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Biomedical subjects

A C Eddy

Publications and source records attributed to A C Eddy.

At least 19 recordsLinked to original sources
PubMed1995

Modified conduit preparation creates a pseudosinus in an aortic valve-sparing procedure for aneurysm of the ascending aorta.

Mechanical valved conduit replacement of the aortic root is a durable and appropriate procedure for many diseases of the ascending aorta, but may sacrifice an anatomically salvageable aortic valve. For young active patients and for patients with "systemic" arterial disease (atherosclerosis, Marfan's syndrome) who may require future operations, life-long anticoagulation with its attendant thromboembolic versus hemorrhagic risks is not ideal. Several techniques have been suggested as aortic valve-sparing options. Recently, a procedure was described that combines the freehand homograft techniques with the standard Bentall techniques (David procedure). This innovative technique replaces the ascending aorta with a Dacron cylinder, spares the aortic valve, and restores competence and thus offers an excellent alternative. The durability of this procedure that places the aortic valve inside a cylindrical conduit without sinuses of Valsalva is unknown. In selected patients, we have used this technique to spare the aortic valve. On the basis of experimental data and preliminary computer modeling, with the hope of improving the durability, we have modified the conduit to create a "pseudosinus" in our most recent nine patients. We have done the David procedure in 10 patients. The pseudosinus modification was done in the most recent nine patients. Patients' ages ranged from 37 to 71 years (mean 49.9 years). There were five female and five male patients. Five patients had Marfan's syndrome and five patients had annuloaortic ectasia. There has been no mortality and all patients have had both early and late follow-up echocardiography. Five patients have zero to trace aortic insufficiency, four patients have trace to mild aortic insufficiency, and one patient has mild or "1+" aortic insufficiency. Aortic insufficiency has not progressed in any patient during the 18 months of follow-up. The patient with 1+ aortic insufficiency has no activity limits, good ventricular function, and no evidence of congestive symptoms. One patient who had extensive thoracoabdominal aneurysmal disease has undergone subsequent replacement of the descending aorta to the level of the renal arteries and has done well. Aortic valve-sparing replacement of the aortic root is an excellent procedure for any patient with an ascending aortic aneurysm and an anatomically salvageable valve. We believe that by modifying the proximal conduit and creating a "pseudosinus" into which the leaflets can retract without contact of the cylindrical conduit we may increase the longevity of the native aortic valve in this procedure.

Aorta↗
PubMed1992

The mechanism of the interaction between amiodarone and warfarin in humans.

Amiodarone decreased the total body clearance of both (R)- and (S)-warfarin in normal subjects but did not change volumes of distribution. Warfarin excretion products were quantified and clearance and formation clearance values calculated. Amiodarone and metabolites inhibited the reduction of (R)-warfarin to (R,S)-warfarin alcohol-1 and the oxidation of both (R)- and (S)-warfarin to phenolic metabolites. Inhibition of warfarin hydroxylation by amiodarone in human liver microsomes was compared with the in vivo results. In agreement, the in vitro data indicates that amiodarone is a general inhibitor of the cytochrome P450 catalyzed oxidation of both enantiomers of warfarin, but the metabolism of (S)-warfarin is more strongly inhibited than that of (R)-warfarin. These data suggest that the enhanced anticoagulant effect observed when amiodarone and warfarin are coadministered is attributable to inhibition of P4502C9, the isozyme of P-450 primarily responsible for the conversion of (S)-warfarin to its major metabolite, (S)-7-hydroxywarfarin.

Adult↗
PubMed1992

Mechanisms of the stereoselective interaction between miconazole and racemic warfarin in human subjects.

