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1. The calcium antagonist, mibefradil, is converted to some 30 metabolites after incubation with hepatic microsomes from the rat, marmoset, cynomolgus monkey, rabbit and man. 2. The wide inter-species differences in metabolic profile stem mainly from variations in the activity of the microsomal esterase, which hydrolyses the ester side-chain of mibefradil to give the alcohol metabolite, Ro 40-5966. Hydrolysis is especially marked in the cynomolgus monkey and rabbit, less in man and least in the rat and marmoset. 3. The biotransformation of this alcohol metabolite by cytochromes P450 is more facile than that of the parent compound, leads to fewer metabolites and the metabolic profiles in all species are similar. 4. The most important cytochrome P450-mediated metabolic process in microsomes in all species is hydroxylation at the benzylic carbon atom of the tetrahydronaphthyl group; further oxidation of the resultant secondary alcohol to a ketone also occurs. These reactions indicate the route of the biosynthetic pathway which leads to the major, naphthyl-glucuronide metabolites previously isolated from rat bile. 5. Dealkylation of the tertiary amino group is also important and leads to compounds lacking either the N-methyl group or the propylbenzimidazole moiety. 6. Hydroxylation of the benzimidazole ring at both the 4- and 5-positions is largely restricted to mibefradil and does not occur to a significant extent with Ro 40-5966.

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A rapid, sensitive and specific analytical method has been developed and validated to quantify the collagenase inhibitor N2-(2(5)-[(hydroxycarbamoyl)methyl)-4-methylvaleryl]-N1, 3-dimethyl-L-valin-amide (I) and its major metabolite (II) from plasma and urine. This method employs an automated solid-phase extraction procedure to isolate the analytes and the internal standard from the biological matrix. Reconstituted extracts were analyzed by HPLC-ionspray MS-MS. Chromatography was performed on a 4.6 mm I.D. reversed-phase guard column. The retention times of the analytes and the internal standard were approximately 1.3 min. The assay has a limit of quantification of 5 ng/ml plasma and a limit of detection of 1 ng/ml, based on 100-micro l plasma aliquots. No sample-drying step was required. The standard curves were linear form 5 to 5000 ng/ml using weighted linear regression analysis (1/y2). The intra- and inter-assay precision were better than + or - 10% with intra- and inter-assay accuracies between 95 and 105%. this new HPLC-MS-MS assay procedure for I and II in plasma and urine has proven to be specific, sensitive, accurate and robust, and is being used routinely for the analysis of I in pre-clinical and clinical trial samples. Up to 200 unknowns may be analyzed each 24 h per analyst.

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A thermospray interface between a HPLC system and a mass spectrometer has been used to develop an assay for pyridostigmine bromide measuring plasma concentrations down to 1 ng ml-1 on a routine basis. Plasma is loaded onto an AASP reversed-phase cartridge, injected onto a HPLC system connected to a Finnigan 4500 mass spectrometer via a thermospray interface and the molecular ion monitored. A deuterated internal standard is used, but calculations with and without the internal standard show its use does not materially improve the quantitation. The precision and accuracy at the limit of quantitation is less than +/- 5% and 95-105%, respectively. The method is used to analyse samples from a bioavailability study by fully automated unattended overnight sample analysis.

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A method is described for the rapid determination of urinary bile salt profiles by fast atom bombardment--mass spectrometry (FAB-MS). Urine was passed through a reverse-phase octadecylsilane bonded silica cartridge and the bile salts eluted with methanol. Negative ion FAB spectra could be obtained from the equivalent of 10 microliter of urine loaded onto the target probe with glycerol as matrix. In samples from normal infants and children bile salt peaks were rarely detectable above the background whereas peaks produced by steroid sulphates and glucuronides and bile alcohol glucuronides could usually be identified. In samples from infants and children with cholestasis the major peaks were produced by the taurine and glycine conjugates of di-, tri- and tetrahydroxycholanoic acids (and their monosulphates). In samples from patients with Zellweger syndrome and infantile Refsum's disease, a unique ion at m/z 572 indicated the presence of taurine-conjugated tetrahydroxy-cholestanoic acid(s). The amide linkage to taurine was cleaved by alkaline hydrolysis but not by cholylglycine hydrolase. Capillary gas chromatography--mass spectrometry (GC-MS) of the bile acids liberated by alkaline hydrolysis indicated the presence of at least two nuclear-tetrahydroxylated cholestanoic acids, probably the 6 alpha- and 1 beta-hydroxylated derivatives of 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestan-26-oic acid.

