Biomedical subjects

C E Wright

Publications and source records attributed to C E Wright.

At least 37 records · Page 2Linked to original sources

PubMed2000

Comparative kinetics and response to the benzodiazepine agonists triazolam and zolpidem: evaluation of sex-dependent differences.

Eighteen healthy volunteers (10 men and 8 women) participated in a single-dose, double-blind, three-way crossover pharmacokinetic and pharmacodynamic study. Treatment conditions were 0.25 mg of triazolam, a full-agonist benzodiazepine ligand; 10 mg of zolpidem, an imidazopyridine having relative selectivity for the type 1 benzodiazepine receptor subtype; and placebo. Weight-normalized clearance of triazolam was higher in women than in men (8.7 versus 5. 5 ml/min/kg), but the difference was not significant. In contrast, zolpidem clearance was lower in women than in men (3.5 versus 6.7 ml/min/kg, P <.06). Compared to placebo, both active medications produced significant benzodiazepine agonist-like pharmacodynamic effects: sedation, impaired psychomotor performance, impaired information recall, and increased electroencephalographic beta-amplitude. Effects of triazolam and zolpidem in general were comparable and less than 8 h in duration. There was no evidence of a substantial or consistent sex difference in pharmacodynamic effects or in the kinetic-dynamic relationship, although subtle differences could not be ruled out due to low statistical power. The complete dependence of triazolam clearance on CYP3A activity, as opposed to the mixed CYP participation in zolpidem clearance, may explain the differing sex effects on clearance of the two compounds.

Adult↗

PubMed1999

Risk neutralization in cardiac operations: detection and treatment of associated carotid disease.

BACKGROUND: A screening and treatment protocol was implemented to extend the benefit of prophylactic carotid endarterectomy to patients who had open heart operations. METHODS: Patients aged 65 or older or who at any age had left main coronary disease, transient ischemic attack, or stroke were eligible for preoperative carotid duplex screening. Carotid endarterectomies and open heart operations were planned as a staged (n = 59) or combined procedure (n = 55) for angiographically confirmed carotid stenosis of at least 80%. RESULTS: Duplex scans were obtained in 1,719 of 7,035 open heart surgical patients over 8 years. The overall stroke rate was 1.5% (108 of 7,035). Seven of these were strokes of carotid origin (0.1%). There were 129 patients with at least 80% stenosis. One hundred fourteen had carotid endarterectomy preceding open heart operation, and none had carotid artery stroke. Twelve patients with at least 80% carotid stenosis by duplex scan had open heart operations without prophylactic carotid endarterectomies. There were four carotid strokes in these 12 patients (p = 0.0001; odds ratio, 20.2). Stroke risk remained significantly elevated (16.8%, p = 0.005) in the 50% to 79% group. The changes associated with the reduced risk afforded by this screening and treatment strategy amounted to $346 for each patient in the study. CONCLUSIONS: The risk of carotid stroke at the time of cardiac operation can be defined by duplex screening. Prophylactic carotid endarterectomy neutralizes the risk in those with at least 80% stenosis. Consideration for lowering the threshold for assessment and treatment of carotid stenoses appears warranted. The economic investment is recouped by the savings in system resources that would have been depleted through care for carotid stroke and its sequelae.

Adult↗

PubMed1999

A randomized trial of endoscopic versus open saphenous vein harvest in coronary bypass surgery.

