Administration of precursor

Aromatic biguanides such as proguanil (181) have been found useful as antimalarial agents. Investigation of the metabolism of this class of drugs revealed that the active compound was in fact the triazine produced by oxidative cyclization onto the terminal alkyl group. The very rapid excretion of the active entity means that it cannot be used as such in therapy. Consequently, treatment usually consists in administration of either the metabolic precursor or, alternately, the triazine as some very insoluble salt to provide slow but continual release of drug. 

The nigrostriatal system is predominantly involved in motor control, which is particularly evident in Parkinson s disease (PD), where a progressive loss of these neurons results in loss of motor function. In the early stages of the disorder, the motor impairment can be reversed by the administration of the dopamine precursor l-DOPA (L-3,4-dihydroxyphenylalanine), which bypasses the need for TH in dopamine... 

Histamine is synthesised by decarboxylation of histidine, its amino-acid precursor, by the specific enzyme histidine decarboxylase, which like glutaminic acid decarboxylase requires pyridoxal phosphate as co-factor. Histidine is a poor substrate for the L-amino-acid decarboxylase responsible for DA and NA synthesis. The synthesis of histamine in the brain can be increased by the administration of histidine, so its decarboxylase is presumably not saturated normally, but it can be inhibited by a fluoromethylhistidine. No high-affinity neuronal uptake has been demonstrated for histamine although after initial metabolism by histamine A-methyl transferase to 3-methylhistamine, it is deaminated by intraneuronal MAOb to 3-methylimidazole acetic acid (Fig. 13.4). A Ca +-dependent KCl-induced release of histamine has been demonstrated by microdialysis in the rat hypothalamus (Russell et al. 1990) but its overflow in some areas, such as the striatum, is neither increased by KCl nor reduced by tetradotoxin and probably comes from mast cells. 

NMOR is a potent hepatocarcinogen in the rat and induces tracheal and nasal cavity tumors in the Syrian golden hamster (43, 44, 45). It is formed readily from nitrite and morpholine in vitro and administration of these precursors to rodents causes tumors indicative of NMOR formation in vivo (44, 55, 56), NMOR has been detected in crankcase emissions of diesel engines and in factories engaged in rubber and tire manufacturing (57, 58). 

Levodopa, a dopamine precursor, is the most effective agent for PD. Patients experience a 40% to 50% improvement in motor function. It is absorbed in the small intestine and peaks in the plasma in 30 to 120 minutes. A stomach with excess acid, food, or anticholinergic medications will delay gastric emptying time and decrease the amount of levodopa absorbed. Antacids decrease stomach acidity and improve levodopa absorption. Levodopa requires active transport by a large, neutral amino acid transporter protein from the small intestine into the plasma and from the plasma across the blood-brain barrier into the brain (Fig. 29-2). Levodopa competes with other amino acids, such as those contained in food, for this transport mechanism. Thus, in advanced disease, adjusting the timing of protein-rich meals in relationship to levodopa doses may be helpful. Levodopa also binds to iron supplements and administration of these should be spaced by at least 2 hours from the levodopa dose.1,8,16,25... 

Zhang Y, Yoneyama H, Wang Y, et al. Mobilization of dendritic cell precursors into the circulation by administration of MIP-lalpha in mice. J Natl Cancer Inst 2004 96(3) 201-209. 

In more recent studies the use of HPLC allowed isolation and counting of individual sterols after administration of labelled precursors. The sterols isolated from mantles and viscera of the nudibranch Doris verrucosa were identified as cholestanol, cholesterol, 24-dehydrocholesterol and 7-dehydrocholesterol [103]. After injection of dl-[2-14C]-mevalonic acid DBED salt, cholesterol (57) and 7-dehydrocholesterol (58) were isolated as the acetates by reversed phase HPLC. Both sterols were found significantly labelled specific radioactivity associated with 7-dehydrocholesterol was higher by one order of magnitude than that associated with cholesterol. This fact would indicate either that the reduction of the A1 double bond of 7-dehydrocholesterol to afford cholesterol occurs at a low rate, or that the cholesterol found in D. verrucosa comes partly from a dietary source. 

The 5-HT syndrome can also be produced by a number of treatments whose primary actions are not expressed at serotonergic receptors. For example, in MAOI-pretreated rats, the intraventricular administration of dopamine or systemic treatment with the dopamine precursor /-dihydroxyphenylalanine (/-DOPA) in combination with an MAOI results in the 5-HT syndrome... 

Mechanistic insight into this process was obtained by administration of labeled trideca- or undeca-3,6,9-trienoic acid instead of the natural C12 precursor (Figure 2). In this case, the artificial 2H metabolites can be analyzed by mass spectrometry without interference from the plants own 1H metabolites, since a homo- or norectocarpene is formed. The sequence of the oxidative decarboxylation/cyclization reaction proceeds without loss of 2H atoms from the double bonds but with loss of a single 2H atom from certain methylene groups of the precursor acids (Figure 3). If C(l) and a 2H atom from C(5) of the labeled precursor is lost, finavarrene is the product of the reaction channel. If the methylene group... 

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