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The synthesis of 9-(4-chlorophenyl)-7,7-dimethyl-5(Z), 8-nonadienoic acid (7) and its methyl ester 6, and their effects on arachidonic acid metabolism in vitro are described. The IC50 values of 19.6 and 20.6 microM were observed for inhibition of leukotriene synthesis in human granulocytes for 6 and 7, respectively. Additionally, the compounds inhibited thromboxane B2 (TxB2) synthesis, with respective IC50 values of 6.1 and 20 microM, while producing pronounced 3-8-fold increases in PGE2 synthesis in human mononuclear cells. Increased PGE2 synthesis may have reflected shunting of free arachidonic acid substrate at the thromboxane synthetase and endoperoxide E isomerase branchpoint of arachidonic acid metabolism.

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The resolution of the hypoglycemic agent (+/-)-2-tetradecyloxiranecarboxylic acid (3) as its d- and l-ephedrine salts is presented. The active enantiomer (R)-(+)-3 was also synthesized by the Sharpless chiral epoxidation procedure and its methyl ester (R)-(+)-4 was shown to be identical with the corresponding ester from the resolved acid. Single-crystal X-ray structure analysis of the diastereomeric salt of (+)-3 and (-)-ephedrine allowed assignment of (+)-3 as the R configuration. The effects on fatty acid oxidation and glucose tolerance of the racemic and enantiomeric forms of 3, 4, and the CoA ester of 3 are presented. A postulated mechanism of action for the active enantiomer as an enantioselective, active-site-directed, irreversible inhibitor of carnitine palmitoyl transferase is suggested.

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A series of alkylglycidic acid analogues and derivatives were synthesized and tested for their ability to inhibit long-chain fatty acid oxidation in vitro and to lower blood sugar in rats. The extent of inhibition of carnitine acyl transferase, the enzyme at the mitochondrial membrane necessary to transport long-chain fatty acids into the mitochondria for subsequent beta-oxidation, was determined for the series. Structure-activity relationships using in vitro inhibition of [1-14C]palmitic acid oxidation in rat hemidiaphragm muscle indicate that potent activity resides mainly in 2-alkyl (C12-C16) glycidates. Replacement of the oxirane ring with cyclopropyl, thiirane, or other rings diminishes activity, as does substitution of the glycidate ring at the 3-position. In vivo potency in the rat glucose tolerance test roughly parallels the hemidiaphragm results. The lead compound, methyl 2-tetradecylglycidate (8), is a potent hypoglycemic agent following oral administration to several animal species. The hypoglycemic analogues interfere with fatty acid oxidation by specific and irreversible inhibition of mitochondrial carnitine palmitoyl transferase-A.

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We apply rigorous statistical methods to assess the diagnostic value of creatine kinase, creatine kinase-MB, aspartate aminotransferase, lactate dehydrogenase, and alpha-hydroxybutyrate dehydrogenase in realistic circumstances. The trade-off between false positives and false negatives obtained with various decision rules is examined with the receiver-operator characteristic function and with discriminant analysis. During the three days after an infarction, lactate and alpha-hydroxybutyrate dehydrogenase can provide diagnostic thresholds of constant sensitivity and specificity. By contrast, sensitivity progressively decays for creatine kinase, creatine kinase-MB, and aspartate aminotransferase. The diagnostic uncertainty introduced by the infarction's varying age at hospitalization is evaluated by subjecting the mixed patient population to discriminant analysis. For some enzymes, repeating the same assay on the second day contributes to sensitivity, while adding a different assay on the first day enhances specificity. The effects of lower or higher infarction prevalences on sensitivity and specificity are most favorable when creatine kinase-MB is combined with lactate or alpha-hydroxybutyrate dehydrogenase. Adding a third assay is ineffective. The further differentiation according to infarction stage produces only 81% correct classifications, even when five different assays are used on two consecutive days. As a general strategy, we recommend the assay of two enzymes on two consecutive days.

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We have developed an integrated method that overcomes the two main procedural difficulties of gas-liquid chromatography, namely, solvent-solvent extraction and chemical derivatization. Drugs are extracted from serum by column chromatography on granular diatomaceous earth (kieselguhr). Subsequent gas-liquid chromatography of underivatized samples can be performed on either of two liquid phases. A mixed liquid phase, used for quantitative gas-chromatographic assay on patients with a known therapeutic regimen, has enabled quantitation of 12 drugs in serum. Alternatively, a single liquid phase, used with the mixed liquid phase, permits the gas-chromatographic identification of unknown drugs on the basis of the characteristic pattern of the two relative retention times; by this approach more than 40 drugs have been identified in cases of suspected intoxication, both in serum and in gastric aspirate. Besides providing ease of performance and wide applicability, the proposed procedure offers a degree of precision and accuracy that compares favorably with established methods.

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Immunoassay of creatine kinase-MB provides numerical information, which makes it possible to estimate quantitatively the diagnostic performance following myocardial infarction. Two graphical methods for such an evaluation are presented. The relationship between technical sensitivity and specificity was analyzed using a continuous function, the receiver-operator characteristic curve. Using this function, a diagnostic threshold ("upper normal limit") was chosen, which balances both technical specificity and sensitivity on the first day following infarction. On the second and third days this threshold caused a progressive loss of technical sensitivity. The relationship between effectiveness and the prevalence of myocardial infarction in the tested population was evaluated with a nomogram correlating these two quantities. With the chosen diagnostic threshold, effectiveness is independent of prevalence on the first day, but the loss in technical sensitivity on subsequent days causes effectiveness to decay when the prevalence is high.

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Glucose oxidase, uricase, and urease were immobilized on the interior surface of activated polyamide tubing. The shelf-life of such enzyme bearing tubes was at least six months. The tubes were used for continuous-flow analysis of glucose, uric acid, and urea with conventional systems and with hybrid micro-scale systems in which modules of different manufacture were combined. The length of enzyme-bearing tube required for each system was ascertained empirically. Each tube could be used for several thousand assays, but glucose oxidase-bearing tubes were more stable than urease- or uricase-bearing tubes. Results for patients' samples correlated well with results obtained by accepted methods.

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A specific inhibitor of fatty acid oxidation, methyl 2-tetradecylglycidate (McN-3716) has been found to produce a dose dependent hypoglycemic effect when administered orally to rats, mice, and dogs. In addition to being more potent than other inhibitors of fatty acid oxidation, McN-3716 was also found to be 15--20 times more potent than tolbutamide in lowering the blood glucose of fasting rats. Furthermore, evidence is presented that McN-3716 produces hypoglycemia by a mechanism which differs from that of other oral hypoglycemic agents, the biguanides and the sulfonylureas. As predicted by the Randle glucose-fatty acid cycle, McN-3716 lowered glucose concentrations only under conditions where fatty acids were being used as the major energy substrates (fasting, diabetes, and feeding of high fat diets) but not under conditions where energy was derived mainly from carbohydrate (fed state or following hypophysectomy). Administration of McN-3716 produced a remarkable lowering of the plasma glucose and the glycosuria of depancreatized dogs but did not result in complete normalization of glucose, especially the excursions of blood glucose following feeding. It did, however, produce virtually complete reversal of the ketoacidosis of alloxan diabetic rats and depancreatized dogs without worsening the plasma lipid profile. Thus, McN-3716 may have potential utility as an oral therapeutic agent for the treatment of ketosis-prone juvenile or maturity-onset diabetes.

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