BACKGROUND: The purpose of this study was to determine whether or not endoscopic vein harvest is a reliable, beneficial, and cost-effective method for saphenous vein harvest in coronary bypass surgery (CABG). METHODS: A total of 100 patients having primary CABG were prospectively randomized to either endoscopic (EVH; n = 47) or open saphenous vein harvest (OVH; n = 50). Three patients in the EVH group required both techniques and were excluded from analysis. RESULTS: The groups did not differ in preoperative characteristics, including: age, gender, left ventricular function, height, weight, percent over ideal body weight, incidence of diabetes, peripheral vascular disease, or preoperative laboratory values (creatinine, albumin, or hematocrit). The EVH group had longer vein harvest and preparation times than the OVH group, while the incision length was significantly shorter. There was no difference between groups in mortality, perioperative myocardial infarction, intensive care unit or postoperative length of stay, blood product utilization, or discharge laboratory measures. There was more drainage noted from leg incisions at hospital discharge in the OVH (34%) versus EVH group (8%; p = 0.001), but more ecchymosis in the EVH group. Although there was a trend towards reduced leg incision pain in the EVH group, there was no statistically significant difference in pain or in the quality of life measure at any point in time. There was no difference between groups in readmission to hospital, administration of antibiotics, or incidence of leg infection. While mean hospital charges for the EVH group were approximately $1,500 greater than for OVH, this difference did not reach statistical significance. CONCLUSIONS: EVH is a safe, reliable, and cost-neutral method for saphenous vein harvest. The best indication for EVH may be in patients who are at increased risk for wound infection and in those for whom cosmesis is a major concern.

Aged↗

PubMed1999

A prospective randomized study of megestrol acetate and ibuprofen in gastrointestinal cancer patients with weight loss.

The use of megestrol acetate in the treatment of weight loss in gastrointestinal cancer patients has been disappointing. The aim of the present study was to compare the combination of megestrol acetate and placebo with megestrol acetate and ibuprofen in the treatment of weight loss in such patients. At baseline, 4-6 weeks and 12 weeks, patients underwent measurements of anthropometry, concentrations of albumin and C-reactive protein and assessment of appetite, performance status and quality of life using EuroQol-EQ-5D and EORTC QLQ-C30. Thirty-eight and 35 patients (median weight loss 18%) were randomized to megestrol acetate/placebo or megestrol acetate/ibuprofen, respectively, for 12 weeks. Forty-six (63%) of patients failed to complete the 12-week assessment. Of those evaluable at 12 weeks, there was a decrease in weight (median 2.8 kg) in the megestrol acetate/placebo group compared with an increase (median 2.3 kg) in the megestrol acetate/ibuprofen group (P<0.001). There was also an improvement in the EuroQol-EQ-5D quality of life scores of the latter group (P<0.05). The combination of megestrol acetate/ibuprofen appeared to reverse weight loss and appeared to improve quality of life in patients with advanced gastrointestinal cancer. Further trials of this novel regimen in weight-losing patients with hormone-insensitive cancers are warranted.

Aged↗

PubMed1999

Heterogeneity of prejunctional NPY receptor-mediated inhibition of cardiac neurotransmission.

Neuropeptide Y (NPY) has been proposed as the candidate inhibitory peptide mediating interactions between sympathetic and vagal neurotransmission in several species, including man. Here, we have defined the NPY receptors involved in modulation of cardiac autonomic neurotransmission using receptor-selective agonists and antagonists in the rabbit and guinea-pig isolated right atria. In isolated atrial preparations, sympathetically-mediated tachycardia (ST; with atropine 1 microM) or vagally-mediated bradycardia (VB; with propranolol 0.1-1 microM) in response to electrical field stimulation (EFS, 1-4 pulses) were tested 0-30 min after incubation with single concentrations of vehicle, NPY (0.01-10 microM), the Y2 receptor agonist N-Acetyl-[Leu28,31]NPY(24-36) (termed N-A[L]NPY(24-36)) or the Y1 receptor agonist [Leu31,Pro34]NPY (LP). The effect of NPY on the concentration-chronotropic response curves to isoprenaline and bethanechol were also assessed. Guinea-pig atria: NPY and N-A[L]NPY(24-36) caused concentration-dependent inhibition of VB and ST to EFS. Both peptides caused maximal inhibition of VB and ST within 10 min incubation and this remained constant. LP caused a concentration-dependent, transient inhibition of ST which was antagonized by the Y1-receptor antagonist GR231118 (0.3 microM), with apparent competitive kinetics. Rabbit atria: NPY (1 or 10 microM) had no effect on VB at any time point, but both NPY and LP caused a transient (approximately 10 min) inhibition of sympathetic tachycardia. This inhibition could be prevented by 0.3 microM GR231118. N-A[L]NPY(24-36) had no effect on ST. NPY had no effect on the response to beta-adrenoceptor stimulation by isoprenaline nor muscarinic-receptor stimulation by bethanechol in either species. Thus, in the guinea-pig, NPY causes a stable inhibition of both VB and ST to EFS via Y2 receptors and transient inhibition of ST via Y1 receptors. In contrast in the rabbit, NPY has no effect on the cardiac vagus and prejunctional inhibition of ST is transient and mediated by a Y1-like receptor (rather than Y2). Therefore it would be surprising if NPY plays a functional role in modulation of cardiac neurotransmission in the rabbit.

