Biomedical subjects
Publications and source records attributed to C Bertucci.
The enantiomers of 3-alpha-tropyl 2-(phenylthio)butyrate (SM32, 1) were prepared by chiral synthesis and tested for analgesic, cognition-enhancing, and ACh-releasing properties. They show enantioselectivity in some of the tests, the eutomer being related in configuration to R-(+)-hyoscyamine.
A modified albumin was prepared by selective reaction of Lys199 with acetyl salicylic acid. Protein binding investigation was carried out on native and modified proteins by difference circular dichroism (delta CD). Acetylation of Lys199 reduces significantly the effects of the interaction between drugs in the stereoselective HSA binding at specific binding areas.
Simultaneous binding of two drugs to human serum albumin (HSA) was investigated by difference circular dichroism (delta CD) spectroscopy. Phenylbutazone and diazepam were chosen as specific markers for binding areas I (cumarines) and II (indoles), respectively, and their stereospecific interactions with protein were selectively characterized. Displacers were drugs known to specifically bind to areas I (salicylate) and II (racemic ibuprofen). The results indicate two different interaction mechanisms: a direct competition one (diazepam-ibuprofen and phenylbutazone-salicylate) and an indirect competition one (diazepam-salicylate and phenylbutazone-ibuprofen). The two major binding areas on HSA are distinct, but not independent, entities. Finally, the dissociation constants of marker ligands and competitors complexed to HSA were determined by quantitative analysis of CD data.
5-Fluorouracil (FU) is an important and widely used antineoplastic drug that is carried in the serum by plasma proteins. Protein binding studies of this drug to human serum albumin (HSA) have been carried out by several spectroscopic techniques. Difference circular dichroism and UV studies provided information on the class of binding sites involved in the interaction. In particular, displacement experiments showed that FU has at least one secondary binding site in the coumarin binding area, but does not interact with the benzodiazepine binding area. Binding was also investigated by difference 1H NMR and by measuring the increase in the 19F NMR signal of FU when bound to HSA. Finally, evidence was obtained that chemical acetylation of Lys199 results in a decreased apparent binding affinity constant (nK) for FU. Such a modification is induced under physiological conditions by aspirin.
We studied 316 patients undergoing cardiopulmonary bypass for coronary artery surgery in order to determine perioperative risk factors for postoperative renal dysfunction. A preliminary univariate analysis was performed by chi 2 analysis for categorical data and Mann-Whitney U-test for continuous variables to detect significant correlations between each risk factor and the occurrence of moderate or severe renal dysfunction. Subsequently, a multiple logistic regression was applied to the three risk factors identified as predictive for severe renal dysfunction. Low cardiac output syndrome and need for banked blood transfusions combined with a low haematocrit value during cardiopulmonary bypass increase the probability of severe renal dysfunction in the postoperative course.
BACKGROUND: Surgical repair is the procedure of choice for atrial septal defect correction. Even though surgical mortality is low (< 1%), morbidity is significant (anesthesia, thoracotomy, cardiopulmonary bypass, longer hospitalization and intensive care unit monitoring). Transcatheter methods to occlude atrial septal defects have been in development during the last two decades. We report our experience in Italy with the Sideris buttoned double-disk device. METHODS: From March 1992 to April 1993, 14 patients aged 20 months to 52 years, weight 10 to 82 kg, underwent transcatheter atrial septal defect occlusion with the Sideris buttoned device. The buttoned device is a miniaturized two disk device introduced through small venous sheaths (8-9 F). The diameter of atrial septal defects by echocardiography varied between 9 and 23 mm, while the balloon stretched diameter of the defects varied between 13 and 24 mm. The devices selected were 19 +/- 4 mm larger than the stretched diameter of the defect, but less than the total length of the septum (33-56 mm) by echo. RESULTS: Pulmonary-to-systemic flow ratio varied between 1.5 to 4.0. Mean pulmonary artery pressure varied between 10 and 24 mmHg (mean value 17 +/- 3.5 mm Hg). The relationship between different atrial septal defect measurements (echo, shunt flow, stretched diameter) was statistically analysed: transthoracic echo diameter had a good correlation with the balloon stretched diameter (r = 0.63, p < 0.001). The atrial septal defect was occluded in 12 patients (86% success rate). There was one early "unbuttoning" which was surgically corrected with success. The other patient underwent surgical correction 3 months later because of unsuitability for transcatheter closure. Minimal residual shunt detected by color flow mapping at 1 month follow-up was seen in 4 patients (33%). No complications occurred in any of our patients. CONCLUSIONS: This initial experience with the Sideris buttoned double-disk device demonstrated that transcatheter closure of atrial septal defect is feasible and effective. It can be accomplished through small introducing sheaths. Further clinical trials are justified. This method could become the procedure of choice for the correction of small ASDs.
