Metabolic protection

Butaprost (82) not only has the typical C-15 hydroxyl of the natural prostaglandins moved to C-16, as do several of the analogues discussed above, but it has a rather interesting gem dialkyl substitution at C-17, presumably for metabolic protection, in the form of a cyclobutyl ring. It is a bronchodilator and is prepared in a manner analogous to that of rioprostil discussed above [17]. 

El-Bacha RS, Minn A. Drug metabolizing enzymes in cerebrovascular endothelial cells afford a metabolic protection to the brain. Cell Mol Biol 1999 45 15-23 Minn A, Ghersi-Egea JF, Perrin R, Leininger B, Siest G. Drug metabolizing enzymes in the brain and cerebral microvessels. Brain Res Rew 1991 16 65-82. 

The effects of coenzyme Q10 on coronary artery disease and chronic stable angina are modest but appear promising. A theoretical basis for such benefit could be metabolic protection of the ischemic myocardium. Double-blind, placebo-controlled trials have demonstrated that coenzyme Q10 supplementation improved a number of clinical measures in patients with a history of acute myocardial infarction (AMI). Improvements have been observed in lipoprotein a, high-density lipoprotein cholesterol, exercise tolerance, and time to development of ischemic changes on the electrocardiogram during stress tests. In addition, very small reductions in cardiac deaths and rate of reinfarction in patients with previous AMI have been reported (absolute risk reduction 1.5%). 

The transport-enhancing effect of Zot was shown to be reversible and nontoxic (Fasano et al. 1991 Cox et al. 2002). More recently a smaller fragment of Zot in the size of 12 kDa referred to as /1G was identified (Di Pierro et al. 2001). AG displayed significant potential as permeation enhancer. In vitro studies showed that it is capable of significantly increasing the apparent permeability coefficients for a wide variety of drugs across Caco-2 monolayer (Salama et al. 2003, 2004). In the presence of peptidase inhibitors AG improved the bioavailability of mannitol, inulin and PEG 4000 after intraduodenal administration to rats (Salama et al. 2003, 2004). In another in vivo study the oral bioavailability of cyclosporin A was increased up to 50-fold due to the co-administration of AG when metabolic protection was provided (Salama et al. 2005). Results of this study are illustrated in Fig. 5.2. 

Drug metabolizing enzymes in cerebrovascular endofhelial cells afford a metabolic protection to the brain. Cellular and Molecular Biology (Noisy-le-Grand, France), 45, 15-23. 

A large array of agents has been tested for metabolic protection of the myocardium, but most have been discarded either after proving ineffective in clinical trials or protective in only a limited subset of STEMI patients. Some interest in glucose-insulin-potassium (GIK) continues to exist, but it is likely that the volume load associated with its administration will limit GIK to patients without significant pump dysfunction (76). 

Tandon, M., et al. The design and preparation of metabolically protected new arylpiperazine 5-HTia ligands. Bioorg. Med. Chem. Lett. 2004, 14, 1709-1712. 

Vina J., Sastre, J., Anton, V., Bruseghini, L., Esteras, A., and Asensi, M., 1992, Effect of aging on glutathione metabolism. Protection by antioxidants, in Free Radicals and Aging (I. Emerit and B. Chance, eds.), pp. 136-144, Birkhauser, Basel. 

Maritz, G. S., 1993, The influence of maternal nicotine exposure on neonatal lung metabolism Protective effect of ascorbic acid. Cell Biol. Internat. 17 579-585. 

Nitronaphthalene is metabolized to the carcinogenic 2-naphthylarnine in the human body (39). Respirators, protective clothing, proper engineering controls, and medical monitoring programs for workers involved in making by-product 2-nitronaphthalene should be used. 

K. A. HassaH, The Biochemistry and Uses of Pesticides Structure, Metabolism, Mode of Action and Uses in Crop Protection, 2nd ed., VCH VedagsgeseUschaft, Weinheim, Germany, 1990. 

FIGURE S.47 The role of glutathione and metabolic pathways involved In the protection of tissues against Intoxication by electrophiles, oxidants and active oxygen species. (Used with permission.)... 

It is hoped that these volumes will be useful not only to the chemist who wishes to carry out synthesis in the steroid field, but also to the broader group of organic chemists who are interested in carrying out selective and stereo-chemically defined reactions, as well as protective chemistry on extraneous functional groups, during a broad range of synthetic applications. The chapter on the introduction of deuterium and by inference tritium into steroids was included because of the importance of this technique in mechanistic and metabolic studies both in the steroid and nonsteroid field. 

Although gap junctions allow cells to communicate metabolically under normal conditions, the ability to close gap junctions provides the tissue with an important intercellular regulation mechanism. In addition, gap junctions provide a means to protect adjacent cells if one or more cells are damaged or... 

Organoselenium compounds in particular, once ingested, are slowly released over prolonged periods and result in foul-smelling breath and perspiration. The element is also highly toxic towards grazing sheep, cattle and other animals, and, at concentrations above about 5 ppm, causes severe disorders. Despite this, Se was found (in 1957) to play an essential dietary role in animals and also in humans — it is required in the formation of the enzyme glutathione peroxidase which is involved in fat metabolism. It has also been found that the Incidence of kwashiorkor (severe protein malnutrition) in children is associated with inadequate uptake of Se, and it may well be involved in protection... 

Gemeprost (73 16.16-dimethvl-trans-A -prostaglandin-E]) is dramatically more potent on a dosage basis as an abortifacient than prostaglandin E2 itself and has fewer side effects. The gem-dimethyl groups at C-16 protect the alcohol moiety at C-15 from rapid metabolic oxidation. 

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