Animals↗

PubMed1999

The antitussive effect of dextromethorphan in relation to CYP2D6 activity.

AIMS: To test the hypothesis that inhibition of cytochrome P450 2D6 (CYP2D6) by quinidine increases the antitussive effect of dextromethorphan (DEX) in an induced cough model. METHODS: Twenty-two healthy extensive metaboliser phenotypes for CYP2D6 were studied according to a double-blind, randomised cross-over design after administration of: (1) Placebo antitussive preceded at 1 h by placebo inhibitor; (2) 30 mg oral DEX preceded at 1 h by placebo inhibitor (DEX30); (3) 60 mg oral DEX preceded at 1 h by placebo inhibitor (DEX60); (4) 30 mg oral DEX preceded at 1 h by 50 mg oral quinidine sulphate (QDEX30). Cough frequency following inhalation of 10% citric acid was measured at baseline and at intervals up to 12 h. Plasma concentrations of DEX and its metabolites were measured up to 96 h by h.p.l.c. RESULTS: Inhibition of CYP2D6 by quinidine caused a significant increase in the mean ratio of DEX to dextrorphan (DEX:DOR) plasma AUC(96) (0.04 vs 1.81, P<0.001). The mean (+/-s.d.) decrements in cough frequency below baseline over 12 h (AUEC) were: 8% (11), 17% (14.5), 25% (16.2) and 25% (16.9) for placebo, DEX30, DEX60 and QDEX30 treatments, respectively. Statistically significant differences in antitussive effect were detected for the contrasts between DEX60/placebo (P<0.001; 95% CI of difference +80, +327) and QDEX30/placebo (P<0.001, +88, +336), but not for DEX30/placebo, DEX30/DEX60 or DEX30/QDEX30 (P=0.071, -7, +241; P=0.254, -37, +211; P=0.187, -29, +219, respectively). CONCLUSIONS: A significant antitussive effect was demonstrated after 60 mg dextromethorphan and 30 mg dextromethorphan preceded by 50 mg quinidine using an induced cough model. However, although the study was powered to detect a 10% difference in cough response, the observed differences for other contrasts were less than 10%, such that it was possible only to imply a dose effect (30 vs 60 mg) in the antitussive activity of DEX and enhancement of this effect by CYP2D6 inhibition.

Adolescent↗

PubMed1999

Enhanced total peripheral vascular responsiveness in hypertension accords with the amplifier hypothesis.

