Biomedical subjects

A C Eddy

Publications and source records attributed to A C Eddy.

29 records · Page 2Linked to original sources

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↗

PubMed1989

Inhibition of human liver microsomal epoxide hydrolase by valproate and valpromide: in vitro/in vivo correlation.

On the basis of drug interactions with carbamazepine epoxide, it has been hypothesized that valproic acid and valpromide are inhibitors of epoxide hydrolase, but the role of epoxide hydrolase in these interactions has not been clearly established. In this study, therapeutic concentrations of valproic acid (less than 1 mmol/L) and valpromide (less than 10 mumol/L) inhibited hydrolysis of carbamazepine epoxide and styrene oxide in human liver microsomes and in preparations of purified human liver microsomal epoxide hydrolase. Valpromide (KI = 5 mumol/L) was 100 times more potent than valproic acid (KI = 550 mumol/L) as an inhibitor of carbamazepine epoxide hydrolysis in microsomes. After administration of carbamazepine epoxide to volunteers, the transdihydrodiol formation clearance was decreased 20% by valproic acid (blood concentration approximately 113 mumol/L) and 67% by valpromide (blood concentration less than 10 mumol/L). For both valproic acid and valpromide, a striking similarity exists between in vitro and in vivo inhibitory potencies. Valproic acid and valpromide are the first drugs known to inhibit microsomal epoxide hydrolase, an important detoxification enzyme, at therapeutic concentrations.

Anticonvulsants↗

PubMed1989

Lack of effect of cimetidine on acetaminophen disposition in humans.

The effect of cimetidine administration on the disposition of acetaminophen was evaluated in seven men and six women. One gram of acetaminophen was administered to each volunteer after an overnight fast on two occasions in a balanced crossover design with and without cimetidine, 300 mg every 6 hours beginning 50 hours before acetaminophen administration and continuing for 22 hours after. N-Acetylcysteine was administered on both occasions when acetaminophen was ingested to protect against glutathione depletion. Blood samples were collected serially for 12 hours after acetaminophen administration, and total urine volume was collected for 24 hours. Fractional clearances of acetaminophen through renal and metabolic routes (sulfation, glucuronidation, 3-hydroxylation, and glutathione conjugate formation) were not altered by cimetidine administration. Studies in microsomes prepared from two human organ donors indicated that cimetidine inhibited acetaminophen reactive metabolite formation noncompetitively, with Ki values of 0.35 mmol/L and 0.32 mmol/L for the respective livers, which is 5 to 10 times the putative cimetidine concentration required for therapeutic effect.

Acetaminophen↗

PubMed1989

Traumatic rupture of the thoracic aorta in the pediatric patient.

Traumatic rupture of the thoracic aorta is rare in pediatric patients. Proper management of this injury is essential and requires a systematic approach, similar to that used in adult patients. Preoperatively, the multiply injured child must have other injuries properly prioritized and addressed. Proper selection of graft size, expeditious intraoperative management, and careful postoperative management result in a minimal number of complications associated with this injury.

Accidents, Traffic↗

PubMed1988

Right ventricular dysfunction in multiple trauma victims.

We studied 17 victims of multiple trauma and found that right ventricular function can be reliably monitored at the bedside using the thermodilution method. In addition, we noted that right ventricular dysfunction occurred early in victims of major trauma without affecting the left ventricular function. If right ventricular function does not improve, the patient is likely to die. Further studies are needed to determine if early intervention aimed at improving right ventricular function can improve survival.

Adolescent↗

PubMed1988

Traumatic pneumoperitoneum following combined abdominal and thoracic injury.

Pneumoperitoneum following blunt abdominal trauma in the absence of other signs of severe intraabdominal injury is a rare finding. Although the vast majority of all cases of pneumoperitoneum are due to a ruptured intraabdominal hollow viscus, free abdominal air may result from significant barotrauma to the thorax. This type of secondary pneumoperitoneum can occur in the absence of chest x-ray evidence of a pneumothorax or pneumomediastinum. The complications associated with a missed visceral injury warrant an exploratory laparotomy, even if an extraabdominal source for the pneumoperitoneum is suspected.

