An asymmetric synthesis of (+)-grandisol, a constituent of the aggregation pheromone of the cotton boll weevil, via a kinetic resolution.

A novel approach to the asymmetric synthesis of (+)-grandisol, (1R, 2S)-isopropenyl-1-methylcyclobutaneethanol, involves the use of catalytic kinetic resolution of a primary allylic alcohol, [(1RS, 5SR)-5-methylbicyclo[3.2.0]hept-2-en-2-yl] methanol. The allylic alcohol is prepared in four steps from simple achiral materials involving the use of a modified Shapiro reaction. The resolved alcohol (95% ee) is then reduced in two steps to the corresponding methyl alkene, (1S,5R)-2,5-dimethylbicyclo[3.2.0]hept-2-ene. This alkene is converted to (+)-grandisol (95% ee), in three steps, by modified literature procedures.

Marked enantioselective protein binding in humans of ketorolac in vitro: elucidation of enantiomer unbound fractions following facile synthesis and direct chiral HPLC resolution of tritium-labelled ketorolac.

The protein binding of the enantiomers of the nonopiate analgesic, ketorolac, was investigated in vitro using human plasma and solutions of human serum albumin (HSA) at physiological pH and temperature. In order to detect the very low levels of unbound enantiomers in protein solutions, tritium-labelled rac-ketorolac was synthesised by regiospecific isotopic exchange of the parent drug with tritiated water as the isotope donor. Radiochemical purification of this compound by reversed-phase HPLC followed by direct resolution using a chiral alpha 1-acid glycoprotein (Chiral-AGP) HPLC column afforded labelled enantiomers of high specific activity. The in vitro use of (R)- and (S)-[3H4]ketorolac enabled reproducible radiometric detection of enantiomers in protein solution ultrafiltrate. The unbound fractions of (R)- and (S)-ketorolac [fu(R) and fu(S), respectively] were determined when drug was added to various plasma or albumin solutions as either the separate enantiomers or as the racemate. Over an enantiomeric plasma concentration range of 2.0-15.0 micrograms/ml, fu(S) (mean range: 1.572-1.795%) was more than 2-fold greater (P < 0.001) than fu(R) (mean range: 0.565-0.674%). Both fu(R) and fu(S) were constant over this concentration range, and each was unaffected by the presence of the corresponding antipode (P > 0.05). At a concentration of 2.0 micrograms/ml in 40.0 g/liter fatty acid-free HSA, fu(R) and fu(S) were approximately 0.5 and 1.1%, respectively, and both values declined with increasing concentrations of the long chain fatty acid, oleic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

[Value of protocol using standardised activities of daily living for the programming of rate responsive pacing]. / Intérêt d'un protocole comportant des exercices de la vie courante standardisés pour la programmation des stimulations à fréquence asservie.

To optimise the regulation of rate responsive pacemakers, the authors propose standardized tests of everyday activities. Seven tests were selected with monitoring of the heart rate (HR) by telemetry every 30 seconds: two reference tests--cycloergometry: 2 steps of 3 minutes at 30 then 60 watts and a symptoms-limited Bruce protocol on the treadmill--and 5 everyday activities, walking, going upstairs, going downstairs, squats and hyperventilation. Fifteen normal subjects (65 +/- 10 years) were used to establish normal values and 10 patients implanted with a Telelctronics Meta DDDR 1250 rate responsive pacemaker with minute ventilation sensing, were studied after choice of minimal and maximal HR on clinical criteria (age, pathology). The rate response frequency (RRF) was adjusted so that the pacemaker HR was within normal values. At the beginning of each test, the sensor was hypokinetic (p = 0.01). Hyperventilation caused hyperkinesia of the sensor (p = 0.01). A good correlation was obtained between PM patients and normal subjects on walking, going up down stairs and for squats (p = NS). On cycle ergometry and treadmill, the PM remained slightly hypokinetic (p = 0.02). The study of "ideal" RRF measured at "peak exercise" as proposed by the manufacturer was only satisfactory in 1 of the 10 cases. This study confirms the value of using everyday activities for programming rate responsive pacemakers, the limitations of automatic adjustment and the need for personalized programming.

[Cardiac compression by a large thymic cyst. Apropos of a case, review of the literature]. / Compression cardiaque par un volumineux kyste thymique en bissac. A propos d'un cas, revue de la littérature.

Thymic cysts are rare and almost always asymptomatic. The authors report the case of a 45 year old woman with a thymic cyst diagnosed after recurrent right sided heart failure resulting in signs suggestive of adiastole, regressing after "pleural" (mainly cystic) aspiration and diuretic therapy without any morphological or functional changes on Doppler echocardiography. This report concerns a rare tumour, with an exceptional volume (2 litres) extending down the cardiac borders and causing cardiac compression. It illustrates the diagnostic difficulty of a pathology with an unusual clinical presentation, despite complementary investigations including CT scan and MRI, very sensitive in this type of problem. A complete cure was obtained by total surgical ablation.

Plasma protein binding of ketoprofen enantiomers in man: method development and its application.

The protein binding of ketoprofen enantiomers was investigated in human plasma at physiological pH and temperature by ultrafiltration. 14C-labelled (RS)-ketoprofen was synthesized and purified by high-performance liquid chromatography and utilized as a means of quantifying the unbound species. In vitro studies were conducted with plasma obtained from six healthy volunteers. The plasma was spiked with (R)-ketoprofen alone, (S)-ketoprofen alone, and (RS)-ketoprofen in the enantiomeric concentration range of 1.0 to 19.0 micrograms/ml. The plasma protein binding of ketoprofen was nonenantioselective. At a racemic drug concentration of 2.0 micrograms/ml the mean (+/- SD) percentage unbound of (R)-ketoprofen was 0.80 (+/- 0.15)%. The corresponding value for (S)-ketoprofen, 0.78 (+/- 0.18)%, was not statistically different (P greater than 0.05). At this racemic drug concentration (2.0 micrograms/ml) the percentage unbound of each enantiomer was unaffected (P greater than 0.05) by the presence of the glucuronoconjugates of ketoprofen (10 micrograms/ml) in plasma. At clinically relevant concentrations, the plasma binding of ketoprofen did not exhibit enantioselectivity or concentration dependence nor was the binding of either enantiomer influenced by its optical antipode (P greater than 0.05).

Isolation and characterization of pneumolysin-negative mutants of Streptococcus pneumoniae.

Pneumolysin-negative mutants of Streptococcus pneumoniae were isolated after mutagenesis with ethyl methane sulfonate. Though totally devoid of pneumolysin, these strains produced alpha hemolysis on blood agar when incubated aerobically. It is concluded that the alpha hemolysis typical of pneumococci is unrelated to their pneumolysin content.