The inclusion complex of the calcium salt of (S)-2-(3-phenoxyphenyl)propionic acid with cyclomaltoheptaose (beta-cyclodextrin) was investigated by 1H NMR spectroscopy. The stoichiometry of the complex was determined by the continuous variation method and the association constant by the Benesi-Hildebrand procedure. Measurements of proton selective relaxation rates allowed the dynamics of the complex to be investigated and the determination of intermolecular 1H(1H)-NOE enhancements revealed the stereochemistry in solution.
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The interaction between the benzodiazepine and the warfarin binding sites in human serum albumin (HSA) has been investigated using an HSA-based HPLC chiral stationary phase (HSA-CSP). (R)-Warfarin and (S)-warfarin were added to the mobile phase and racemic mixtures of oxazepam, lorazepam, and their hemisuccinic derivatives were injected onto the HSA-CSP. The presence of (R)-warfarin in the mobile phase did not significantly affect the chromatographic retention (expressed as capacity factor, k') of the investigated benzodiazepine hemisuccinate derivatives. The presence of (S)-warfarin did not significantly affect the k' of oxazepam and oxazepam hemisuccinate, but resulted in a dramatic increase in the k' of (S)-lorazepam hemisuccinate and also improved the enantiomeric resolution of lorazepam. These results confirm the existence of an allosteric interaction between the benzodiazepine binding site and the warfarin binding site. Furthermore, the study indicates that chromatography on the silica-immobilized HSA can detect interactions between binding sites on the protein. This can be of great importance in the determination of drug-drug interactions.
While color Doppler flow mapping has yielded a quick and relatively sensitive method for visualizing the turbulent jets generated in valvular insufficiency, quantification of the degree of valvular insufficiency has been limited by the dependence of visualization of turbulent jets on hemodynamic as well as instrument-related factors. Color Doppler flow imaging, however, does have the capability of reliably showing the spatial relations of laminar flows. An area where flow accelerates proximal to a regurgitant orifice is commonly visualized on the left ventricular side of a mitral regurgitant orifice, especially when imaging is performed with high gain and a low pulse repetition frequency. This area of flow convergence, where the flow stream narrows symmetrically, can be quantified because velocity and the flow cross-sectional area change in inverse proportion along streamlines centered at the orifice. In this study, a gravity-driven constant-flow system with five sharp-edged diaphragm orifices (ranging from 2.9 to 12 mm in diameter) was imaged both parallel and perpendicular to the direction of flow through the orifice. Color Doppler flow images were produced by zero shifting so that the abrupt change in display color occurred at different velocities. This "aliasing boundary" with a known velocity and a measurable radial distance from the center of the orifice was used to determine an isovelocity hemisphere such that flow rate through the orifice was calculated as 2 pi r2 x Vr, where r is the radial distance from the center of the orifice to the color change and Vr is the velocity at which the color change was noted. Using Vr values from 54 to 14 cm/sec obtained with a 3.75-MHz transducer and from 75 to 18 cm/sec obtained with a 2.5-MHz transducer, we calculated flow rates and found them to correlate with measured flow rates (r = 0.94-0.99). The slope of the regression line was closest to unity when the lowest Vr and the correspondingly largest r were used in the calculation. The flow rates estimated from color Doppler flow imaging could also be used in conjunction with continuous-wave Doppler measurements of the maximal velocity of flow through the orifice to calculate orifice areas (r = 0.75-0.96 correlation with measured areas).(ABSTRACT TRUNCATED AT 250 WORDS)
The continuity equation, applied to the flow convergence region (FCR), fournishes a simple alternative to calculate stenotic valve area. The flow rate in the FCR can be calculated by multiplying the hemispheric isovelocity surface area by the velocity of the isovelocity surface. Since according to the continuity principle the flow rate through any isovelocity surface equals the flow rate through the stenotic orifice, the stenotic orifice area can be calculated as: 2 pi r2Vr/Vm, where 2 pi r2 is the hemispheric isovelocity area, Vr is the velocity at the radial distance r from the orifice and Vm is the peak jet velocity. This study was designed to analyze the validity of application of the continuity equation to the FCR for estimating mitral orifice area by Dopler ultrasound. We studied 35 consecutive patients with rheumatic mitral stenosis. Three patients were excluded; the final study population consisted of 32 patients (8 men and 24 women; mean age 56 years). Nine patients were in normal sinus rhythm and 23 in atrial fibrillation. Doppler examination was performed from the apical approach within 24 hours of cardiac catheterization. On color Doppler image Vr was defined as the first aliasing limit (lowered to 38 cm/s to increase FCR r); r represented the maximal early diastolic distance between the first alias and the stenotic orifice in a direction parallel to that of the transducer; Vm was the early diastolic peak jet velocity by continuous wave Doppler.(ABSTRACT TRUNCATED AT 250 WORDS)
The stereochemistry of an achiral (Diazepam) and two chiral (3-methyl and 3-succinyloxy substituted) 1,4-benzodiazepin-2-ones interacting with human serum albumin (HSA) has been investigated by making use of difference absorption (UV) and circular dichroism (CD) spectroscopies. Evidence is obtained for a higher affinity with HSA for one of the two possible conformations of the seven-membered benzodiazepine ring. The red shift revealed by the absorption difference spectrum between the free and the bound drug accounts for the CD difference spectra observed.