Abdominal Injuries↗

PubMedDate not supplied

Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions.

Previous kinetic studies have identified a high-affinity (S)-warfarin 7-hydroxylase present in human liver microsomes which appears to be responsible for the termination of warfarin's biological activity. Inhibition of the formation of (S)-7-hydroxywarfarin, the inactive, major metabolite of racemic warfarin in humans, is known to be the cause of several of the drug interactions experienced clinically upon coadministration of warfarin with other therapeutic agents. In order to identify the specific form(s) of human liver cytochrome P-450 involved in this particular toxicity, we have determined the metabolic profiles of 11 human cytochrome P-450 forms expressed in HepG2 cells toward both (R)- and (S)-warfarin. Of the 11 forms examined only 2C9 displayed the regioselectivity and stereoselectivity appropriate for the high-affinity human liver microsomal (S)-7-hydroxylase. We further compared Michaelis-Menten and sulfaphenazole inhibition constants for (S)-warfarin 7-hydroxylation catalyzed by cDNA-expressed 2C9 and by human liver microsomes. Similar kinetic constants were obtained for each enzyme source. It is concluded that 2C9 is likely to be a principal form of human liver P-450 which modulates the in vivo anticoagulant activity of the drug. It is further concluded that those drug interactions with warfarin that arise as a result of decreased clearance of the biologically more potent S-enantiomer may have as their common basis the inhibition of P-450 2C9.

Aryl Hydrocarbon Hydroxylases↗

PubMedDate not supplied

Carbamazepine dose requirements during stiripentol therapy: influence of cytochrome P-450 inhibition by stiripentol.

The inhibitory effect of stiripentol (STP) on disposition of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZE) was quantitated to establish CBZ dosage reduction guidelines for future clinical add-on efficacy trials of STP. In seven epileptic patients, STP (1,500-3,000 mg/day for 2 weeks) inhibited CBZ clearance by 50 +/- 16% (p = 0.001) and reduced the CBZE/CBZ plasma ratio by 45 +/- 14% (p = 0.0005). The inhibitory effect was gradually manifested over a period of 7-10 days after initiation of STP therapy. In contrast to inhibition of CBZE formation, STP had no effect (p greater than 0.05) on elimination clearance or half-life (t1/2) of CBZE in six healthy volunteers. STP most likely exerts inhibitory effects through inhibition of cytochrome P-450. This hypothesis was confirmed in the present study by the finding that a therapeutic concentration of STP (7 micrograms/mL) inhibited 10,11-epoxidation of CBZ in human liver microsomes by 40-50%. On the basis of results from this study, we propose that (a) CBZ dosage should be reduced in steps over a period of 7-10 days after initiation of STP, and (b) a CBZ dosage of 4.3 to 8.7 mg/kg/day will maintain therapeutic CBZ plasma levels of 5-10 micrograms/mL.

Adult↗

PubMedDate not supplied

Stereoselective sulfoxidation by human flavin-containing monooxygenase. Evidence for catalytic diversity between hepatic, renal, and fetal forms.

