potential therapeutic levels. The study provides further support that the new agent could be safely used in treating glaucoma.

Adrenergic beta-Antagonists↗
PubMed1995

Soft drugs. 18. Oral and rectal delivery of loteprednol etabonate, a novel soft corticosteroid, in rats--for safer treatment of gastrointestinal inflammation.

PURPOSE: As a safe anti-inflammatory corticosteroid, the utility of loteprednol etabonate (LE) for the treatment of gastrointestinal inflammation, via oral and rectal administration, was investigated in rats. METHODS: In vivo, LE solution and suspension were orally administered (20 mg/kg), and various LE preparations (solution, suspension & suppository) were applied in rectal loops (0.2 mg per loop). In vitro, various GI tissues were used to study the stability and partition of LE. RESULTS: After oral administration of LE solution, LE reached the upper GI tract effectively, but not the colon, due to absorption and/or decomposition. In suspension, LE reached most of the GI tract (except rectum) in 8 hr and showed little absorption. After rectal applications, LE remained intact in the rectal loop for more than five hours with a slow rate of disappearance, however, LE distributed in the rectal membrane to some extent. The concentrations of LE and its inactive metabolites in plasma after both oral and rectal administrations were lower than the detection limit (0.1 microgram/ml) at anytime during the experiments. In vitro, LE in solution was stable in stomach, but not in cecum, due to the hydrolysis by the cecal resident micro flora. In solution, LE distributed into the mucosal membranes efficiently (about 2.5-4.0 micrograms/g tissue). CONCLUSIONS: The results suggest that LE can be orally or rectally delivered in the GI tract for the topical treatment of the inflammatory bowel disease.

Administration, Oral↗
PubMed1995

Soft drugs. 19. Pharmacokinetics, metabolism and excretion of a novel soft corticosteroid, loteprednol etabonate, in rats.

PURPOSE: Pharmacokinetics, metabolism and excretion of loteprednol etabonate (LE) were investigated in rats. METHODS: The pharmacokinetic studies were performed by iv injections of LE (1-20 mg/kg). In the metabolism and excretion studies, 0.5-10 mg/kg of LE were iv administered, bile and urine samples were collected for 6 hr. RESULTS: The pharmacokinetic of LE showed a rapid, dose-dependent elimination with a total blood clearance (CLtotal) of higher than 60 ml/min/kg. The metabolism and excretion of LE also showed a marked dose-dependency. At 6 hr after iv of LE (0.5-10 mg/kg), the total recoveries (LE and the metabolites, AE & A, in bile and urine) were 99.35-26.72%. However, only about 2% of LE was excreted from the body through the urine. There were 0.93-2.12% and 0.66-0.26% of AE, and 75.67-19.69% and 20.74-2.77% of A excreted in the bile and urine, respectively. The excretion of A was dose dependent, and significantly higher at the lower dose. Using the (% of total excretion) vs. (log dose) plots, it could be predicted that almost all of the administered LE will be metabolized, and excreted as A when the systemic dose is lower than 0.25 mg/kg. CONCLUSIONS: The results indicate that LE absorbed systemically, after topical administration, can be rapidly transformed to the inactive metabolites, and eliminated from the body mainly through the bile and urine.

Androstadienes↗
PubMed1995

Soft drugs. XX. Design, synthesis, and evaluation of ultra-short acting beta-blockers.

A new type of ultra-short acting beta-blocker which might prove advantageous in treating acute arrhythmias was designed, synthesized and investigated. Based on the soft drug "inactive metabolite approach," the inactive phenylacetic acid metabolite of both metoprolol and atenolol was reactivated by esterification with sulfur-containing aliphatic alcohols. Since the sulfur-containing moieties are labile to the ubiquitous esterases, the new compounds should be inactivated by a one step enzymatic cleavage back to the inactive phenylacetic acid derivative. Pharmacological and pharmacokinetic profiles of the new compounds were evaluated in rats and rabbits. Isoproterenol-induced tachycardia was inhibited with short-term infusion of each compound. This tachycardia blocking effect rapidly disappeared upon termination of infusion, while beta-blocking activity was 2-4-fold longer after comparable doses of the short-acting beta-blocker, esmolol. The rapid recovery from the beta-receptor blockade is believed due to fast hydrolysis of the soft drugs in the body. This is supported from in vitro results showing the t1/2 of esmolol is about 10-fold longer than the new soft drugs in rat, rabbit, dog and human blood. Hydrolysis studies in phosphate buffered solutions indicated that the esters are labile to base-catalyzed hydrolysis. However, the relative t1/2 values measured in biological media compared to phosphate buffered solution clearly support rapid enzymatic cleavage of the soft drugs. Interestingly, one of the soft beta-blockers, the sulfonyl ester derivative, showed a unique property of exhibiting good beta-receptor blocking activity without significant hypotensive action.