BACKGROUND: Increases in vascular resistance (or the reciprocal, vascular conductance) in response to constrictor drugs are amplified (or attenuated) in the hindquarter vascular bed of hypertensive rats and rabbits. However, such changes have not been observed for the total peripheral circulation. OBJECTIVE: To assess whether the vascular amplifier applies to the total peripheral circulation in conscious hypertensive rabbits. METHODS: Rabbits were implanted with a flow probe for measuring cardiac output, a left atrial catheter for infusing dilator (adenosine) and constrictor (methoxamine) drugs, and ear artery and vein catheters for measuring mean arterial pressure (MAP) and for giving ganglion blockade. Data from full dose-total peripheral resistance (TPR) or total peripheral conductance (TPC) response curves to adenosine and methoxamine were combined into a logistic function extending from near full dilatation to near maximum constriction. RESULTS: Changes in MAP induced by methoxamine and adenosine were markedly greater in the 'wrap' rabbits (those with renal cellophane wrapping) compared with the sham animals. In the 'wrap' rabbits, the slopes and ranges of the adenosine-TPR response curve and the methoxamine-TPC response curve were 200% and 60%, respectively, of sham values. These data show that TPR changes are amplified, and TPC changes attenuated, to dilator and constrictor stimuli. The relationship between dose-average vascular radius (r; based on Poiseuille's law) over the full range of vascular tone showed that r was narrower in hypertension, but, in contrast to TPR, the degree of narrowing was almost the same between maximum dilatation and constriction. CONCLUSION: The total peripheral circulation in experimental hypertension is a TPR amplifier, or TPC attenuator, in the rabbit, consistent with well-established data in the major vascular beds.

Adenosine↗

PubMed1999

In vivo regulation of beta-MHC gene in rodent heart: role of T3 and evidence for an upstream enhancer.

Cardiac beta-myosin heavy chain (beta-MHC) gene expression is mainly regulated through transcriptional processes. Although these results are based primarily on in vitro cell culture models, relatively little information is available concerning the interaction of key regulatory factors thought to modulate MHC expression in the intact rodent heart. Using a direct gene transfer approach, we studied the in vivo transcriptional activity of different-length beta-MHC promoter fragments in normal control and in altered thyroid states. The test beta-MHC promoter was fused to a firefly luciferase reporter gene, whereas the control alpha-MHC promoter was fused to the Renilla luciferase reporter gene and was used to account for variations in transfection efficiency. Absolute reporter gene activities showed that beta- and alpha-MHC genes were individually and reciprocally regulated by thyroid hormone. The beta-to-alpha ratios of reporter gene expression demonstrated an almost threefold larger beta-MHC gene expression in the longest than in the shorter promoter fragments in normal control animals, implying the existence of an upstream enhancer. A mutation in the putative thyroid response element of the -408-bp beta-MHC promoter construct caused transcriptional activity to drop to null. When studied in the -3, 500-bp beta-MHC promoter, construct activity was reduced ( approximately 100-fold) while thyroid hormone responsiveness was retained. These findings suggest that, even though the bulk of the thyroid hormone responsiveness of the gene is contained within the first 215 bp of the beta-MHC promoter sequence, the exact mechanism of triiodothyronine (T3) action remains to be elucidated.

Animals↗

PubMed1999

The LifeLink Foundation and cadaver kidney transplantation in Tampa.

