Single specialty capitation: a case study in obstetrics and gynecology.

Faced with a declining maternity census and shrinking market share, representatives of the hospital and physicians developed a proposal to subcontract their Ob/Gyn services to a large multispecialty group. This case study reviews the steps taken to subcontract the group and the lessons learned along the way.

Octafluorotoluene as a derivatizing agent for steroids in human plasma.

The use of octafluorotoluene (OFT) as a versatile gas chromatographic/mass spectrometric derivatizing agent for steroids containing alcoholic, phenolic or alpha, beta-unsaturated keto functions, is described. Two distinct derivatizing schemes can be utilized, involving (method 1) a phase-transfer reaction, employing a two-phase system of CH2Cl2 and N NaOH with n-Bu4NHSO4 as catalyst (suitable for alcoholic and phenolic steroids) and (method 2) a reaction conducted in anhydrous dimethylformamide at 155 degrees C with CsF as base (appropriate for alpha, beta-unsaturated keto steroids). Perfluorotolyl (PFT) ethers and/or enol ethers have thus been generated. The electron impact spectra display abundant high-mass molecular ions where derivatization has occurred at a phenolic or enolic function. An extraction, derivatization and gas chromatographic/mass spectrometric scheme has been devised involving method 2 for the analysis of steroids in human plasma. A preliminary quantitative investigation of the levels of testosterone in plasma has been carried out employing these methods. The anomalously high level found is explained in terms of the presence in plasma of lipid-soluble derivatives of testosterone (probably fatty acid esters) which generate the testosterone bis-OFT derivative under the reaction conditions employed.

1-Alkyl analogues of aminoglutethimide. Comparative inhibition of cholesterol side chain cleavage and aromatase and metabolism of the 1-propyl derivative, a highly selective inhibitor of aromatase.

A homologous series of 1-n-alkyl-derivatives of aminoglutethimide (AG) has been synthesised and tested for inhibitory activity towards the cholesterol side chain cleavage enzyme (desmolase) from bovine adrenals and human placental aromatase in an attempt to find a selective aromatase inhibitor. Activity against desmolase declined from an IC50 value of 30 microM for the parent drug to 220 microM for the n-propyl derivative but increased again thereafter. Against aromatase, activity was least for the methyl and ethyl derivatives and highest (IC50 = 1.6 microM) for the hexyl and octyl analogues. The optimal ratio IC50 (desmolase):IC50 aromatase of 44 was found for the n-propyl derivative, which was therefore selected for preliminary metabolism studies using rat and mouse liver microsomes and hepatocytes and in these species in vivo. There were parallels with AG, most notably in the analogous formation from the n-propyl derivative of an arylhydroxylamine in the mouse.

The sterility testing of dispensed radiopharmaceuticals.

The benefits of retrospective sterility tests on radiopharmaceuticals, were assessed by following the survival of bacteria in non-radioactive and radioactive kits and generator eluate over a period of 5 days. The response of bacteria inoculated into non-radioactive materials ranged through death, survival and growth. The response of bacteria inoculated into radioactive materials was either death or survival. The value of retrospective sterility testing is doubtful and an improved test method is suggested.

Effect of omega-trifluorination on the microsomal metabolism of ethyl and pent-1-yl p-nitrophenyl ether.

p-Nitrophenyl pent-1-yl ether was metabolized (65-70%) in the presence of liver microsomes from phenobarbital-treated rats to give the 4-(major), 3-(minor), and 2-hydroxypent-1-yl (minor) derivatives which were characterized by g.l.c.-mass spectrometry; O-dealkylation (reflecting 1-hydroxylation) and 5-hydroxylation did not occur to a significant extent. 5,5,5-Trifluorination of the pent-1-yl group markedly reduced the extent of metabolism (to approximately 10%). p-Nitrophenyl 2,2,2-trifluoroethyl ether was virtually completely resistant to microsomal metabolism under conditions where the ethyl analogue was extensively O-dealkylated.

Metabolism of 1,1,1,2,2-pentafluorohexane and 1,1-difluorocyclohexane by rat liver microsomes in vitro.

Metabolism of 1,1,1,2,2-pentafluorohexane with liver microsomes from phenobarbital-treated rats gave only one metabolite, namely, the 5-hydroxy derivative. Under similar conditions 1,1-difluorocyclohexane was metabolized to give mainly the 3- and 4-hydroxy derivatives in the ratio 1: approximately 5.5. The structures of these metabolites were established by chemical ionization (CI) and/or electron impact (EI) mass spectrometry and confirmed by synthesis in the case of 1,1-difluorocyclohexan-4-ol. Oxidation of 1,1-difluorocyclohexane with lead tetrakis(trifluoroacetate) also gave, inter alia, the 3- and 4-hydroxy derivatives. In saturated hydrocarbons complete replacement of hydrogen by fluorine at one particular carbon will not only block microsomal hydroxylation thereat but will also inhibit hydroxylation at neighbouring hydrogen-bearing carbons, (alpha almost completely, beta markedly, gamma slightly).

Quantification by gas chromatography of N,N'-di-(2-chloroethyl)-phosphorodiamidic acid in the plasma of patients receiving isophosphamide.

A sensitive method, based on gas chromatography using a phosphorus-specific flame photometric detector, has been developed for quantifying N,N'-di-(2-chloroethyl)phosphorodiamidic acid (isophosphoramide mustard), the putative active metabolite of isophosphamide, in human plasma. Phosphoramide mustard was used as internal standard, and the two compounds were converted into separable trimethyl derivatives by reaction with methyliodide in the presence of silver oxide. The chemistry of the derivatization process has been elucidated using gas chromatography-electron impact mass spectrometry and selected ion monitoring. Levels of isophosphamide and of isophosphoramide mustard were measured in the plasma of patients receiving isophosphamide (2 g/sq m). Peak plasma levels of isophosphoramide mustard of 18.6 to 30.3 nmol/ml occurred at 2 to 4 hr, and levels were still appreciable (6.3 to 11.3 nmol/ml) at 24 hr.