A human serum albumin-based HPLC chiral stationary phase (HSA-CSP) has been examined as a tool to investigate binding of chiral drugs to HSA and drug-drug protein-binding interactions. Rac-oxazepam hemisuccinate (OXH) was used as a model compound and the chromatographic retention (k') of its enantiomers was determined after addition of displacers to the mobile phase. Compounds known to bind at the same site as OXH and at different sites were tested for their displacing capacities. Competitive binding interactions between the OXH enantiomers and displacers in the mobile phase were reflected by decreases in the k's of (R)- and (S)-OXH. The results indicate that retention on the HSA-CSP accurately reflects binding to native HSA and the technique can determine enantioselective and competitive binding interactions at specific sites on HSA. The HSA-CSP was also able to recognize separate binding areas for (S)- and (R)-OXH.
The application of a circular dichroism (c.d.) detection system in HPLC using a chiral stationary phase is presented. The simultaneous measurement of the absorbance and c.d. signal allows the evaluation of the anisotropy factor (g = delta epsilon/epsilon) and thus the determination of the enantiomeric excess (e.e.) of the eluates. When this detection system is used in preparative chiral chromatography the collection of the enantiomeric fractions can be readily optimized.
Pure enantiomers of 3-substituted-1,4-benzodiazepin-2-ones, obtained by HPLC resolution on chiral stationary phases, show significant differences in their pharmacological activity. The occurrence of biotransformation during the pharmacological test is monitored using a new chromatographic method. The reliability of the pharmacological activity data is discussed.
In this study, we explored the use of continuous wave Doppler-echocardiography guided by color Doppler flow-mapping as a method for noninvasively calculating the rate of pressure rise (RPR) in the left ventricle. Continuous wave Doppler determination of the velocities in mitral regurgitant jets allows calculation of instantaneous pressure gradients between the left ventricle and the left atrium. Left atrial pressure variations in early systole can be considered negligible; therefore, the rising segment of the mitral regurgitation velocity curve should reflect left ventricular pressure increase. We studied 50 patients (mean age, 51 years; range, 25-66 years) in normal sinus rhythm with color Doppler-proven mitral regurgitation and compared the Doppler-derived left ventricular RPR with peak dP/dt obtained at cardiac catheterization. Doppler studies were performed simultaneously with cardiac catheterization in 11 patients and immediately before in the remaining cases. Two points were arbitrarily selected on the steepest rising segment of the continuous wave mitral regurgitation velocity curve (point A, 1 m/sec, point B, 3 m/sec), and the time interval (t) between them was measured. Following the Bernoulli relation, the pressure rise between points A and B is 32 mm Hg (4vB2-4vA2) and the RPR is 32 mm Hg/t. Results showed a linear correlation between the Doppler RPR and peak dP/dt (r = 0.87, SEE = 316 mm Hg/sec). The RPR in the left ventricle can be derived from the continuous wave Doppler mitral regurgitation velocity curve.
Doppler characteristics of normally functioning tilting disk prostheses in aortic position were studied in 55 patients (30 Medtronic-Hall and 25 Sorin) whose valvular function was considered normal using clinical and echocardiographic evaluation. Peak gradients, mean gradients and effective orifice area were estimated for different sizes of prostheses. The peak gradient calculated from maximal aortic velocity was 27.3 +/- 11.1 mmHg in Sorin and 21.1 +/- 9.7 mmHg in Medtronic-Hall valves; the mean gradients were 12.9 +/- 6.2 mmHg and 10.8 +/- 5.7 mmHg in Sorin and Medtronic-Hall valves respectively. The effective orifice area calculated by the continuity equation was 1.4 +/- 0.5 cm2 in Sorin and 1.5 +/- 0.57 cm2 in Medtronic-Hall prostheses; the performance index calculated as the ratio between functional area and manufactured area was 0.4-0.6 for Medtronic-Hall and 0.45-0.52 for Sorin prostheses. Prosthetic regurgitation was found in 64% of Sorin valves and 80% of Medtronic-Hall valves; prosthetic regurgitation was mild in 81% and moderate in 19% of cases. Doppler echocardiography is a reliable method for the characterization of the normal function of prosthetic aortic valves and provides information similar to cardiac catheterization.
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