1. LifeLink Foundation, a not-for-profit organization, has been the driving force and absolutely essential entity for kidney and liver transplantation in Tampa providing all the components (patient, organs and clinicians) save for inpatient hospitalization. It also plays a big role in the heart transplant program. LifeLink has increased the kidney transplant rate from the first 1,000 done in 17 years to the second 1,000 in 7 years and is on a pace for the third 1,000 in 5 1/2 years. 2. Because of its innovative programs, cadaver donor procurement by the Tampa LifeLink OPO has been roughly double the national average for the past 10 years. Because of cadaver kidney availability the median wait time from activation on the wait list to transplantation over the past 5 years was 159 days. The recent transplant rate is 14.7-22.7% higher than the national average, dependent upon the parameter measured. Similar results are seen for Tampa patients awaiting heart and liver transplantation. 3. The overall outcome of 1,184 cadaver kidney transplants performed in the decade 1989-98 was similar to that reported from the UNOS database in this series of publications. a) One- and 2-year graft survival increased 2% per year over the decade with a recent one-year graft survival rate of 96%. The overall T1/2 was 10 years. b) Our disastrous 1994 results were quickly reversed by a more intense pretransplant medical evaluation, the introduction of mycophenolate mofetil, more aggressive and earlier treatment of rejection episodes, and mandatory T- and B-cell flow cytometry crossmatching for all transplants. The incidence of rejection episodes decreased from 40 to 20%, and the first year immunological graft loss decreased from 5%, to 1.9%, to 0.8%, to 1.4% and 0% over the succeeding 4 years. 4. Individual factors affecting allograft survival were strikingly similar to national data, although all did not react statistical significance probably due to the smaller numbers. a) Primary and second grafts had similar survival rates (p = 0.97) whereas the third or subsequent graft survival was 7-32% poorer (p = 0.02). b) Black recipients had survival rates 10-13% lower than Caucasians and other races (p = 0.003). c) Patients with a peak PRA > 50 had survival values 4-13% poorer than those with < 50 PRA (p = 0.14). d) Patients with 2-4 HLA mismatches had graft survival rates 4-10% poorer than those with 0-1 mismatch (p = 0.12), whereas those with 5-6 mismatches had rates 6-17% poorer (p = 0.04). e) Although 22% of our transplants were to patients > 60 years of age, there was no difference (p = 0.81 to 0.90) in graft survival for the age groups 0-40, 41-60 and > 61. However, the proportion of grafts lost due to patient death compared with all allografts lost, was very different at 21% in the youngest group, 43% in those 41-60 years of age, and 63% in recipients > 61 years. 5. The rate of delayed graft function with imported kidneys was higher (27 vs. 16%, p = 0.006) but essentially the same as local kidneys with the same ischemia times. However, 41% of local kidneys were transplanted within 12 hours of procurement. Totally, 78% of local kidneys were transplanted within 18 hours (11% DGF rate) versus 79% of imports being transplanted at > 18 hours (32% DGF rate). Ischemia time, not the kidney source is the key issue since: a) There was no difference in overall graft survival of imported versus local kidneys (p = 0.95) nor in comparing local versus import kidneys with (p = 0.66) or without (p = 0.69) DGF. b) There was, however, a 11-17% overall poorer graft survival over 3 years in kidneys with DGF (p < 0.001) seen with both local (9-18% poorer, p = 0.0002) and imported (12-19% poorer, p = 0.008) kidneys. c) Kidneys displaying DGF came from older donors (40 vs. 34 years, p = 0.023) and had longer ischemia times (21 vs. 15 hours, p < 0.0005). 6. Dual kidney transplants were started in late 1996 with older or marginal donors to provide a better chance of success fo

Adolescent↗

PubMed1999

Clinical outcomes and angiographic patency in 125 consecutive off-pump coronary bypass patients.

BACKGROUND: This study compared clinical outcomes, length of stay, and hospital costs in patients having off-pump coronary bypass (OPCAB) versus conventional bypass surgery (CABG). METHODS: From November 1996 through April 9, 1999, OPCAB was performed for 125 consecutive patients and compared with a contemporaneous, matched control group of 625 CABG patients. Patients were matched according to age, gender, incidence of renal failure, diabetes, pulmonary disease, stroke (CVA), hypertension, peripheral vascular disease, and previous myocardial infarction. Follow-up in the OPCAB patients was 100% and averaged 15 months. RESULTS: An average of 2.0 grafts per patient were performed in the OPCAB group (range 1-5). Ninety-four OPCAB patients (75.2%) had a total of 179 grafts assessed angiographically prior to hospital discharge. All but 4/179 grafts (2.2%) were patent, including 94 of 94 IMA grafts (100%). There were no in-hospital deaths in the OPCAB group compared to a mortality rate of 1.4% in the CABG group. OPCAB reduced postoperative hospital stay from 5.5 days in the traditional CABG group to 3.3 days (p=.002), with a decrease in hospital cost of 24% (p = .01). In addition, there was a significant reduction in the rate of transfusion in the OPCAB group (29.6%) compared to the CABG group (56.5%, p = .0001). Two OPCAB patients required postoperative intervention to improve graft patency during the follow-up period. No internal mammary grafts required revision. There was one perioperative CVA and one myocardial infarction in the OPCAB group. CONCLUSIONS: OPCAB surgery reduces hospital cost, postoperative length of stay, and transfusion rate compared to CABG. OPCAB is safe, cost effective, and associated with excellent graft patency and clinical outcomes.

