Physiological and ecological constraints play key roles in the evolution of plant growth patterns, especially in relation to defenses against herbivores. Phenotypic and life history theories are unified within the growth-differentiation balance (GDB) framework, forming an integrated system of theories explaining and predicting patterns of plant defense and competitive interactions in ecological and evolutionary time. Plant activity at the cellular level can be classified as growth (cell division and enlargement) of differentiation (chemical and morphological changes leading to cell maturation and specialization). The GDB hypothesis of plant defense is premised upon a physiological trade-off between growth and differentiation processes. The trade-off between growth and defense exists because secondary metabolism and structural reinforcement are physiologically constrained in dividing and enlarging cells, and because they divert resources from the production of new leaf area. Hence the dilemma of plants: Th...

https://www.jstor.org/stable/pdfplus/2830650.pdf

The dilemma of plants: To grow or defend.

Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. About 5-7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend. To illustrate the applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design, and highlights examples of prodrugs that are either launched or are undergoing human trials.

Prodrugs: design and clinical applications

Of the thousands of novel compounds that a drug discovery project team invents and that bind to the therapeutic target, typically only a fraction of these have sufficient ADME/Tox properties to become a drug product. Understanding ADME/Tox is critical for all drug researchers, owing to its increasing importance in advancing high quality candidates to clinical studies and the processes of drug discovery. If the properties are weak, the candidate will have a high risk of failure or be less desirable as a drug product. This book is a tool and resource for scientists engaged in, or preparing for, the selection and optimization process. The authors describe how properties affect in vivo pharmacological activity and impact in vitro assays. Individual drug-like properties are discussed from a practical point of view, such as solubility, permeability and metabolic stability, with regard to fundamental understanding, applications of property data in drug discovery and examples of structural modifications that have achieved improved property performance. The authors also review various methods for the screening (high throughput), diagnosis (medium throughput) and in-depth (low throughput) analysis of drug properties. * Serves as an essential working handbook aimed at scientists and students in medicinal chemistry * Provides practical, step-by-step guidance on property fundamentals, effects, structure-property relationships, and structure modification strategies * Discusses improvements in pharmacokinetics from a practical chemist's standpoint

Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization

Cyclodextrins are a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. Cyclodextrin molecules are relatively large with a number of hydrogen donors and acceptors and, thus, in general they do not permeate lipophilic membranes. In the pharmaceutical industry cyclodextrins have mainly been used as complexing agents to increase aqueous solubility of poorly soluble drugs, and to increase their bioavailability and stability. Studies in both humans and animals have shown that cyclodextrins can be used to improve drug delivery from almost any type of drug formulation. However, the addition of cyclodextrins to existing formulations without further optimisation will seldom result in acceptable outcome. Currently there are approximately 30 different pharmaceutical products worldwide containing drug/cyclodextrin complexes on the market.

Cyclodextrins in drug delivery

Trichome diversity and development

The aim of this study was to investigate the effect of cyclodextrins (s-CD, HP-s-CD and (SBE)7m-s-CD), and coadministration of water-soluble polymer (hydroxypropyl-methylcellulose; HPMC) and cyclodextrins (CDs) on aqueous solubility and oral bioavailability of glibenclamide (GBA). GBA was administered orally and intravenously to dogs. GBA showed AL-type diagram for s-CD and Ap-type diagrams for both s-CD derivatives studied. HPMC (0.05 %) enhanced the solubilizing effect of CDs but did not affect the type of phase-solubility diagram. Orally administered GBA and its physical mixture with HP-s-CD showed poor absolute bioavailability while GBA/s-CD, GBA/HP-s-CD and GBA/(SBE)7m-s-CD enhanced significantly the absolute bioavailability of GBA. Orally administered GBA/s-CD/HPMC and GBA/(SBE)7m-s-CD/HPMC showed similar absolute bioavailability compared to formulations not containing HPMC even though 80 % (in the case of (SBE)7m-s-CD) or 40 % (in the case of s-CD) less CD was used. In conclusion, the oral bioavailability of GBA was significantly increased by CD-complexation and the amount of CD needed was significantly reduced by co-administration of HPMC.

Co-administration of a water-soluble polymer increases the usefulness of cyclodextrins in solid oral dosage forms.

Method for evaluating drug release from liposomes in sink conditions

Various novel morpholinyl- (3a,b) and methylpiperazinylacyloxyalkyl (3c−f) esters of 2-(6-methoxy-2-naphthyl)propionic acid were synthesized and evaluated in vitro for topical drug delivery as potential prodrugs of naproxen (1). Compounds 3a−f were prepared by coupling the corresponding naproxen hydroxyalkyl ester with the morpholinyl- or (4-methyl-1-piperazinyl)acyl acid in the presence of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine (DMAP) and quantitatively hydrolyzed (t1/2 = 1−26 min) to naproxen in human serum. Compounds 3c−f showed higher aqueous solubility and similar lipophilicity, determined by their octanol−buffer partition coefficients (log Papp), at pH 5.0 when compared to naproxen. At pH 7.4 they were significantly more lipophilic than naproxen. The best prodrug 3c led to a 4- and 1.5-fold enhancement of skin permeation when compared to naproxen at pH 7.4 and 5.0, respectively. The present study indicates using a methylpiperazinyl group yields prodrugs that are partially un-io...

Synthesis and in Vitro Evaluation of Novel Morpholinyl- and Methylpiperazinylacyloxyalkyl Prodrugs of 2-(6-Methoxy-2-naphthyl)propionic Acid (Naproxen) for Topical Drug Delivery

Piperazinylalkyl prodrugs of naproxen improve in vitro skin permeation

Bisphosphonate prodrugs: synthesis and in vitro evaluation of alkyl and acyloxymethyl esters of etidronic acid as bioreversible prodrugs of etidronate.

Hannu Taipale

Papers

Co-administration of a water-soluble polymer increases the usefulness of cyclodextrins in solid oral dosage forms.

Method for evaluating drug release from liposomes in sink conditions

Synthesis and in Vitro Evaluation of Novel Morpholinyl- and Methylpiperazinylacyloxyalkyl Prodrugs of 2-(6-Methoxy-2-naphthyl)propionic Acid (Naproxen) for Topical Drug Delivery

Piperazinylalkyl prodrugs of naproxen improve in vitro skin permeation

Bisphosphonate prodrugs: synthesis and in vitro evaluation of alkyl and acyloxymethyl esters of etidronic acid as bioreversible prodrugs of etidronate.