Synthesis of stable isotope labelled internal standards for drug-drug interaction (DDI) studies.

The syntheses of stable isotope labelled internal standards of important CYP-isoform selective probes, like testosterone 1, diclofenac 3, midazolam 5, and dextromethorphan 7, as well as their corresponding hydroxylated metabolites 6ß-hydroxytestosterone 2, 4'-hydroxydiclofenac 4, 1'-hydroxymidazolam 6 and dextrorphan 8 are reported. Microwave-enhanced H/D-exchange reactions applying either acid, base, or homogeneous and heterogeneous transition metal catalysis, or combinations thereof proved to be highly efficient for direct deuterium labelling of the above mentioned probes. Compared to conventional stepwise synthetic approaches, the combination of H/D exchange and biotransformation provides the potential for considerable time- and cost savings, in particular for the synthesis of the stable isotope labelled internal standards of 4'-hydroxydiclofenac 4 and 1'-hydroxymidazolam 6.

[Evaluation of a programme for the prenatal screening for Down's syndrome by ultrasonographic nuchal translucency measurement and serum determinations in the first trimester of pregnancy]. / Evaluatie van een programma voor prenatale screening op downsyndroom door echoscopische nekplooimeting en serumbepalingen in het eerste trimester van de zwangerschap.

OBJECTIVE: To determine the diagnostic value of the combination screening test for Down's syndrome in women in the first trimester of pregnancy. DESIGN: Secondary data analysis. METHOD: The data from 2026 consecutive combination tests that were carried out in the period 1 May 2001-31 October 2003 in the VU Medical Centre in Amsterdam, The Netherlands, were analysed. The combination test comprised ultrasonographic neck fold measurement together with determination of the serum levels of free human beta-chorionic gonadotrophin and pregnancy-associated plasma protein A. The chance of Down's syndrome in the foetus was calculated using the median values of the Fetal Medicine Foundation (FMF) and medians based on the population in the VU Medical Centre. A chance > or = 1:200 was considered elevated. Follow-up data were collected from the medical records and from patient reports. RESULTS: The data from 25 patients were excluded because of incompleteness of the investigation or the presence of diabetes mellitus in the pregnant subject. Follow-up data were obtained from 1759 of the 2001 remaining women (88%). Of the 1759 women, 49% were < or = 35 years old and 51% were > or = 36 years of age. Down's syndrome was diagnosed in 21 pregnancies, 16 of which were in the advanced maternal age group of patients. The detection percentage of Down's syndrome by nuchal translucency measurement was 67 with 3 false-positives when calculated on the basis of the FMF-medians and 76 with 6 false-positives when calculated on the basis of the VU Medical Centre medians. With the combination test, the detection percentage of Down's syndrome was 86 with 11 false-positives when calculated on the basis of the FMF-medians and 90 with 5 false-positives when calculated on the basis of the VU Medical Centre medians. CONCLUSION: The diagnostic value of the first-trimester combination test was greater than that of only nuchal translucency measurement. Moreover, the diagnostic value was greater if the chances were calculated on the basis of the median values of the VU Medial Centre population than when other median values were used.

New technique for emboli detection and discrimination based on nonlinear characteristics of gas bubbles.

Detection and characterization of emboli in the blood stream is of high clinical importance for making decisions after surgery. In this study, a new technique based on the nonlinear oscillations of gas bubbles was applied to gaseous emboli detection, characterization and sizing. To simulate gaseous emboli, an experimental system was developed to produce air bubbles of uniform diameters ranging from 19 microm up to 200 microm. The ultrasonic setup consisted of low-frequency transducers operating at 130 kHz and 250 kHz and using low acoustic pressures (30 kPa and 55 kPa). The experimental and theoretical results show that, depending on the transmitted frequency and the bubble sizes, higher harmonic components were produced in the frequency spectrum of the backscattered echo. Nonresonating bubbles scatter either linearly when their sizes are far away from the resonance size or nonlinearly at the second or third harmonic frequency when their sizes are getting close to the resonance size. Only resonant bubbles or bubbles very close to the resonance size are able to scatter at higher harmonic frequencies (fourth and fifth). This property is used to discriminate resonating bubbles from other bubble sizes. The appearance of harmonic component in the frequency spectrum seems to be an unambiguous tool to differentiate gaseous emboli from solid emboli that scatter linearly.