Chi-Square Distribution↗

PubMed1998

In vitro approaches to predicting drug interactions in vivo.

In vitro metabolic models using human liver microsomes can be applied to quantitative prediction of in vivo drug interactions caused by reversible inhibition of metabolism. One approach utilizes in vitro Ki, values together with in vivo values of inhibitor concentration to forecast in vivo decrements of clearance caused by coadministration of inhibitor. A critical limitation is the lack of a general scheme for assigning intrahepatic exposure of enzyme to inhibitor or substrate based only on plasma concentration; however, the assumption that plasma protein binding necessarily restricts hepatic uptake is not tenable. Other potential limitations include: flow-dependent hepatic clearance, "mechanism-based" chemical inhibition, concurrent induction, or a major contribution of gastrointestinal P450-3A isoforms to presystemic extraction. Nonetheless, the model to date has provided reasonably accurate forecasts of in vivo inhibition of clearance of several substrates (desipramine, terfenadine, triazolam, alprazolam, midazolam) by coadministration of selective serotonin reuptake-inhibitor antidepressants and azole antifungal agents. Such predictive models deserve further evaluation, since they may ultimately yield more cost-effective and expeditious screening for drug interactions, with reduced human drug exposure and risk.

Animals↗

PubMed1998

Do alprazolam-induced changes in saccadic eye movement and psychomotor function follow the same time course?

The purpose of this study was to determine whether short-term tolerance develops to GABA-agonist-induced changes in saccadic eye movements (SEMs), and whether the time course for GABA-agonist induced onset and offset of impairment is similar for SEMs and for psychomotor function. An additional goal was to determine whether there are differences in sensitivity between SEMs and psychomotor function. Six healthy volunteers participated in this balanced double-blind, three-way crossover, single-dose study of placebo and two different dosage forms of the GABA-agonist alprazolam: a rapidly absorbed oral 1.5-mg compressed tablet (CT) and a 3.0-mg sustained release (SR) tablet. Treatments were separated by a 7-day washout period. Peak concentrations did not differ between CT and SR treatments, although area under the concentration-time curve (AUC) of alprazolam was greater after administration of SR than after CT, because plateau concentrations were attained after SR. Both SEM and psychomotor tests showed time-dependent responses consistent with the development of tolerance. SEMs discriminated the differences in rate of drug input of the CT and SR formulations, with impairment evident at low concentrations during absorption. SEM impairment also persisted longer than did psychomotor impairment. Peak saccade velocity is a more sensitive indicator of pharmacologic effects mediated by the GABA-benzodiazepine receptor complex than are psychomotor responses. This is probably the result of the very high GABA dependency of SEMs, along with their limited sensitivity to motivation.

Adult↗

PubMed1998

Off-pump multivessel coronary bypass via sternotomy is safe and effective.

BACKGROUND: In an attempt to avoid the deleterious effects of cardiopulmonary bypass, off-pump coronary artery bypass grafting has been rediscovered and refined. The purpose of this study was to compare clinical outcomes, length of stay, and hospital costs with coronary artery bypass grafting on cardiopulmonary bypass. METHODS: Coronary artery bypass was performed on 51 patients without cardiopulmonary bypass. Patients were selected on the basis of coronary anatomy, with significant stenoses in the left anterior descending, ramus intermedius, diagonal, right coronary, acute marginal, or posterior descending territories. Outcomes were compared with those of a computer-generated matched control group having coronary artery bypass grafting on cardiopulmonary bypass (n = 248) during the same time period. RESULTS: No preoperative differences were noted between groups. There were no deaths in the off-pump group and a mortality rate of 1.6% (4/248) in the control group. There was no incidence of stroke, myocardial infarction, or reentry for bleeding among patients in the off-pump group. There was a reduction in length of stay by 3 days (p = 0.01), blood transfusions by 50% (p = 0.0001), and hospital charges by one third (p = 0.05) in the off-pump group. Twenty-six patients had repeat coronary angiography before discharge; 41/43 grafts were widely patent, 1/43 was totally occluded, and 1/43 was narrowed by more than 50%. All internal mammary artery grafts were widely patent. CONCLUSIONS: Off-pump multivessel cardiopulmonary bypass grafting is a safe and effective means of revascularization for patients with coronary stenoses in the anterior or inferior regions, with excellent short-term patency rates and minimal morbidity.