Adrenergic beta-Antagonists↗
PubMed1995

Quantitative structure activity relationships of catechol derivatives on nerve growth factor secretion in L-M cells.

PURPOSE: Although many catechol derivatives are potent stimulators of Nerve Growth Factor synthesis in L-M cells, not much is known about their mechanism of action. In order to obtain a Quantitative Structure Activity Relationship (QSAR), AM1 quantum mechanical calculations were performed on a group of 23 catechol derivatives with different levels of activity. METHODS: A set of 18 parameters/descriptors were obtained by AM1 quantum mechanical calculations for each catechol derivative. Linear combinations of the calculated descriptors were fitted to the activity (as extracted from literature data) of the compounds by using simple or multiple regression analysis. RESULTS: Good correlation with activity was obtained for specific parameters such as the adiabatic ionization potential and other 'oxidation'-related descriptors of the molecules while poor correlation was observed for most of the other parameters as, for example, for log P. CONCLUSIONS: Our results show that activity is associated with parameters related to the oxidation of the catechol derivatives, strongly supporting recent literature suggesting that an oxidative process is involved in their action.

Catechols↗
PubMed1995

Sequential bioactivation of methoxime analogs of beta-adrenergic antagonists in the eye.

Selected beta-adrenoreceptor antagonists are the antiglaucoma drugs of first choice in most cases. However, a number of significant central nervous system (CNS), cardiovascular and respiratory side-effects following topical ocular installation of beta-blockers have also been reported. Site- and stereo-specific delivery to the eye of beta-blockers was achieved by application of a sequential bioactivation of the chemical delivery system (CDS) analogs of these drugs, which are converted to the active beta-blockers only in the eye, thus systemic side effects are avoided. The corresponding ketoxime analogs of the various beta-blockers were successfully applied and one of them, Alprenoxime, was tested in humans. The main problem with these compounds, however, is formulation stability: Alprenoxime has a t90 of only 2-3 months. Thus, alternate structures were searched. Methoxime analogs of selected beta-blockers were synthesized and their chemical stability established at different pH's. Subsequently, their in vivo sequential enzymatic conversion was confirmed using HPLC. Comparative intraocular pressure (IOP) reducing activity of the methoximes were then studied using normotensive rabbits. The methoxime analogs showed significantly improved hydrolytic stability at pH approximately 7.0, the t90 is over 1 year. The in vivo sequential bioactivation, however, proceeds similarly to the oximes. The intermediate ketones and the active beta-blockers can be detected in the various eye compartments at different time intervals following topical administration of the methoximes. The mechanism of the eye-selective bioactivation and the results of the IOP reducing activity studies will be discussed.

Administration, Topical↗
PubMed1994

Effect of molecular manipulation on the estrogenic activity of a brain-targeting estradiol chemical delivery system.

The structural parameters important for biological efficacy of an estradiol chemical delivery system (CDS), a brain-targeting approach based on redox trapping, were examined by molecular manipulation of a prototype derivative, estradiol 17-(1-methyl-1, 4-dihydronicotinate) (E2-CDS). Seven E2-CDS analogs in which the N-methyl substituent was altered were prepared including N-substituted short and medium straight chain alkyl, short branched chain alkyl, and aralkyl derivatives. Chemical and in vitro testing indicated that the most stable derivative was the N-benzyl E2-CDS. The analogs were tested in an intact male rat model to assess various central estrogenic manifestations including the rate of body weight gain, serum E2 and testosterone concentrations, and seminal vesicle, prostate and pituitary weight changes. Results indicated that all prepared CDS derivatives exerted some degree of central estrogenization with the most potent compounds being the parent E2-CDS and its ethyl homologue. Importantly, while the ethyl E2-CDS was equipotent to E2-CDS in various biological assays, it did not significantly elevate serum E2 compared to vehicle control at day 14.

Animals↗
PubMed1994

Designing safer ophthalmic drugs by soft drug approaches.

