PubMed Health⌕ Search

Biomedical subjects

Nicholas Bodor

Publications and source records attributed to Nicholas Bodor.

13 recordsLinked to original sources
PubMed2006

Soft quaternary anticholinergics: comprehensive quantitative structure-activity relationship (QSAR) with a linearized biexponential (LinBiExp) model.

A comprehensive quantitative structure-activity relationship (QSAR) study is presented for quaternary soft anticholinergics including two distinctly different classes designed on the basis of the soft analogue and the inactive metabolite approaches. Because of the clear biphasic (bilinear) nature of the activity data when all structures (n = 76) were considered as a function of molecular size (volume), a nonlinear model had to be used, and a linearized biexponential (LinBiExp) model proved very adequate. LinBiExp can fit activity data that show a maximum (or a minimum) around a given parameter value but tend to show linearity away from this turning point. Contrary to Hansch-type parabolic models, LinBiExp represents a natural extension of linear models, and a direct correspondence between its parameters and those obtained earlier by linear regression on compound subsets covering more limited parameter ranges could be easily established. Stereospecificity was confirmed as important, and the presence of an acid moiety was found to essentially eliminate activity. The consideration of bilinear behavior, which most likely results from size limitations at the binding site, can also explain the embarrassingly low activity found for a relatively large compound predicted as highly active by Lien, Ariëns, and co-workers based on their QSAR study.

Animals↗
PubMed2006

Corticosteroid design for the treatment of asthma: structural insights and the therapeutic potential of soft corticosteroids.

Inhaled and intranasal corticosteroids (ICSs) still are the most effective treatment available for allergic airway diseases and are likely to remain the cornerstone of managing persistent asthma/allergic rhinitis in the foreseeable future. Even if the therapeutic index of this class increased significantly with the introduction of newer corticosteroids, and even if new therapeutic potentials are beginning to emerge with our increasing understanding of the mechanisms of asthma, chronic obstructive pulmonary disease, and rhinitis, corticosteroid development still remains a very important field for drug designers. After a brief review of issues related to the structure-activity relationships of glucocorticoids and the main determinants of their receptor-binding affinity at the glucocorticoid receptor, the main focus of the present article will be on the development of soft corticosteroids, as they are particularly well suited to separate local activity from systemic side effects, which still is an important issue for ICSs. Design consideration required in the search for safe and effective soft drugs on one hand, and safe and effective ICSs on the other hand, will be briefly discussed and illustrated with a number of cases, in particular, with that of loteprednol etabonate and etiprednol dicloacetate, soft corticosteroids that are being developed for a full spectrum of therapeutic applications including asthma and allergic rhinitis.

Adrenal Cortex Hormones↗
PubMed2005

Ophthalmic drug design based on the metabolic activity of the eye: soft drugs and chemical delivery systems.

Despite its apparent easy accessibility, the eye is, in fact, well protected against the absorption of foreign materials, including therapeutic agents, by the eyelids, by the tear-flow, and by the permeability barriers imposed by the cornea on one side and the blood-retinal barrier on the other. Most existing ophthalmic drugs were adapted from other therapeutic applications and were not specifically developed for the treatment of eye diseases; hence, they are not well suited to provide eye-specific effects without causing systemic side effects. A real breakthrough in the area of ophthalmic therapeutics can be achieved only by specifically designing new drugs for ophthalmic applications to incorporate the possibility of eye targeting into their chemical structure. Possibilities provided along these lines by designing chemical delivery systems (CDSs) and soft drugs within the framework of retrometabolic drug design are reviewed here. Both are general concept applicable in almost any therapeutic area. This review will concentrate on beta-adrenergic agonists and anti-inflammatory corticosteroids, where clinical results obtained with new chemical entities, such as betaxoxime, adaprolol, loteprednol etabonate, and etiprednol dicloacetate, exist to support the advantages of such metabolism-focused, ophthalmic-specific drug design approaches.

Adrenal Cortex Hormones↗
PubMed2005

Pharmacokinetic and pharmacodynamic evaluations of the zwitterionic metabolite of a new series of N-substituted soft anticholinergics.

PURPOSE: This study was conducted to evaluate the zwitterionic common metabolite of a novel series of N-substituted soft analogs of glycopyrrolate both as racemates and as 2R isomers. METHODS: Activities were assessed using both in vitro (receptor binding assay, guinea pig ileum pA2 assay) and in vivo techniques (rabbit mydriatic response, rat cardiac effects). Pharmacokinetic characterizations in rats were also performed. RESULTS: The metabolite was highly water-soluble and very stable in buffer solutions as well as in rat biological media. Following i.v. administration in rats, it was very rapidly eliminated, mainly through renal excretion with a half-life of about 10 min. Receptor binding and guinea pig ileum assays indicated this metabolite as more than 1 order of magnitude less active than its parent soft drugs or glycopyrrolate. Moderate M3/M2 muscarinic receptor subtype selectivity was observed, further reducing the likelihood of cardiac side effects. The metabolite showed to some extent mydriatic effect and protective effect against carbachol-induced bradycardia, but of much shorter durations than glycopyrrolate; it had, however, no effect on resting heart rate. CONCLUSIONS: N-Substituted zwitterionic metabolites retain some, but only considerably reduced activity of their parent quaternary ammonium ester soft anticholinergic drugs, and they are very rapidly eliminated from the systemic circulation. They are suitable for their assigned role within the framework of inactive metabolite-based soft anticholinergic design.