Miconazole decreased the total body clearance of both (R)- and (S)-warfarin in normal subjects but did not change volumes of distribution. Miconazole inhibited the oxidation of both (R)- and (S)-warfarin to phenolic metabolites, although (S)-warfarin was inhibited to the greater extent. In particular, (S)-7-hydroxylation, the pathway primarily responsible for termination of the anticoagulant effect, was most strongly inhibited. Inhibition of warfarin hydroxylation by miconazole in human liver microsomes and the in vivo results showed a good rank order correlation. The enhanced anticoagulant effect observed when miconazole and warfarin are coadministered may result from inhibition of P4502C9, the isozyme of P450 primarily responsible for the conversion of (S)-warfarin to (S)-7-hydroxy-warfarin. Because miconazole inhibits a number of P450 isozymes, in addition to P4502C9, it can be expected to lead to interactions with other drugs whose primary metabolism is controlled by these enzymes.

Adult↗
PubMed1991

Metabolic enantiomeric interactions: the inhibition of human (S)-warfarin-7-hydroxylase by (R)-warfarin.

Inhibition of the metabolism of (S)-warfarin, the more pharmacologically active enantiomer of the racemic drug, by (R)-warfarin was investigated in microsomes obtained from three human livers. In each case the production of both (S)-6- and (S)-7-hydroxywarfarin was found to be competitively inhibited by (R)-warfarin. The KiS for inhibition of (S)-6- and (S)-7-hydroxylation by (R)-warfarin ranged from 7.0 to 8.4 microM and from 6.0 to 6.9 microM, respectively, while the KmS for the 6- and 7-hydroxylation of (S)-warfarin ranged from 3.6 to 3.8 microM and from 3.3 to 3.9 microM, respectively. In contrast, except for the 4'-hydroxylation pathway (S)-warfarin was found to be a weak inhibitor of the metabolism of (R)-warfarin. Possible implications of these findings include the following: (1) the kinetic parameters defining the interactions of two enantiomers of a racemic drug with the cytochrome P-450s or other macromolecular systems in the living organism can only be properly defined from experiments with the pure enantiomers, (2) an enantiomer of a racemic drug may contribute significantly to biological effect not by its inherent activity but by altering the pharmacokinetics of the eutomer, and (3) enantiomeric interactions are not easily detected unless directly sought and may be relatively common.

Aryl Hydrocarbon Hydroxylases↗
PubMed1991

Anterior sternal retraction for reoperative median sternotomy.

The incidence of reoperative median sternotomy for repeat cardiac surgery is increasing. Reoperative median sternotomy is associated with a higher morbidity and mortality than first-time cardiac surgery. A portion of this morbidity and mortality may be due to direct injury to the heart and great vessels in the process of reopening the sternum. We report a new technique utilizing anterior sternal retraction that allows division of adhesions between the undersurface of the sternum and the heart and great vessels under direct vision. This technique enables the surgeon to minimize the risk of serious injury to these underlying structures during reoperative cardiac surgery.

Cardiac Surgical Procedures↗
PubMed1991

Tricuspid valve repair for tricuspid valve endocarditis: tricuspid valve "recycling".

Tricuspid valve endocarditis traditionally has been treated with either valve excision or valve replacement. To avoid implantation of foreign material in an infected field, we have applied the principles of mitral valve repair to 4 patients with tricuspid valve endocarditis. On preoperative echocardiography, all patients had 3 to 4+ tricuspid regurgitation, evidence of progressive right ventricular enlargement, and mobile vegetations. In each case, up to three quarters of the anterior leaflet was excised en bloc with infected chordae and papillary muscle heads. Surgical procedures included standard quadrangular resection, conversion to a bicuspid valve, and pericardial patch replacement of the anterior leaflet with mobilization of basal chordae to replace resected marginal chordae. On postoperative echocardiography, tricuspid regurgitation and right ventricular dimensions were reduced in 2 of 4 patients in spite of loss of leaflet tissue. All excised valve tissue demonstrated bacteria on Gram stain or culture. Nonetheless, all repaired valves were successfully sterilized without recurrent infections. Tricuspid valve repair can allow eradication of infection with potential for improving valve competency in complicated tricuspid valve endocarditis.