There are two major novel metabolism-based drug design concepts which have significant advantages when used in the design of safe, specific ophthalmic drugs. One is based on predictable enzymatic activation processes by enzymes found exclusively or preferentially at the site of action--in this case, within the eye, primarily in the iris-ciliary body. The second major retrometabolic design technique involves soft drug approaches. Among the various soft drug design strategies, it was found that the "inactive metabolite" and the "soft analog" approaches are the most useful for designing safe and selective ophthalmic drugs. In the first case, the design process starts with a known (or predicted) inactive metabolite (Mi) of the drug (D). This Mi is then structurally modified in the "chemical activation" stage to the soft drug (SD), which is isosteric and/or isoelectronic with D to produce activity at the target receptors, similar to that of D. By design, however, SD is also subject to a facile, predictable (generally hydrolytic) metabolism leading in one step to the starting inactive Mi. As this deactivation takes places everywhere in the body, the desired activities are produced virtually exclusively at the target site at or near the place of application. Successful use of this general concept has led to soft beta-blockers as safe antiglaucoma agents, soft anticholinergics as short acting mydriatic agents, and soft corticosteroids as a type of novel, safe anti-inflammatory agents, which due to their unique design, do not elevate intraocular pressure IOP and do not produce other systemic and local side effects.

Administration, Topical↗
PubMed1994

Enhanced delivery of ganciclovir to the brain through the use of redox targeting.

Enhanced delivery of ganciclovir to the brain was demonstrated by a redox-based chemical delivery system. A ganciclovir monoester in which a 1-methyl-1,4-dihydronicotinate was covalently attached to one of the hydroxymethyl functions was prepared. The stability of the ganciclovir chemical delivery system (DHPG-CDS) was evaluated in aqueous buffers and organ homogenates. In vivo distribution studies in the rat indicated that while ganciclovir poorly penetrated into the central nervous system and was rapidly eliminated, DHPG-CDS provided for therapeutically relevant (2.7 microM) and sustained levels of the parent compound through 6 h. An analysis of the area under the concentration curve indicated that the chemical delivery system delivered five times more ganciclovir than that of the parent drug. The high levels in the brain and reduced levels in the blood gave a brain-to-blood drug concentration ratio of 2.54 for ganciclovir when delivered by the chemical delivery system, compared to a ratio of 0.063 when the parent drug was administered. These data suggest that DHPG-CDS could be a useful adjunct for the treatment of cytomegalovirus encephalitis.

Animals↗
PubMed1994

Synthesis and evaluation of a redox chemical delivery system for brain-enhanced dopamine containing an activated carbamate-type ester.

A chemical delivery system (CDS) for enhanced delivery of dopamine to brain tissue, based on a dihydropyridine<==>pyridinium salt redox system, was modified to include an activated carbamate ester. The dihydronicotinate moiety was chemically attached to the amino group of dopamine (DA) by acylation with chloroethyl chloroformate, followed by condensation with sodium nicotinate under mild conditions. The product was selectively N-alkylated at the pyridine ring and subjected to regioselective reduction to the corresponding 1,4-dihydropyridine derivative, DA-CDSac. In vitro stability of the new compound was studied in phosphate buffers at mild acidic, physiological, and mild alkaline pH values. Oxidation studies showed facile conversion of the dihydronicotinate, DA-CDSac, is readily converted to the corresponding quaternary salt, both chemically and enzymatically. In vivo studies in rats did not detect sustained increases in brain levels of the quaternary salt after i.v. dosing with DA-CDSac. However, the new CDS appeared to change spontaneous locomotor activity in rats after i.v. administration which may be due to altered central DA neuronal activity.

Acylation↗
PubMed1993

An AM1 molecular orbital study of alpha-D-glucopyranose and beta-maltose: evaluation and implications.

Chemical reactivity and other characteristics of alpha-D-glucopyranose and beta-maltose were evaluated within a semiempirical molecular orbital (AM1) framework. Theoretically generated structures compared well to those determined by X-ray crystallographic techniques. Calculations suggested that the secondary hydroxy functions (OH-2 and OH-3) of the mono- and di-saccharides were more acidic than the primary alcohol (OH-6), which is consistent with experimental findings. In addition, the enhanced reactivity of the OH-3 locus, which is observed upon OH-2 alkylation of the object sugars, was rationalized in terms of increased OH-3 acidity. The chemical behavior of the monomers examined may be insightful in explaining the reactivity of glucopyranose polymers.

Carbohydrate Conformation↗