Administration, Topical↗
PubMed2005

Unified pharmacogenetics-based parent-metabolite pharmacokinetic model incorporating acetylation polymorphism for talampanel in humans.

The N-acetylation of the noncompetitive AMPA antagonist talampanel (TLP) represents a route of varying significance in various species. For a detailed analysis in humans, plasma concentrations of TLP and its N-acetyl metabolite (NAc-TLP) were measured for up to 48 h after administration of a single oral dose of 75 mg in 28 healthy volunteers following genotyping for the N-acetyltansferase NAT2 isozymes (alleles NAT2*4, *5, *6, and *7). Unified parent-metabolite pharmacokinetic (PK) models that allowed three different rates of acetylation were used to simultaneously fit plasma levels for both the parent drug and its metabolite following genotype-based classification as slow, intermediate, or fast acetylator. A perfect correspondence was found between the phenotype inferred from genotyping and the phenotype determined by using plasma metabolite-to-parent molar ratios indicating that this route of metabolism is indeed mediated by NAT2. Linear parent-metabolite PK models (first-order input, first-order elimination through two parallel routes one of which is through a metabolite with polymorphic rate of formation) gave adequate and sufficiently consistent fit. Parameters obtained suggest that for TLP in humans, N-acetylation represents only about 1/4th of the total elimination even in true (*4/*4 homozygous) fast acetylators, acetylation is about 8-12 times faster in fast and 3-6 times faster in intermediate acetylators than in slow acetylators, and the N-acetyl metabolite is eliminated faster than the parent drug. Such PK models can provide quantitative estimates of relative in vivo metabolism rates for routes catalyzed by functionally polymorphic enzymes.

Acetylation↗
PubMed2004

New evidence for the selective, long-lasting central effects of the brain-targeted estradiol, Estredox.

The present study examined the dose- and time-dependent central effects of an estradiol chemical delivery system cyclodextrin complex (E(2)-CDS-CD) on the reestablishment of copulatory behavior of castrated male and ovariectomized female rats with concomitant determination of the blood luteinizing hormone (LH) and E(2) levels. In orchidectomized males, Estredox, after single doses of 0.3 and 3.0 mg/kg iv, reestablished the mounting and intromission up to 4 weeks. The LH suppressive effect lasted to Day 7 and 28, respectively. After repeated administration for 10 days at a dose of 0.01mg/kg iv, significant effect was obtained by Day 14. Ovariectomized females were treated iv daily for 5 days either with E(2)-CDS-CD, estradiol benzoate (EB) or vehicle, and the lordosis quotient was determined. At a dose of 0.03 mg/kg the duration of EB's effect was 10 days shorter and only one-third of that of E(2)-CDS-CD. The LH suppression lasted to Day 18. On the other hand, after EB treatment there was no significant decrease in LH levels. The low plasma E(2) levels indicated fast rate of peripheral elimination in both males and females. The brain-targeting E(2) indicates better efficacy and increased safety in replacement therapies because of the reduced peripheral side effects.

Animals↗
PubMed2004

Designing safer (soft) drugs by avoiding the formation of toxic and oxidative metabolites.

Integration metabolic considerations into the drug-design process can allow safer pharmaceuticals to be designed. "Soft" drugs are designed to be deactivated in a predictable and controllable way after achieving their therapeutic role. They are designed to be metabolized rapidly and by avoiding oxidative pathways into inactive and nontoxic species. Successful application of such design principles has already resulted in a number of marketed drugs. The present article illustrates advantages inherent in avoiding the formation of oxidative metabolites, with examples that include soft bufuralol analogs and soft insecticides such as chlorobenzilate and malathion. Design principles for various soft drug classes are briefly summarized together with computerized tools intended to make the application of these principles more quantitative and more accessible.

Animals↗
PubMed2003

Potency and specificity of the pharmacological action of a new, antiasthmatic, topically administered soft steroid, etiprednol dicloacetate (BNP-166).

In the present study, the pharmacological effects of etiprednol dicloacetate (BNP-166; ethyl-17alpha-dichloroacetoxy-11beta-hydroxyandrosta-1,4-diene-3-one-17beta-carboxylate), a new soft steroid, intended to use for the treatment of asthma, were investigated in an animal model of allergen sensitized and challenged Brown Norway rats using local treatment. The examinations involved the determination of the effect of the compound on the extent of allergen induced broncho-alveolar fluid and lung tissue eosinophilia, goblet cell hyperplasia and mucus production, perivascular edema formation, and airways hyperresponsiveness. The activity of etiprednol dicloacetate was compared with that of budesonide. Using in vitro methods, the soft character of etiprednol dicloacetate was investigated together with its capability to dissociate transrepressing and transactivating properties. We found that combining all the examined parameters etiprednol dicloacetate was at least equipotent with budesonide in the animal model, but in several investigated variables it surpassed the activity of budesonide. The effect of etiprednol dicloacetate in vitro was shown to be the function of the quantity of the serum, present in the assay, it was also strongly affected by the incubation time and decreased significantly when it was preincubated with human plasma. These features are characteristics of a soft drug that is quickly inactivated in the systemic circulation. In addition, it was revealed that while the transrepressing potential of etiprednol dicloacetate remained high, its transactivating activity was greatly reduced. These data indicate that the strong local effect of the compound will very likely be accompanied with a significantly reduced systemic activity predicting favorable selectivity in the pharmacological action of etiprednol dicloacetate.