Echocardiography↗
PubMed1991

Bioactivation of aflatoxin B1 by human liver microsomes: role of cytochrome P450 IIIA enzymes.

Based on our previous observations (H. S. Ramsdell and D. L. Eaton, 1990, Cancer Res. 50, 615-620) that the proportion of aflatoxin B1 (AFB1) converted to the highly reactive AFB1-8,9-epoxide in microsomal incubations varies with substrate concentration, we have examined the hypothesis of T. Shimada and F. P. Guengerich (1989, Proc. Natl. Acad. Sci. USA 86, 462-465) that cytochrome P450 IIIA4 is principally responsible for the activation (epoxidation) of AFB1 by human liver microsomes. The initial rates of formation of AFB1-8,9-epoxide and hydroxylated AFB1 metabolites were determined in microsomes prepared from livers of organ donors (n = 14) at AFB1 concentrations of 124 and 16 microM. Microsomal oxidation of nifedipine, catalyzed primarily by P450 IIIA enzymes, was also determined by HPLC. Rates of formation of AFB1 metabolites and nifedipine oxidation were poorly correlated at either AFB1 concentration (r2 = 0.13-0.41). A somewhat better correlation between AFB1 epoxidation and nifedipine oxidation was observed at 124 microM AFB1 (r2 = 0.41) than at 16 microM AFB1 (r2 = 0.26). Treatment of pooled microsomes with troleandomycin, an apparently specific inhibitor of P450 IIIA enzymes, resulted in 35% inhibition of AFB1-8,9-epoxide formation at the high AFB1 level but had little effect at 16 microM AFB1. An antibody against rat cytochrome P450 IIIA1 significantly inhibited AFB1 epoxidation at high, but not low, AFB1 concentrations, whereas AFQ1 formation was strongly inhibited at all substrate levels examined. These results are consistent with the hypothesis that cytochrome P450 IIIA enzyme(s) can form AFB1-8,9-epoxide, but are effective at only relatively high substrate concentrations. Another P450 enzyme(s) appears to be principally responsible for AFB1-8,9-epoxide formation at the low AFB1 levels that would be typical for dietary exposures.

Aflatoxin B1↗
PubMed1991

Influence of dexmedetomidine and clonidine on human liver microsomal alfentanil metabolism.

Perioperative administration of the alpha 2 agonist clonidine has been shown to increase plasma alfentanil concentrations; however, the mechanism for this pharmacokinetic drug interaction is unknown. Because alfentanil undergoes extensive hepatic biotransformation, clonidine inhibition of alfentanil metabolism may alter alfentanil disposition. The first purpose of this investigation was to test the hypothesis that clonidine impairs human liver alfentanil metabolism. The new highly selective alpha 2 agonist dexmedetomidine (D-medetomidine) is a substituted imidazole and thus may inhibit hepatic drug biotransformation. The second purpose of this study, therefore, was to assess the effect of D-medetomidine and its levo (L) isomer on alfentanil biotransformation. Human liver microsomal alfentanil metabolism was assessed in vitro using a gas chromatography--mass spectrometry assay. Clonidine, at concentrations as great as 10 microM (far exceeding therapeutic levels), had no significant effect on alfentanil oxidation. In contrast, D-medetomidine and its optical isomer L-medetomidine were potent inhibitors of human liver microsomal alfentanil metabolism. The concentration producing 50% inhibition (IC50) of alfentanil (10 microM) oxidation was 0.7-1.0 and 2.8-4.0 microM for D-medetomidine and L-medetomidine, respectively. Preincubation of D-medetomidine with microsomes did not enhance the inhibition of alfentanil metabolism. These results suggest that the increased alfentanil plasma concentrations and potentiation of alfentanil anesthesia associated with clonidine do not result from clonidine inhibition of alfentanil metabolism. D-medetomidine impairment of alfentanil metabolism, however,if present at therapeutic concentrations, may influence alfentanil disposition.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1991

Hemodynamic and metabolic effects of aortic unclamping following emergency surgery for traumatic thoracic aortic tear in shunted and unshunted patients.

