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Peter Buchwald

Publications and source records attributed to Peter Buchwald.

13 recordsLinked to original sources
PubMed2006

A general bilinear model to describe growth or decline time profiles.

Linear models are widely used because of their unrivaled simplicity, but they cannot be applied for data that have a turning-or rate-change-point, even if the data show good linearity sufficiently far from this point. To describe such bilinear-type data, a completely generalized version of a linearized biexponential model (LinBiExp) is proposed here to make possible smooth and fully parametrizable transitions between two linear segments while still maintaining a clear connection with the linear models. Applications and brief conclusions are presented for various time profiles of biological and medical interest including growth profiles, such as those of human stature, agricultural crops and fruits, multicellular tumor spheroids, single fission yeast cells, or even labor productivity, and decline profiles, such as age-effects on cognition in patients who develop dementia and lactation yields in dairy cattle. In all these cases, quantitative model selection criteria such as the Akaike and the Schwartz Bayesian information criteria indicated the superiority of the bilinear model compared to adequate less parametrized alternatives such as linear, parabolic, exponential, or classical growth (e.g., logistic, Gompertz, Weibull, and Richards) models. LinBiExp provides a versatile and useful five-parameter bilinear functional form that is convenient to implement, is suitable for full optimization, and uses intuitive and easily interpretable parameters.

Adolescent↗
PubMed2006

The time-profile of cell growth in fission yeast: model selection criteria favoring bilinear models over exponential ones.

BACKGROUND: There is considerable controversy concerning the exact growth profile of size parameters during the cell cycle. Linear, exponential and bilinear models are commonly considered, and the same model may not apply for all species. Selection of the most adequate model to describe a given data-set requires the use of quantitative model selection criteria, such as the partial (sequential) F-test, the Akaike information criterion and the Schwarz Bayesian information criterion, which are suitable for comparing differently parameterized models in terms of the quality and robustness of the fit but have not yet been used in cell growth-profile studies. RESULTS: Length increase data from representative individual fission yeast (Schizosaccharomyces pombe) cells measured on time-lapse films have been reanalyzed using these model selection criteria. To fit the data, an extended version of a recently introduced linearized biexponential (LinBiExp) model was developed, which makes possible a smooth, continuously differentiable transition between two linear segments and, hence, allows fully parametrized bilinear fittings. Despite relatively small differences, essentially all the quantitative selection criteria considered here indicated that the bilinear model was somewhat more adequate than the exponential model for fitting these fission yeast data. CONCLUSION: A general quantitative framework was introduced to judge the adequacy of bilinear versus exponential models in the description of growth time-profiles. For single cell growth, because of the relatively limited data-range, the statistical evidence is not strong enough to favor one model clearly over the other and to settle the bilinear versus exponential dispute. Nevertheless, for the present individual cell growth data for fission yeast, the bilinear model seems more adequate according to all metrics, especially in the case of wee1Delta cells.

Biophysics↗
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

General linearized biexponential model for QSAR data showing bilinear-type distribution.

A major impediment of many QSAR-type analyses is that the data show a maximum or minimum and can no longer be adequately described by linear functions that provide unrivaled simplicity and usually give good description over more restricted ranges. Here, a general linearized biexponential (LinBiExp) model is proposed that can adequately describe data showing bilinear-type distribution as a function of not just often-employed lipophilicity descriptors (e.g., log P) but as a function of any descriptor (e.g., molecular volume). Contrary to Hansch-type parabolic models, LinBiExp allows the natural extension of linear models and fitting of asymmetrical data. It is also more general and intuitive than Kubinyi's model as it has a more natural functional form. It was obtained by a differential equation-based approach starting from very general assumptions that cover both static equilibria and first-order kinetic processes and that involve abstract processes through which the concentration of the compound of interest in an assumed "effect" compartment is connected to its "external" concentration. Physicochemical aspects placing LinBiExp within the framework of linear free energy relationship (LFER) approaches are presented together with illustrative applications in various fields such as toxicity, antimicrobial activity, anticholinergic activity, and glucocorticoid receptor binding.

Alcohols↗
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

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

Direct, differential-equation-based in-vitro-in-vivo correlation (IVIVC) method.

A new, differential equation-based in-vitro-in-vivo correlation (IVIVC) method is proposed that directly relates the time-profiles of in-vitro dissolution rates and in-vivo plasma concentrations by using one- or multi-compartment pharmacokinetic models and a corresponding system of differential equations. The rate of in-vivo input is connected to the rate of in-vitro dissolution through a general functional dependency that allows for time scaling and time shifting. A multiplying factor that accounts for the variability of absorption conditions as the drug moves along is also incorporated. Two data sets incorporating slow-, medium-, and fast-release formulations were used to test the applicability of the method, and predictive powers were assessed with a leave-one-formulation-out approach. All fitted parameters had realistic values, and good or acceptable fits and predictions were obtained as measured by plasma concentration mean squared errors and percent AUC errors. Introduction of step-down functions that account for the transit of the dosage form past the intestinal sites of absorption proved useful. By avoiding the integral transforms used in the existing deconvolution- or convolution-based IVIVC models, the present method can provide increased transparency, improved performance, and greater modelling flexibility.

Area Under Curve↗
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↗