Adrenal Cortex Hormones↗
PubMed2003

Design, pharmacokinetic, and pharmacodynamic evaluation of a new class of soft anticholinergics.

PURPOSE: To design and evaluate a new class of soft anticholinergics with subtype selectivity. METHODS: A new class of soft anticholinergics was designed based on the "inactive metabolite" approach. Four compounds were synthesized. The potency and soft nature of the compounds were evaluated by receptor binding, cardiac, and mydriatic studies. Stability and pharmacokinetic studies were also performed on these newly synthesized soft anticholinergics. RESULTS: Receptor binding studies of the soft anticholinergics on cloned muscarinic receptors indicated pKi values in the range of 7.5 to 8.9. Two compounds, 9a and 13a, of the series showed muscarinic subtype receptor selectivity (M3/M2). In mydriatic studies, 13a and 13b showed shorter duration of action in the treated eyes than tropicamide. In the control eyes, significant dilation of pupils was found only in rabbits treated with atropine and tropicamide, indicating that the soft anticholinergics lack systemic effects because of their facile hydrolytic deactivation. Consistent with their soft nature, this new class of soft anticholinergics displayed much shorter cardiovascular effects in the carbachol-induced bradycardia (10 to 15 min) in rats than atropine (> 60 min). Stability and pharmacokinetic studies suggested that the new soft anticholinergics were rapidly eliminated from plasma (systemic circulation) after i.v. administration. CONCLUSIONS: A new class of anticholinergics was designed and synthesized, and the PK/PD evaluation confirmed they were potent "soft" anticholinergics; two of them showed muscarinic receptor subtype selectivity (M3/M2).

Administration, Topical↗
PubMed2002

Barriers to remember: brain-targeting chemical delivery systems and Alzheimer's disease.

Brain-targeted chemical delivery systems (CDSs) represent rational drug design attempts not only to deliver but also to target drugs to their site of action. Using a sequential metabolism approach, the special bidirectional properties of the blood-brain barrier can be exploited to smuggle the precursors of therapeutic compounds across the barrier and lock them inside the brain ready for sustained release of the active drugs. Many potential therapeutic applications can be envisioned for such CDSs; here, the potential of brain-targeted estradiol for the prevention and treatment of Alzheimer's disease is reviewed in detail.

Alzheimer Disease↗
PubMed2002

In vitro and in vivo evaluations of dihydroquinoline- and dihydroisoquinoline-based targetor moieties for brain-specific chemical delivery systems.

Brain-targeted delivery of various drugs can be successfully achieved by chemical delivery systems (CDS) that contain a 1,4-dihydropyridine-based redox targetor moiety and undergo a sequential metabolism. However, the susceptibility of this moiety toward hydration in acidic media may limit the shelf-life of such compounds in aqueous formulation. Here, a systematic investigation of the chemical stability toward oxidation and hydration of ester and amide derivatives of 3-substituted 1,4-dihydropyridine, 1,4-dihydroquinoline, and 4-substituted 1,2-dihydroisoquinoline is reported, together with the in vitro stability and in vivo (rat) distribution of isoquinoline-based testosterone and hydrocortisone chemical delivery systems, which were selected as having the most suitable acid-resistant targetor moieties.

Animals↗
PubMed2002

Synthesis and biological evaluations of brain-targeted chemical delivery systems of [Nva2]-TRH.

Various chemical delivery systems for [Nva2]-TRH were synthesized and their CNS activity was investigated and compared with that of a similar chemical delivery system of [Leu2]-TRH, previously studied. Sequential metabolism of the chemical delivery system delivered to the brain, starting with the conversion of the dihydrotrigonellyl (DHT) to the trigonellyl (T+) moiety, will provide the lock-in to the brain of the T+-chemical delivery system, which will undergo hydrolysis of the cholesteryl ester, formation of the Pr-amide and cleavage of the spacer-T+ part, allowing ultimately the sustained release of the active [Nva2]-TRH. The CNS activity was assessed by measuring the extent of antagonizing barbiturate-induced sleeping time in mice. The fully packaged DHT-Pro-Pro-Gln-Nva-Pro-Gly-OCh produced robust antagonism, reducing sleeping time from 89 min to 48 min, similar to the Leu2-analogue (49 min). However, the partially substituted [Nva2]-TRH analogues showed little or no CNS activity. The results indicate that the fully packaged delivery system is necessary to produce the successful brain targeting of the precursor construct and effective release of the Gln-Nva-ProNH2.

Amino Acids↗