Nine cases of traumatic aortic tear treated during 1986-1987 were reviewed. Two patients had functioning Gott shunts, six patients had simple crossclamp, and one patient had a Gott shunt placed which was nonfunctional. Anesthetic management was similar in all patients. Clamp times ranged in unshunted patients from 25 to 38 minutes, and in shunted patients from 42 to 50 minutes. The crossclamp time of the patient with the nonfunctional shunt was 42 minutes. Declamping was accompanied in unshunted patients by decreases in core temperature of up to 1 degree C and acute decreases in PaO2. Marked respiratory and metabolic acidosis occurred with declamping. Respiratory acidosis resolved within 30 minutes with hyperventilation, but metabolic acidosis persisted despite bicarbonate therapy (mean = 1.2 mEq/kg) up to 6 hours after declamping. Associated elevations in serum potassium resolved as pH returned to baseline. Acid-base and electrolyte abnormalities were less marked in patients who were shunted.

Acid-Base Equilibrium↗
PubMed1990

Treatment of traumatic rupture of the thoracic aorta. A 15-year experience.

Traumatic rupture of the thoracic aorta is increasing in incidence and remains a highly lethal injury. The morbidity associated with this injury also remains high. We retrospectively reviewed the records of all patients admitted to our emergency department with ruptured thoracic aortas during a 15-year period to determine the reason for this persistently high morbidity and mortality and to identify any factors that might improve the outcome. We found that patients who are in unstable condition on arrival in the emergency department or who become unstable before reaching the operating room are not likely to survive. Patients who are injured in automobile accidents have a greater chance of survival than do those injured in motorcycle accidents or car-pedestrian accidents. Patients who are in hemodynamically stable condition after aortic injury survive only if diagnosis and treatment are prompt. Major complications of repair following thoracic aortic injury relate primarily to the length of cross-clamp time, and every effort should be devoted to keeping the cross-clamp time less than 30 minutes.

Adult↗
PubMed1990

Chemical synthesis, absolute configuration, and stereochemistry of formation of 10-hydroxywarfarin: a major oxidative metabolite of (+)-(R)-warfarin from hepatic microsomal preparations.

The synthesis of a diastereomerically pure 10-hydroxywarfarin [4-hydroxy-3-(2-hydroxy-3-oxo-1-phenylbutyl)-2H-1 benzopyran-2-one] was accomplished in three steps from racemic warfarin. The relative configuration of the synthetic product was established by conversion to a cyclic derivative followed by NMR and X-ray diffraction analysis. Absolute stereochemistry was determined by enzymatic conversion of either of the pure enantiomers of warfarin to a 10-hydroxy metabolite of known relative configuration. Metabolic formation of 10-hydroxywarfarin was studied using hepatic microsomal preparations from female rats and man. The formation of 10-hydroxywarfarin catalyzed by hepatic microsomes from both dexamethasone-treated rats and man was highly stereoselective [(R)/(S): 3.4-9.0] for (R)-warfarin. In contrast, little stereoselectivity was observed in reactions catalyzed by untreated rat liver microsomes. The resultant stereochemistry at the site of oxidation was also found to be highly dependent on substrate stereochemistry. (R)-Warfarin gave (9R;10S)-10-hydroxywarfarin with only a trace of the (9R;10R) isomer irrespective of which enzyme preparation was used for catalysis, while (S)-warfarin gave (9S;10R)-10-hydroxywarfarin with only a trace of the (9S;10S) isomer, again irrespective of which enzyme preparation was used for catalysis.

Animals↗
PubMed1990

Rapid diagnosis of thoracic aortic transection using intravenous digital subtraction angiography.