Cardiac depression after experimental air embolism in pigs: role of addition of a surface-active agent.

OBJECTIVE: Air bubbles entering the coronary artery may have harmful effects on cardiac function. From the physical point of view it is the relatively high surface tension of the blood-air interface which causes bubbles to trap in small vessels. The aim of the present study was to reduce depression of myocardial function from air embolism by lowering the surface tension of air bubbles. METHODS: The effect of using antifoam as a surface-tension-reducing agent on air bubble entrapment and cardiac function was investigated in 6 anesthetized pigs (27 +/- 1 kg) and analyzed using a two-compartment diffusion model. Air bubbles with a diameter of 150 microns were selectively injected into the left anterior descending coronary artery (LADCA) in a carrying fluid in the presence or absence of antifoam. Myocardial systolic segment shortening in the LADCA region (SS-LADCA) was measured by sonomicrometry. Presence of emboli was detected by measuring the amount of reverberation of ultrasound scattered by trapped air bubbles. RESULTS: SS-LADCA transiently decreased after injections of air bubbles in both the absence and presence of antifoam. However, in the presence of antifoam the regional depression recovered to normal sooner, the average depth of the depression was reduced, and bubbles from the embolized area cleared faster. These observations can be explained by a model derived from Laplace's law.

Effect of arterial blood pressure and ventilation gases on cardiac depression induced by coronary air embolism.

In this study the time course of cardiac depression after selective intracoronary injection of air bubbles was investigated in six anesthetized pigs (30 +/- 2 kg) with different mixtures of ventilation gases and different mean arterial blood pressures (MAP). Air bubbles of 150 microns diam were injected into the left anterior descending coronary artery (LADCA) in a volume of 2 microliters/kg body wt. In each animal an injection of air bubbles was applied during ventilation with N2-O2 and a MAP of 77 +/- 3 mmHg (N2-O2/low pressure) or 111 +/- 3 mmHg (N2-O2/high pressure) and during ventilation with pure O2 and a MAP of 77 +/- 3 mmHg (O2/low pressure) or 110 +/- 3 mmHg (O2/high pressure). Systemic hemodynamic variables such as left ventricular pressure, its peak first derivatives, and MAP changed < 10% after injection of air bubbles. During N2-O2/low pressure, systolic segment length shortening in the LADCA region (SS-LADCA) decreased from baseline and did not return to baseline within the 10 min after injection of air bubbles. During N2-O2/high pressure and O2/low pressure, SS-LADCA was decreased between 60 and 120 s, whereas for O2/high pressure this period was from 60 to 90 s. By calculating the time integral of the deviation from baseline of SS-LADCA, it could be demonstrated that the depression of regional myocardial function was less severe during O2/high pressure and O2/low pressure than during N2-O2/low pressure. We conclude that, when coronary air embolism occurs during hypertension and during ventilation with pure O2 instead of a normal N2-O2 mixture, the resulting depression of regional myocardial function is reduced.

Heart function after injection of small air bubbles in coronary artery of pigs.

By its nature, vaporization of atherosclerotic plaques by laser irradiation or spark erosion may produce a substantial amount of gas. To evaluate the effect of gas embolism possibly caused by vaporization techniques, air bubbles with diameters of 75, 150, or 300 microns, each in a volume of 2 microliters/kg, were selectively injected subproximal in the left anterior descending coronary artery of seven anesthetized pigs (28 +/- 3 kg). Systemic hemodynamics such as heart rate, left ventricular pressure and its peak positive first derivative, and mean arterial pressure did not change after air injection, whereas there was a minor change in peak negative first derivative of left ventricular pressure. After injection of air bubbles there was a maximal relative reduction of systolic segment shortening (SS) in the myocardium supplied by the left anterior descending coronary artery of 27, 45, and 58% for 75-, 150-, and 300-microns bubbles, respectively, and a relative increase of postsystolic SS (PSS) of 148, 200, and 257% for 75-, 150-, and 300-microns bubbles, respectively. Recovery of SS and PSS started after 2 min and was completed after 10 min. A difference in SS and PSS changes between different bubble size injections could be demonstrated. From this study it is clear that depression of regional myocardial function after injection of air bubbles could pass unnoticed on the basis of global hemodynamic measurements.

