<b>Pharmacology of Second Messengers: A Critical Appraisal</b>

Garattini, Silvio

doi:10.3109/03602539208996292

Cited by 3 publications

(1 citation statement)

References 322 publications

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“…Aspirin irreversibly blocks cyclooxygenase leading to the inhibition of thromboxane A, (an aggregating agent) synthesis in platelets; since platelets do not have genes, further cyclooxygenase will be synthesized when new platelets form. Therefore, repeated low or high doses of aspirin will have the same antiaggregating effect over a given period of time (3). Another example is methylpredinosolone; a dose of one or 15 mg/kg i.v.…”

Section: Higher Concentrations Greater Effects?mentioning

confidence: 98%

Contributions of Toxicokinetics to Toxicology of Drugs

Garattini

1994

Drug Information Journal

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Toxicology is a discipline which employs a series of tests to predict the toxic effects of drugs in man. This prediction is made by extrapolating data from animal studies and-with a number of notable exceptions-has been relatively useful in developing new drugs. There is still room for considerable improvement, however, in the available methods. In synthesis, the toxic effect of a drug depends on two major components: the concentration present at the target site and the sensitivity of the target site. These are both subject to important changes in relation to a large number of variables including the animal species, strain, age, the environment, and the pathology. This paper concentrates on one of these components, the levels of the drug at the target site; the discipline involved in these studies is known as toxicokinetics and shares various methods with pharmacokinetics. LARGER DOSES, HIGHER CONCENTRATIONS?THE TOXICOLOGIST USUALLY employs increasing doses of a drug in order to obtain toxic effects; the dose inducing a toxic effect (biochemical, functional, or morphological) is then compared with the dose inducing the desired pharmacological effect and the ratio between the two is considered the safety margin or the therapeutic index. This approach assumes that the concentrations of a drug at the site of action are directly proportional to the dose and this assumption is frequently the cause of errors if it is not experimentally verified. Raising the dose can result in concentrations which are sometimes higher and sometimes lower than the increase (1). There are several reasons for this, including saturation of the enzymes devoted to the metabolism or excretion of the drug, or saturation of intestinal absorption. In other cases the same dose may result in different concentrations depending on the route of administration or on the concentration of the administered solution; for instance, monosodium glutamate (MSG) can induce brain lesions, particularly in the nucleus arcuatus of the hypothalamus, when given by gavage but not when mixed with food, even at a dose 20 times higher. The reason for this lies in the different plasma levels of MSG reached in the two conditions. Furthermore, if MSG is given at the same dose in a 20% or 2% solution, the former produces double the plasma levels of the latter (2). Thus, a better evaluation of the therapeutic index can be made by comparing, not the dose, but the plasma concentrations at 255

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Section: Higher Concentrations Greater Effects?mentioning

confidence: 98%

Contributions of Toxicokinetics to Toxicology of Drugs

Garattini

1994

Drug Information Journal

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Therapeutic potential of protein kinase C inhibitors

et al. 1993

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The serine/threonine protein kinase, protein kinase C (PKC) is a family of closely related isoforms which are physiologically activated by diacylglycerol generated by the binding of a variety of agonists to their cellular receptors. Free fatty acids may also play a role in activating PKC. The enzyme apparently mediates a wide range of signal transduction processes in cells and, therefore, inhibitors directed selectively against PKC may have wide-ranging therapeutic potential. This review highlights the evidence that inappropriate activation of PKC occurs in a number of disease states. Such evidence, however, is often seriously flawed because it relies on the use of phorbol esters, which are potent and direct PKC activators but may not mimic the physiological triggering of the enzyme in cells, or on the use of non-selective protein kinase inhibitors such as H7 and staurosporine. A new generation of bis-indolylmaleimides, derived from the lead provided by staurosporine, shows a high degree of selectivity for PKC over closely related protein kinases and such agents may provide more appropriate tools to investigate the role of PKC in cellular processes.

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Protein kinase C: a family of isoenzymes with distinct roles in pathogenesis

Lord

Pongrácz²

1995

Molecular Pathology

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Pharmacology of Second Messengers: A Critical Appraisal

Cited by 3 publications

References 322 publications

Contributions of Toxicokinetics to Toxicology of Drugs

Contributions of Toxicokinetics to Toxicology of Drugs

Therapeutic potential of protein kinase C inhibitors

Protein kinase C: a family of isoenzymes with distinct roles in pathogenesis

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