Dose-response, amino acids

Finally, in another study related to nutrition and the immune response in the aged, old mice were given oral doses of two amino acids (qv), lysine and arginine. The treated mice showed evidences of recovered mitogenic responsiveness, expression of T-ceU markers, and production of thymic semm factor (thymulin). The effect of the amino acid combination, sold commercially as Neoiodarsolo, seems to consist mainly of the reactivation of the... 

Not all toxic organophosphoms compounds have uses beneficial to humans. Sarin is an extremely toxic nerve gas that is lethal to humans. In March 1995 this substance was released in a terrorist attack on a Japanese subway, resulting in several deaths and many serious injuries. Sarin and related nerve gases bind an amino acid in the enzyme responsible for muscle action. When this enzyme is deactivated, muscles contract but cannot relax. Even a small dose can be lethal if the nerve gas reaches the muscles of the heart. 

The prevalent receptor model for the excitatory amino acid is a tetrameric complex. As mentioned in the text, there is evidence that the channel conductance depends on the number of subunits that bind a ligand. Estimate the EC50 value and Hill coefficient for a dose-response curve assuming that the occupation at each subunit has a Kd value of 1 pi I, an % of 1, and that activation induces a transition to an active state independent of the state of the other subunits ... 

The first step in these studies has been the search for the shortest fragment of the ACTH chain that is essential for (maintenance of) activity. Next, changes in the peptide backbone and modification of the side-chains of the amino acid residues have been studied. As a test system the delay of extinction of an active avoidance response in rats as measured in a pole-jumping test after subcutaneous administration has been used (7 ) this assay method gives a graded dose-response relationship which allows the estimation of an ED50 and thus potency ratio s. The heptapeptide ACTH--(4-10) has been used as the reference peptide (8 ). For a more extensive review see ref. 9. 

Levodopa, the metabolic precursor of dopamine, is the most effective agent in the treatment of Parkinson s disease but not for drug-induced Parkinsonism. Oral levodopa is absorbed by an active transport system for aromatic amino acids. Levodopa has a short elimination half-life of 1-3 hours. Transport over the blood-brain barrier is also mediated by an active process. In the brain levodopa is converted to dopamine by decarboxylation and both its therapeutic and adverse effects are mediated by dopamine. Either re-uptake of dopamine takes place or it is metabolized, mainly by monoamine oxidases. The isoenzyme monoamine oxidase B (MAO-B) is responsible for the majority of oxidative metabolism of dopamine in the striatum. As considerable peripheral conversion of levodopa to dopamine takes place large doses of the drug are needed if given alone. Such doses are associated with a high rate of side effects, especially nausea and vomiting but also cardiovascular adverse reactions. Peripheral dopa decarboxylase inhibitors like carbidopa or benserazide do not cross the blood-brain barrier and therefore only interfere with levodopa decarboxylation in the periphery. The combined treatment with levodopa with a peripheral decarboxylase inhibitor considerably decreases oral levodopa doses. However it should be realized that neuropsychiatric complications are not prevented by decarboxylase inhibitors as even with lower doses relatively more levodopa becomes available in the brain. 

At behavlorally effective lntraperitoneal doses (10 mg/kg), SNA has been reported to Increase serotonin (5-HT) concentrations In rat brain.60 5-Hydroxylndoleacetlc acid concentrations are first decreased and then Increased. It has been claimed that SNA causes a decrease followed by a compensatory increase in 5-HT turnover. However, these studies have been criticized on experimental grounds,56 and later studies showed that SNA produces a decrease In 5-HT.58 No effects on aromatic amino acid decarboxylase and monoamine oxidase, two enzymes Involved In 5-HT formation and destruction, were observed SNA has been shown to reduce the concentration of the 5-HT precursor tryptophan. The uptake of 5-HT Into rat brain preparations in vitro and Into the brain stem In vivo Is somewhat Inhibited. There also seems to be a strain difference In response to SNA.61 In general, acute administration of SNA does not seem consistently to cause marked changes In brain serotonin content or turnover. 

The glucocorticoids have important dose-related effects on carbohydrate, protein, and fat metabolism. The same effects are responsible for some of the serious adverse effects associated with their use in therapeutic doses. Glucocorticoids stimulate and are required for gluconeogenesis and glycogen synthesis in the fasting state. They stimulate phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and glycogen synthase and the release of amino acids in the course of muscle catabolism. 

Mammals have two isozymes of prostaglandin H2 synthase, COX-1 and COX-2. These have different functions but closely similar amino acid sequences (60% to 65% sequence identity) and similar reaction mechanisms at both of their catalytic centers. COX-1 is responsible for the synthesis of the prostaglandins that regulate the secretion of gastric mucin, and COX-2 for the prostaglandins that mediate inflammation, pain, and fever. Aspirin inhibits both isozymes about equally, so a dose sufficient to reduce inflammation also risks stomach irritation. Much research is aimed at developing new NSAIDs that inhibit COX-2 specifically, and several such drugs have become available. 

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