Impact of a color-flow duplex surveillance program on infrainguinal vein graft patency: a five-year experience.

PURPOSE AND METHODS: The contribution of color-flow duplex surveillance to improving vein graft patency was evaluated in two patient groups after 201 infrainguinal bypass procedures were performed during a 5-year period. Incidence of revision procedures and the primary and assisted primary patency rates were compared for 160 bypass grafts monitored during the first 2 years by use of color-flow duplex scanning of the vein graft and adjacent arterial segments (color-flow surveillance group) versus 41 bypass grafts monitored by use of clinical assessment alone (clinical follow-up group). Only grafts that were patent after the first postoperative month are considered. RESULTS: The two groups were comparable with regard to most of the pertinent clinical factors. Stenotic lesions were identified in 58 bypass grafts, and severity was determined by use of intraarterial digital subtraction angiography. Eighteen bypass grafts with stenoses did not undergo a revision for reasons that were determined by the doctor, the hospital, or the patient. The occlusion rates of revised and nonrevised stenotic grafts were compared for lesions of different severity. None of the grafts for stenoses with 30% to 49% diameter reduction (DR) failed during follow-up. Occlusion occurred in 57% of the nonrevised and 9% of revised grafts (p = 0.047) for stenoses with 50% to 69% DR. Stenoses with 70% or greater DR were associated with graft failure in 100% of nonrevised bypasses and in 10% of revised grafts (p = 0.004). The assisted primary patency rate was higher in grafts that underwent color-flow surveillance compared with grafts with that underwent clinical follow-up (3-year patency rates of 91% and 72%, respectively; p = 0.004). The independent correlation of color-flow surveillance with higher patency rates was demonstrated in a proportional hazard analysis. The relative risk (probability of occlusion) in color-flow surveillance grafts is less than one third of the relative risk in bypass grafts that underwent clinical follow-up. CONCLUSIONS: We conclude that revision procedures were more optimally used during color-flow surveillance, whereas asymptomatic stenotic graft lesions are missed with clinical follow-up, which results in a higher percentage of graft failures. Overall graft patency rates can be improved with use of color-flow duplex surveillance and repair of significant stenotic lesions.

A simple scoring system for the treatment of cervical incompetence diagnosed during the second trimester.

Twenty-four women with second-trimester cervical incompetence underwent emergency cerclage. The appropriateness of cervical cerclage was analyzed according to a scoring system (Cervical Incompetence Scale; CIS) which measures the degree of cervical effacement, cervical dilatation and protrusion of fetal membranes into the cervical canal. Patients with low CIS (0-3 points) were found to have a more favorable pregnancy outcome than patients with high-score cervical incompetence (5-8 points), i.e. fewer complications following the procedure, 33.3 and 87.5%, respectively, fewer pregnancy losses (22.2 and 75%, respectively) and a significantly prolonged postoperative pregnancy course (mean gestation 33.2 and 24.4 weeks at delivery, respectively). The chances of a successful pregnancy outcome were evaluated at 87.5%; the outcome was successful in patients with low CIS presenting with effacement of the uterine cervix of less than 50%, cervical dilatation of less than 1.5 cm and with fetal membranes remaining in the cervical canal. On the basis of these results, we conclude that the emergency cerclage operation in carefully selected patients with midtrimester cervical incompetence may improve the outcome of pregnancy. This selection is facilitated by the use of a new cervical incompetence scoring system described herein.