Precursor administration

Stable Isotope Administration. The biosynthesis of I. penne 11 i i glucose esters was investigated using deuterium labeled precursors. Compound leaves of L. pennellii were removed and briefly rinsed in 100% EtOH before precursor administration. The preincubation sample of the trichome exudate was saved to establish fatty acyl composition prior to precursor feeding its removal served to increase the proportion of labeled glucose esters after precursor incubations. 

Fig. 17 a-c. Electrophoretic separations of RNA from salivary gland cell cytoplasm a, gastric caeci b and midgut c 2 days after precursor administration to the medium (25 pCi [ H]uridine and 25 pCi [ H]cytidine in 5 ml of culture medium for 20 h after which the animals were left in isotope-free medium for a further 48 h before killing). It can be seen that the late mRNA is only present in salivary gland cell cytoplasm. (After Edstrom and Tan-guay, 1974)... 

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. 

Prodrug. A precursor that, after administration and subsequent transformation in the body, forms the active 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... 

GHB has been used both for legitimate clinical and chnical research purposes and for a range of iUicit purposes. It was marketed legally in the United States until 1990, when the U.S. Food and Drug Administration (FDA) banned its sale to consumers. Except for the one indication described later in this section, GHB is a Schedule I controlled substance without other FDA-approved indications. The FDA has also declared y-butyrolactone (GBL) as a List I chemical and 1,4-butanediol (1,4-BD) as a Class I health hazard, practically designating these GHB precursors, which are also industrial solvents, as illicit and unapproved new drugs (National Institute on Drug Abuse 2000). 

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). 

Dyn is not yet known, it is likely that such changes reflect variations in the activity of the associated pathways. One possible explanation is that increases in neuropeptide tissue levels are due to decreased release of the transmitter, which dunmishes the extracellular peptide metabolism and results in accumulation of these peptide substances. Another possible contributing factor is a drug-related alteration in neuropeptide synthesis. For example, Bannon et al. (1987) reported that METH administration increased the quantity of striatal messenger RNA for the SP precursor preprotachykinin. Thus, increases in peptide synthesis might contribute to increases in peptide content caused by treatment with METH or the other amphetamine analogs. 

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 acute and chronic effects of Li+ in patients are quite different (reviewed by Goodnick [146]). Initially, Li+ treatment causes an increase in the level of 5-HT and decrease in 5-HT uptake in platelets, with an increase in the level of 5-HIAA in the CSF. The neuroendocrine responses to the 5-HT precursors, tryptophan and 5-hydroxytryptophan [160], and to flenfluramine [161], a 5-HT releaser, are enhanced by Li+. Thus the combined effect of acute Li+ treatment is to increase the efficiency of synaptic 5-HT. However, chronic Li+administration results in almost the opposite effect, resulting in responses close to the levels... 

If the RANKL/OPG system is a final effector on the biology of osteoclasts, then this system should be the basis for the antiresorptive effects of estrogen. Indeed, estrogen stimulates OPG synthesis for osteoblastic cells (Hofbauer et al. 1999), estrogen deficiency induced by OVX results in a decrease in OPG and increased RANKL production, an action that is prevented by estradiol administration, and OPG administration prevents bone loss induced by OVX (Simonet et al. 1997 Hofbauer et al. 2000 Hofbauer 1999). In addition, estrogen can suppress RANKL and M-CSF-induced differentiation of myelomonocytic precursors into multinucleated TRAP+ osteoclasts through an ER-dependent mechanism that does not require mediation by stromal cells (Shevde et al. 2000). Finally, treatment with estradiol inhibits the response of osteoclast precursors to the action of RANKL (Srivastava et al. 2001). 

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