Blood Transfusion↗

PubMed1998

Modifying risk for extracorporeal circulation: trial of four antiinflammatory strategies.

BACKGROUND: Despite recent rediscovery of beating heart cardiac surgical techniques, extracorporeal circulation remains appropriate for most heart operations. To minimize deleterious effects of cardiopulmonary bypass, antiinflammatory strategies have evolved. METHODS: Four state-of-the-art strategies were studied in a prospective, randomized, preoperatively risk stratified, 400-patient study comprising primary (n = 358), reoperative (n = 42), coronary (n = 307), valve (n = 27), ascending aortic (n = 9), and combined operations (n = 23). Groups were as follows: standard, roller pump, membrane oxygenator, methylprednisolone (n = 112); aprotinin, standard plus aprotinin (n = 109); leukocyte depletion, standard plus a leukocyte filtration strategy (n = 112); and heparin-bonded circuitry, centrifugal pumping with surface modification (n = 67). RESULTS: Analysis of variance, linear and logistic regression, and Pearson correlation were applied. Actual mortality (2.3%) was less than half the risk stratification predicted mortality (5.7%). The treatment strategies effectively attenuated markers of the inflammatory response to extracorporeal circulation. Compared with the other groups the heparin-bonded circuit had highly significantly decreased complement activation (p = 0.00001), leukocyte filtration blunted postpump leukocytosis (p = 0.043), and the aprotinin group had less fibrinolysis (p = 0.011). Primary end points, length of stay, and hospital charges, were positively correlated with operation type, age, pump time, body surface area, stroke, pulmonary sequelae, predicted risk for stroke, predicted risk for mortality, and risk strata/treatment group interaction (p = 0.0001). In low-risk patients, leukocyte filtration reduced length of stay by 1 day (p = 0.02) and mean charges by $2,000 to $6,000 (p = 0.05). For high-risk patients, aprotinin reduced mean length of stay up to 10 fewer days (p = 0.02) and mean charges by $6,000 to $48,000 (p = 0.0007). CONCLUSIONS: These pharmacologic and mechanical strategies significantly attenuated the inflammatory response to extracorporeal circulation. This translated variably into improved patient outcomes. The increased cost of treatment was offset for selected strategies through the added value of significantly reduced risk.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1998

Ketoconazole inhibition of triazolam and alprazolam clearance: differential kinetic and dynamic consequences.

