Novel soft steroids: effects on cell growth in vitro and on wound healing in the mouse

Bodor, Nicholas; Kiss-Buns, Susan Tatar; Buris, László

doi:10.1016/0039-128x(91)90032-q

Cited by 18 publications

(8 citation statements)

References 13 publications

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“…In other tissues in which wound healing has been studied extensively, e.g., the cornea (Bodor and Varga, 1990) and skin (William and Mertz, 19781, topical glucocorticoids decreased the formation of the fibrotic scar. These steroids act by modulating several aspects of the wound healing process, i.e., epithelialization, including cell migration (William and Mertz, 19781, fibroblast proliferation (Bodor et al, 1991;Weber, 19921, collagen deposition (Goforth and Gudas, 19801, and macrophage recruitment (Leibovich and Ross, 1975). We therefore used topical glucocorticoids to modulate the formation of the lesion interface after cerebral cortical stab wounds in adult rats.…”

Section: Introductionmentioning

confidence: 99%

“…extensively, e.g., the cornea (Bodor and Varga, 1990) and skin (William and Mertz, 1978), topical glucocorticoids decreased the formation of the fibrotic scar. These steroids act by modulating several aspects of the wound healing process, i.e., epithelialization, including ce11 migration (William and Mertz, 1978), fibroblast proliferation (Bodor et al. 1991;Weber.…”

Section: Introductionmentioning

confidence: 99%

“…and decrease macrophage recruitment (Leibovich, 1 9 7 3 , epithelial migration (William and Mertz, 1978), fibroblast proliferation (Bodor, 1991;Weber, 1992), collagen deposition (Go forth, 1980), and glycosaminoglycan synthesis (Sarnstrand et al,, 1982). Glucocorticoids also modulate extracellular matrix secretion and synthesis as seen in an animal model of murine nephritis (Nakamura et al, 1992), in fibroblasts (Ekblom, 1993), in cytotrophoblasts (Guller et al, 1993), in a rat pancreatic acinar ceIl line (Stallmach et al, 1992) and in PC12 cells (Zhang et al, 1993).…”

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Topical glucocorticoids modulate the lesion interface after cerebral cortical stab wounds in adult rats

David

1996

Glia

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A lesion interface, consisting of a glia limitans lined by a laminin‐rich basal lamina and leptomeningeal cells, forms within 2–3 weeks after penetrating wounds to the adult mammalian central nervous system (CNS). This interface prevents the growth of axons across the lesion. We have examined the effects of topically applied steroids on the formation of such an interface after stab wounds to the adult rat cerebral cortex. Immediately after lesioning, the surface of cortex in the region of the wound was treated with a topical application of either 0.1% halcinonide or 0.05% betamethasone dipropionate or their respective placebos. Cryostat sections through the lesioned area were obtained 3 weeks later and assessed by immunofluorescence. Steroid treatment attenuated all components of the lesion. The continuous anti‐laminin labeling along the lesion in untreated rats became patchy after steroid treatment. The number of leptomeningeal cells that infiltrated into the wound was reduced in the laminin‐negative regions in steroid‐treated rats. In addition, astrocytic processes in the laminin‐negative regions after steroid treatment were loosely arranged, compared with the tightly packed parallel processes forming the glia limitans in laminin‐positive regions in controls. The mechanism of steroid‐mediated attenuation of the lesion interface was examined in vitro. Betamethasone but not halcinonide reduced laminin secretion slightly in leptomeningeal cell cultures, but both steroids reduced cell proliferation. These results suggest that steroids modulate the formation of the lesion interface after CNS injury, at least in part by decreasing leptomeningeal cell proliferation. Such modulation of the lesion interface by steroids or other agents may permit the growth of axons across the lesion site and thus could enhance the overall degree of axon regeneration if other factors such as neurotrophic support and neutralization of axon growth inhibitory molecules are optimized. © 1996 Wiley‐Liss, Inc.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Topical glucocorticoids modulate the lesion interface after cerebral cortical stab wounds in adult rats

David

1996

Glia

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“…A number of them maintained high binding affinity at the benzodiazepine receptor (<50 nM), showed good (>100-fold) separation of activity between the (active) ester and the (inactive) acid, and were able to cause loss of the righting reflex (LRR) in rats, an effect associated with benzodiazepine full agonism. Structures such as CNS 7259X (164) [367,369] and CNS 7056 (166) [368,370] (Fig. 37) were selected for development, which has been taken over by CeNeS and later PAION.…”

Section: Soft Benzodiazepine Analogsmentioning

confidence: 99%

Retrometabolism‐Based Drug Design and Targeting

Bodor

Buchwald

2010

Burger's Medicinal Chemistry and Drug Discovery

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Retrometabolic drug design (RMDD) approaches are systematic methodologies aimed to design safe compounds with an improved therapeutic index. RMDDs thoroughly integrate structure– activity and structure‐metabolism considerations into the entire design process and incorporate two major concepts aimed to design soft drugs and chemical delivery systems, respectively. Soft drugs (SDs) are new, active therapeutic agents designed to undergo predictable metabolism resulting in inactive metabolites after exerting their desired therapeutic effect(s). Chemical delivery systems (CDSs) are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. Here, we present a comprehensive review including a general overview of the RMDD principles and a large number of specific examples from various pharmacological areas, including many recent developments, to illustrate RMDD concepts. Whenever possible, the rationale for the design as well as the pharmacokinetic and pharmacodynamic properties of the new therapeutic agents are briefly summarized and compared to those of the other compounds used in the same field.

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“…A considerable number of attempts were aimed to improve this situation. Recently, a classic soft drug approach started in our laboratories [122][123][124][125][126][127][128][129][130][131][132][133][134][135][136] ended successfully and yielded loteprednol etabonate (58, chloromethyl 17␣-ethoxycarbonyloxy-11␤-hydroxy-3-oxoandrosta-1,4-diene, 17␤carboxylate, Fig. 22) an active corticosteroid that lacks serious side effects and that received final FDA approval in 1998 as the active ingredient of two ophthalmic preparations, Lotemax™ and Alrex™.…”

Section: F Soft Corticosteroidsmentioning

confidence: 99%

Soft drug design: General principles and recent applications

2000

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Soft drug design represents a new approach aimed to design safer drugs with an increased therapeutic index by integrating metabolism considerations into the drug design process. Soft drugs are new therapeutic agents that undergo predictable metabolism to inactive metabolites after exerting their therapeutic effect. Hence, they are obtained by building into the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified. In an attempt to systematize and summarize the related work done in a number of laboratories, including ours, the present review presents an overview of the general soft drug design principles and provides a variety of specific examples to illustrate the concepts. A number of already marketed drugs, such as esmolol, remifentanil, or loteprednol etabonate, resulted from the successful application of such design principles. Many other promising drug candidates are currently under investigation in a variety of fields including possible soft antimicrobials, anticholinergics, corticosteroids, β‐blockers, analgetics, ACE inhibitors, antiarrhythmics, and others. Whenever possible, pharmacokinetic and pharmacodynamic properties are briefly summarized and compared to those of other compounds used in the same field. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 1, 58–101, 2000.

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Novel soft steroids: effects on cell growth in vitro and on wound healing in the mouse

Cited by 18 publications

References 13 publications

Topical glucocorticoids modulate the lesion interface after cerebral cortical stab wounds in adult rats

Topical glucocorticoids modulate the lesion interface after cerebral cortical stab wounds in adult rats

Retrometabolism‐Based Drug Design and Targeting

Soft drug design: General principles and recent applications

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