The stereoselective formation of p-tolyl methyl sulfoxide from the corresponding sulfide has been examined in detergent-solubilized human adult liver, adult kidney, and fetal liver microsomes, in order to compare the functional activities of human flavin-containing monooxygenase(s). Solubilization with detergent was performed to eradicate the contribution that cytochrome P-450 would make to the net stereochemistry. Consistent with studies in experimental animal livers, solubilized human fetal liver and adult kidney microsomes formed (R)-p-tolyl methyl sulfoxide in greater than 86% enantiomeric excess. These enzyme activities were sensitive to methimazole inhibition and were markedly thermolabile in the absence of NADPH, attributes that are consistent with a flavin-containing monooxygenase-mediated process. However, solubilized adult human liver microsomes displayed little stereoselectivity (0-40% enantiomeric excess) for the formation of (R)-p-tolyl methyl sulfoxide, although this reaction also displayed several of the characteristics of a flavin-containing monooxygenase-dependent process, including sensitivity to methimazole inhibition and NADPH protection against heat inactivation. Furthermore, this lack of stereoselectivity was not attenuated by the inclusion of activated oxygen scavengers in reaction mixtures. Human tissue metabolite profiling was further studied by using the ethyl, propyl, and isopropyl p-tolyl sulfides. Parallel changes in product stereochemistry as a function of increasing steric bulk were observed with the fetal liver and adult kidney tissue, whereas an anomalous profile was again observed with adult human liver. These data are consistent with the presence of functionally discrete complements of the flavin-containing monooxygenase in detergent-solubilized adult and fetal human liver microsomes.

Adult↗

PubMedDate not supplied

Characteristics of warfarin hydroxylation catalyzed by human liver microsomes.

The oxidative biotransformation of (R)- and (S)-warfarin was studied in human liver microsomes to determine whether an in vitro model could be established that would correspond to the in vivo profile that is generally observed. The quantitative pattern of oxidized products obtained from warfarin in vitro changed dramatically as a function of substrate concentration. Apparent Km values for the formation of 4', 6, 7, and 8-hydroxywarfarin indicated the presence of two easily distinguishable subsets of human liver cytochrome P-450; a high affinity subset (Km 3-15 microM) and a low affinity subset of isozymes (Km greater than 200 microM). The high affinity subset is primarily responsible for the metabolic profile of the biologically more potent (S)-enantiomer in vivo, whereas the low affinity subset is largely responsible for metabolism of the (R)-enantiomer. Apparent Vmax values alone did not reflect the relative in vivo formation clearances of the phenolic metabolites from either antipode, because the low affinity-high capacity component masked the metabolic profile of the (S)-enantiomer. However, the rank order of intrinsic clearance, Vmax/Km, for each metabolite was in good agreement with regio- and stereoselective metabolism in vivo. This investigation highlights the need for rigorous kinetic characterization of an in vitro model before reasonable correlation can be expected with in vivo data.

Humans↗

PubMedDate not supplied

Inhibition of the enantioselective oxidative metabolism of metoprolol by verapamil in human liver microsomes.

In an effort to investigate the metabolic basis of previously reported pharmacokinetic interactions between beta-adrenergic antagonists and calcium channel blockers, the effects of verapamil on the oxidative metabolism of metoprolol were studied in microsomes isolated from four human livers. Deuterium-labeled pseudoracemic metoprolol was used to characterize the substrate stereoselectivity of this metabolic interaction. Biphasic kinetics were observed for both the alpha-hydroxylation and O-demethylation of metoprolol, suggesting that multiple P-450 enzymes with differing KMs are involved in the formation of these oxidative metabolites. alpha-Hydroxylation showed a slight preference for S-(-)-metoprolol, and it was largely mediated by a high-affinity enzyme over a wide range of substrate concentrations. The high-affinity component of the O-demethylation reaction exhibited significant selectivity for the R-(+)-enantiomer. The opposite enantioselectivity was observed for the low-affinity component of O-demethylation. Racemic verapamil inhibited both the alpha-hydroxylation and the O-demethylation of metoprolol. The kinetics of inhibition were consistent with competitive effects of verapamil on the high-affinity components of both oxidative pathways, which previously had been suggested to be mediated by CYP2D6. Potent inhibition of the low-affinity component of O-demethylation was also observed. The inhibitory effect of verapamil on the alpha-hydroxylation of metoprolol was not enantioselective. On the other hand, verapamil preferentially inhibited the O-demethylation of R-(+)-metoprolol compared with S-(-)-metoprolol at low substrate concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytochrome P-450 Enzyme System↗