Rupture of the thoracic aorta associated with blunt trauma remains a frequently lethal injury. Although increasing numbers of patients with ruptured aortas are surviving to reach the hospital, the in-hospital mortality attending this injury remains high. Death due to transected aorta has been related to a delay in diagnosis. In an attempt to decrease the time necessary for diagnosis of this injury, we studied 50 patients using intravenous digital subtraction angiography (IVDSA) and conventional biplane angiography. We found that IVDSA was significantly faster than conventional biplane angiography, and that when IVDSA films are of diagnostic quality, they are sufficient to reliably demonstrate the presence of traumatic aortic transection. Our study was too small to establish whether IVDSA is a sufficiently sensitive test to exclude aortic injury. Further studies in this area need to be performed.

Angiography, Digital Subtraction↗
PubMed1990

The epidemiology of traumatic rupture of the thoracic aorta in children: a 13-year review.

Traumatic rupture of the thoracic aorta (TRA) is a rare but highly lethal injury in children that occurs as a result of car versus pedestrian accidents and motor vehicle accidents. TRA is often associated with life-threatening injuries to other organ systems. Therefore children with TRA like adults sustaining TRA must be treated urgently but systematically. The rarity of this injury makes it all the more important for physicians treating pediatric trauma victims to be cognizant of the importance of the injury and the clinical and radiographic signs. Even when TRA is promptly recognized in children it is associated with a high in-hospital mortality. The proper use of child restraint systems and adherence to the 55 M.P.H. speed limit may be important factors in reducing the mortality of TRA in children after MVA.

Accidents, Traffic↗
PubMed1990

Upper abdominal wall defects: immediate or staged reconstruction?

One-stage reconstruction of the central and lower abdominal wall with vascularized tissue has been well described. A few cases of one-stage reconstruction of the upper abdomen also are reported. We attempted this procedure in six of seven patients who had large abdominal wall defects that reached the xiphoid process. In three patients, the intraabdominal parts of the procedures went well and the reconstructive goals were accomplished. In three other patients, prolonged and difficult intraabdominal operations resulted in considerable intestinal dilatation that compromised the reconstruction. We therefore recommend being prepared to abort a planned immediate abdominal wall reconstruction following a difficult intraabdominal operation. The abdomen should be temporarily closed with skin flaps, skin grafts, or absorbable mesh, and definitive reconstruction of the fascia should be done at a later operation.

Abdominal Muscles↗
PubMed1989

Empyema thoracis in patients undergoing emergent closed tube thoracostomy for thoracic trauma.

The vast majority of thoracic trauma victims require only observation or tube thoracostomy for definitive treatment of their thoracic injury. Although tube thoracostomy is generally considered a limited intervention, 2 to 25 percent of patients who undergo this procedure develop infectious complications. To determine the incidence and risk factors for the development of empyema thoracis after tube thoracostomy, a retrospective study was undertaken. We found that the development of empyema thoracis was increased in patients whose pleural space was incompletely drained and whose thoracic catheters were in place for a prolonged period.

Adolescent↗
PubMed1989

The sensitivity of vital signs in identifying major thoracoabdominal hemorrhage.

Prehospital and emergency room recordings of hemodynamic vital signs frequently play a major role in the evaluation and treatment of trauma victims. Guidelines for resuscitation and treatment are affected by absolute cutoffs in hemodynamic parameters. To determine the sensitivity of various strata of systolic blood pressure and heart rate in identifying patients with major thoracoabdominal hemorrhage, a 1-year retrospective review was conducted. A third of all patients presented to the emergency department with a normal blood pressure and over three-quarters attained a normal blood pressure during the emergency department evaluation. Although the sensitivity of vital signs in identifying this group of patients improved as the variance from normal increased, standard cutoffs were relatively insensitive. We conclude that normal postinjury vital signs do not predict the absence of potentially life-threatening hemorrhage and abnormal vital signs at any point after injury require investigation to rule out significant blood loss.

Abdominal Injuries↗