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This paper traces the forces that stimulated a faculty to completely revise its occupational therapy curriculum. The process of the revision, which was largely adapted from a test development model, is recounted. The paper also describes the broad array of teaching/learning methodologies used. Comparative data from the American Occupational Therapy Association Certification Examination indicate that student achievement has significantly improved since the revised curriculum was implemented.

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Indomethacin, a nonsteroidal antiinflammatory agent which inhibits prostaglandin biosynthesis, has significant activity in inhibiting the growth and/or inducing the regression of transplantable tumors. The present study was designed to determine if, in addition to its chemotherapeutic effects, indomethacin also acts as a cancer chemopreventive agent. Fifty-day-old virgin female Sprague-Dawley rats were given a single intragastric dose of either 8 or 16 mg of 7,12-dimethylbenz(a)anthracene (time 0). Basal diet was supplemented with 25 or 50 mg of indomethacin per kg of diet by the following protocol: (a) -2 to +1 week; (b) +1 week to end; or (c) none. Administration of indomethacin by both protocols resulted in an inhibition of mammary tumorigenesis; however, the effect of -2 to +1 week indomethacin exposure was primarily on the induction of benign mammary tumors, while +1 week to end indomethacin administration inhibited the induction of both benign mammary tumors and mammary cancers. These data indicate that indomethacin has significant protective activity when administered either during the "early" stage (comprising the carcinogen-target cell interaction) or the "late" stage (postcarcinogen tumor development) of mammary carcinogenesis in rats. Possible mechanisms of indomethacin action include both local and systemic effects.

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This study used data from self-administered questionnaires to compare technical- and professional-level students from four occupational therapy educational programs in Illinois. Examination of the similarities and differences in biographic characteristics indicate that registered occupational therapy and certified occupational therapy assistant students come from different backgrounds. The reasons why students chose their levels of education, and the amount and character of contact with occupational therapy that they had prior to entering the program provide useful information for counselors, recruiters, and designers of informational materials. The students' intended roles, desired career goals, and work values furnish suggestions for curriculum developers.

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Undergraduate occupational therapy students were given the Rezler-French Learning Preference and the Kolb Learning Style Inventories at the introduction of professional course work (pretest) and upon completion of junior year course work and Level 1 fieldwork (posttest) 1 year later. The students' course work was a guided-study, modified competency-based program that included guided independent study, laboratory work, small group study, and one-to-one tutorials in preference to, but not excluding, the more traditional lecture method. After experiencing different modes of instruction, the students indicated no significant difference in their preferences for ways of learning or in processing information. Implications of these findings for the teaching-learning process are discussed.

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The predominant diene conjugated acyl residue in triacylglycerols, cholesteryl esters and phospholipids in human serum was identified by high performance liquid chromatography and capillary gas chromatography-mass spectrometry. It is an octadeca -9,11-dienoic acid.

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A comparison has been made of positive- and negative-ion fast-atom-bombardment (FAB) and electron-impact (EI) mass spectrometry for analysis of oligosaccharides and alditols containing alternating and consecutive sequences of neutral and acetamido sugars. Among these were novel chemically synthesized tetrasaccharides with Ii antigen activities. FAB ionization has the advantage that it is applicable to non-derivatized oligosaccharides and it can determine Mr. However, the abundance of fragment ions providing structural information and the amount of material required for analysis (1-50 nmol) varied from sample to sample. In contrast, EI mass spectrometry of 5 nmol of permethylated or peracetylated oligosaccharides reliably gives all the fragment ions formed by cleavage across the glycosidic bonds.

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A biochemical and histological study of hepatic lipid in children dying from the sudden infant death syndrome (SIDS) and children of a similar age dying explicably are reported. Contrary to a previous report based on histological assessment of hepatic lipid, no significant increase of total lipid content in livers of children dying from SIDS was found. Analysis of hepatic phospholipid fatty acid esters, however, revealed a significant difference between SIDS and children of similar age dying acutely and explicably. The phospholipid abnormality found in SIDS was similar to that found in children dying subacutely with hypoxia and would be consistent with increased cell membrane fluidity. The implications of these findings in the pathogenesis of SIDS are discussed.

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