Biochemical pharmacology
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Biochemical pharmacology · Mar 2006
ReviewThe role of pharmacodynamic research in the assessment and development of new antibacterial drugs.
Antibacterial resistance continues to increase world wide, with some bacterial pathogens exhibiting resistance to virtually all available drugs. As the plague of antibacterial resistance continues to grow and create serious therapeutic problems, it is essential that the development of new antibacterial agents continue. ⋯ Characterization of these pharmacodynamic properties for a new drug in development can help direct the design of the best dose and dosing strategy for clinical trials. This review will focus on the tools, methods, and strategies used to characterize the pharmacodynamics of antibacterial agents and aide in their development for clinical use.
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Biochemical pharmacology · Jan 2006
CO from enhanced HO activity or from CORM-2 inhibits both O2- and NO production and downregulates HO-1 expression in LPS-stimulated macrophages.
Carbon monoxide (CO) arising from heme degradation, catalyzed particularly by the stress-inducible heme oxygenase-1 (HO-1), has recently been demonstrated to provide cytoprotection against cell death in macrophages stimulated with bacterial lipopolysaccharide (LPS). In the present study, we determined the effects of CO on the production of reactive oxygen species (ROS) and nitric oxide (NO) by the LPS-stimulated RAW 264.7 macrophages. In addition, effect of CO-exposure on the production of superoxide (O(2)(-)) in the phorbol myristate acetate (PMA)-stimulated PLB-985 neutrophils was determined. ⋯ Combined, these results indicated that enhanced HO activity is essential for the survival of LPS-stimulated macrophages. Thus, upregulation of HO-1 and overproduction of CO may allow the survival of LPS-stimulated macrophages; first, by eliminating the free heme to prevent Fenton reaction, second, by limiting the availability of free heme required for induction of NO-producing heme enzyme (i.e., iNOS), third, by limiting additional production of O(2)(-) and NO via CO-derived inhibition on the activities of heme enzymes like NADPH oxidase and iNOS, respectively. CO may allow the LPS-activated macrophages to return back to the normal quiet state insensitive to additional stimuli causing oxidative stress.
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Biochemical pharmacology · Dec 2005
Amitriptyline prevents thermal hyperalgesia and modifications in rat spinal cord GABA(B) receptor expression and function in an animal model of neuropathic pain.
Using an animal model of neuropathic pain, behavioral and biochemical experiments were performed to assess the effects of this condition on pain threshold and GABA(B) receptor sensitivity and subunit gene expression in the rat lumbar spinal cord. The results indicate that partial sciatic nerve ligation decreases thermal and mechanical pain withdrawal latencies, and increases baclofen-stimulated [35S]GTPgammaS binding and GABA(B) receptor subunit gene expression in the rat lumbar spinal cord, suggesting that neuropathic pain may be due, in part, to a deficiency in GABAergic transmission. The experiments also demonstrate that daily administration (10 mg/kg, i.p.) of amitriptyline, a tricyclic antidepressant used for the treatment of neuropathic pain, for 1 week after surgery prevents the decline in thermal pain threshold, the increase in GABA(B2) gene expression, and development of increased GABA(B) receptor function in spinal cord resulting from nerve damage. These findings indicate that the efficacy of amitriptyline as a treatment for neuropathic pain may be related to an ability to maintain spinal cord GABA(B) receptor activity.
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Biochemical pharmacology · Oct 2005
ReviewNon-COX-2 targets and cancer: expanding the molecular target repertoire of chemoprevention.
Chemoprevention represents a highly promising approach for the control of cancer. That nonsteroidal anti-inflammatory drugs (NSAIDs) prevent colon and other cancers has led to novel approaches to cancer prevention. ⋯ Here we review several pathways of the eicosanoid cascade that are relevant to cancer; summarize the evidence regarding the role of COX-2 as a target for cancer prevention; and discuss several of the molecular targets that may mediate the chemopreventive effect of NSAIDs. The clinically modest results obtained to date with COX-2 specific inhibitors used in cancer prevention; the multiple COX-2-independent targets of both NSAIDs and COX-2 inhibitors; and the limitations of some COX-2 inhibitors indicate that exploiting these (non-COX-2) molecular targets will likely yield effective new approaches for cancer chemoprevention.
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Biochemical pharmacology · Sep 2005
Effects of the cyclin-dependent kinase inhibitor CYC202 (R-roscovitine) on the physiology of cultured human keratinocytes.
CYC202 (R-roscovitine) is a potent cyclin-dependent kinase inhibitor, investigated as a potential anti-cancer agent. The knowledge of the action of this pharmacological agent on normal human cells is still limited. In this study, we have explored the effects of the cyclin-dependent kinase inhibitor CYC202 on normal human epidermal keratinocytes. ⋯ These effects were strongly dependent on cell density and were observed only in highly proliferative keratinocytes. We concluded that CYC202 although highly potent against cancer cells inhibits also the proliferation and induces early apoptotic events in autocrine culture of normal human keratinocytes, activates p38 MAP kinase pathway and alters the expression of the epidermal differentiation markers. These results suggest that despite this potency against tumour cells, CYC202 must be used attentively in the clinical practice.