Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042384 (vasculitis)
 20,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently reported that norepinephrine and angiotensin II activate the Ras/mitogen-activated protein (MAP) kinase pathway through generation of a cytochrome P450 (CYP450) and lipoxygenase metabolites. The purpose of this study was to determine the contribution of Ras/MAP kinase to deoxycorticosterone acetate (DOCA)-salt-induced hypertension in rats. Administration of DOCA and 1% saline drinking water to uninephrectomized rats for 6 weeks significantly elevated mean arterial blood pressure (MABP) (166+/-5 mm Hg, n=19) compared with that of normotensive controls (95+/-5 mm Hg, n=7) (P<0.05). The activity of Ras and MAP kinase measured in the heart was increased in DOCA-salt hypertensive rats. Infusion of the Ras farnesyl transferase inhibitors FPT III (138 ng/min) and BMS-191563 (694 ng/min) significantly (P<0.05) attenuated MABP to 139+/-4 mm Hg (n=14) and 126+/-1 mm Hg (n=4), respectively. Moreover, infusion of MAP kinase kinase inhibitor PD-98059 (694 ng/min) also reduced MABP in hypertensive rats. Morphological studies of the kidney showed that treatment of rats with FPT III, which reduced Ras activity, minimized the hyperplastic occlusive arteriosclerosis and fibrinoid vasculitis observed in untreated hypertensive rats. In addition, the rise in CYP450 activity and MABP in hypertensive rats was prevented by the CYP450 inhibitor aminobenzotriazole (50 mg/kg) and was associated with a decrease in Ras and MAP kinase activity in the heart. These data suggest that the Ras/MAP kinase pathway contributes to DOCA-salt-induced hypertension and associated vascular pathology consequent to activation of CYP450.
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PMID:Contribution of Ras GTPase/MAP kinase and cytochrome P450 metabolites to deoxycorticosterone-salt-induced hypertension. 1064 41

The so called leukotriene antagonists or, more accurately, the leukotriene modifiers are a rather heterogeneous set of drugs that work by several mechanisms. Such mechanisms include: (i) 5-lipoxygenase enzyme inhibition (e.g. zileuton); (ii) 5-lipoxygenase-activating-protein inhibition (e.g. quiflapon, BAYx 1005); (iii) LTD4-receptor antagonism (e.g. zafirlukast, montelukast, MK-571, pranlukast). The first leukotriene modifiers tested (L-649,923 and tomelukast) had adverse gastrointestinal effects. Since then, several leukotriene modifiers have been marketed, including zafirlukast, zileuton and montelukast. Zafirlukast has been associated with 8 cases of Churg-Strauss syndrome, although these were probably not caused by zafirlukast. It is more likely that this syndrome is related to the underlying illness, which was masked by corticosteroids, and revealed after zafirlukast-mediated asthma treatment allowed steroid withdrawal and unmasking of underlying vasculitis. The main adverse effects of zileuton include liver function test abnormalities, while montelukast, the most recently marketed, has so far shown minimal adverse effects. Zafirlukast causes a decrease in warfarin clearance and a clinically significant increase in prothrombin time, probably by cytochrome P450 isoenzyme interactions. Moreover, terfenadine decreases zafirlukast maximum serum concentrations. Calcium antagonists, cyclosporin, cisapride and astemizole are metabolised via the cytochrome P450 system, and interactions with leukotriene modifiers can be expected.
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PMID:Tolerability of leukotriene modifiers in asthma: a review of clinical experience. 1803 Nov 50

A drug interaction that seemed to contribute to sudden worsening of corticosteroid-stabilized vasculitis stimulated this review. A large number of drugs share with corticosteroids critical phase I metabolic steps mediated by hepatic cytochrome P450 (CYP) enzymes, particularly the individual enzyme CYP3A4. In their metabolic interaction with CYP3A4 as substrates, a growing number of these drugs have the potential to induce (upregulate) hepatic CYP3A4 levels, resulting in accelerated clearance (and reduced efficacy) of concomitantly administered glucocorticoids, which are also CYP3A4 substrates. Many other drugs can have the opposite effect, that is, they can inhibit CYP3A4 function by tight binding to its active site. This can result in reduced clearance (and augmented efficacy) of concurrently administered glucocorticoids. Current knowledge of this type of drug interaction, the drugs to watch out for, and multiple clinical reports of altered corticosteroid efficacy, are reviewed after presentation of the case illustrating potential relevance to the management of rheumatic diseases.
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PMID:Drug interactions affecting the efficacy of corticosteroid therapy a brief review with an illustrative case. 1907 74

Myeloperoxidase (MPO) is a heme peroxidase that catalyzes the production of hypochlorous acid. Clinical evidence suggests a causal role for MPO in various autoimmune and inflammatory disorders including vasculitis and cardiovascular and Parkinson's diseases, implying that MPO inhibitors may represent a therapeutic treatment option. Herein, we present the design, synthesis, and preclinical evaluation of N1-substituted-6-arylthiouracils as potent and selective inhibitors of MPO. Inhibition proceeded in a time-dependent manner by a covalent, irreversible mechanism, which was dependent upon MPO catalysis, consistent with mechanism-based inactivation. N1-Substituted-6-arylthiouracils exhibited low partition ratios and high selectivity for MPO over thyroid peroxidase and cytochrome P450 isoforms. N1-Substituted-6-arylthiouracils also demonstrated inhibition of MPO activity in lipopolysaccharide-stimulated human whole blood. Robust inhibition of plasma MPO activity was demonstrated with the lead compound 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999, 8) upon oral administration to lipopolysaccharide-treated cynomolgus monkeys. On the basis of its pharmacological and pharmacokinetic profile, PF-06282999 has been advanced to first-in-human pharmacokinetic and safety studies.
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PMID:Discovery of 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999): A Highly Selective Mechanism-Based Myeloperoxidase Inhibitor for the Treatment of Cardiovascular Diseases. 2650 51