BACKGROUND: Kinetic and dynamic consequences of metabolic inhibition were evaluated in a study of the interaction of ketoconazole, a P4503A inhibitor, with alprazolam and triazolam, two 3A substrate drugs with different kinetic profiles. METHODS: In a double-blind, 5-way crossover study, healthy volunteers received (A) ketoconazole placebo plus 1.0 mg alprazolam orally, (B) 200 mg ketoconazole twice a day plus 1.0 mg alprazolam, (C) ketoconazole placebo plus 0.25 mg triazolam orally, (D) 200 mg ketoconazole twice a day plus 0.25 mg triazolam, and (E) 200 mg ketoconazole twice a day plus benzodiazepine placebo. Plasma concentrations and pharmacodynamic parameters were measured after each dose. RESULTS: For trial B versus trial A, alprazolam clearance was reduced (27 versus 86 mL/min; P < .002) and apparent elimination half-life (t1/2) prolonged (59 versus 15 hours; P < .03), whereas peak plasma concentration (Cmax) was only slightly increased (16.1 versus 14.7 ng/mL). The 8-hour pharmacodynamic effect areas for electroencephalographic (EEG) beta activity were increased by a factor of 1.35, and those for digit-symbol substitution test (DSST) decrement were increased by 2.29 for trial B versus trial A. For trial D versus trial C, triazolam clearance was reduced (40 versus 444 mL/min; P < .002), t1/2 was prolonged (18.3 versus 3.0 hours; P < .01), and Cmax was increased (2.6 versus 5.4 ng/mL; P < .001). The 8-hour effect area for EEG was increased by a factor of 2.51, and that for DSST decrement was increased by 4.33. Observed in vivo clearance decrements due to ketoconazole were consistent with those anticipated on the basis of an in vitro model, together with in vivo plasma concentrations of ketoconazole. CONCLUSION: For triazolam, an intermediate-extraction compound, impaired clearance by ketoconazole has more profound clinical consequences than those for alprazolam, a low extraction compound.

Administration, Oral↗

PubMed1998

Inhibition of triazolam clearance by macrolide antimicrobial agents: in vitro correlates and dynamic consequences.

BACKGROUND: Macrolide antimicrobial agents may impair hepatic clearance of drugs metabolized by cytochrome P4503A isoforms. Potential interactions of triazolam, a substrate metabolized almost entirely by cytochrome P4503A in humans, with 3 commonly prescribed macrolides were identified using an in vitro metabolic model. The actual interactions, and their pharmacodynamic consequences, were verified in a controlled clinical study. METHODS: In an in vitro model using human liver microsomes, 250 mumol/L triazolam was incubated with ascending concentrations (0 to 250 mumol/L of troleandomycin, azithromycin, erythromycin, and clarithromycin. In a randomized, double-blind, 5-trial clinical pharmacokinetic-pharmacodynamic study, 12 volunteers received 0.125 mg triazolam orally, together with placebo, azithromycin, erythromycin, or clarithromycin. In a fifth trial they received placebo plus placebo. RESULTS: Mean 50% inhibitory concentrations versus 4-hydroxytriazolam formation in vitro were as follows: 3.3 mumol/L troleandomycin, 27.3 mumol/L erythromycin, 25.2 mumol/L clarithromycin, and greater than 250 mumol/L azithromycin. Apparent oral clearance of triazolam when given with placebo or azithromycin was nearly identical (413 and 416 mL/min), as were peak plasma concentrations (1.25 and 1.32 ng/mL) and elimination half-life (2.7 and 2.6 hours). Apparent oral clearance was significantly reduced (P < .05) during erythromycin and clarithromycin trials (146 and 95 mL/min). Peak plasma concentration was correspondingly increased, and elimination half-life was prolonged. The effects of triazolam on dynamic measures were nearly identical when triazolam was given with placebo or azithromycin, but benzodiazepine agonist effects were enhanced during erythromycin and clarithromycin trials. CONCLUSION: The in vitro model identifies macrolides that may impair triazolam clearance. Anticipated interactions, and their pharmacodynamic consequences in volunteer subjects, were verified in vivo.

Administration, Oral↗

PubMed1998

Identification of the L-menthol binding site in guinea-pig lung membranes.

1. L-Menthol inhibits both neurokinin A and capsaicin-induced bronchoconstriction in the guinea-pig and relaxes pre-constricted guinea-pig isolated bronchi. Structure-activity relationships have been defined for the action of (-)-menthol and related compounds on cold receptors, suggesting an action of L-menthol at a pharmacological receptor. We have performed radioligand binding studies to characterize the binding sites for [3H]-L-menthol in whole cell membranes prepared from guinea-pig lung tissue. 2. In kinetic studies. [3H]-L-menthol was found to bind rapidly and reversibly. Binding of [3H]-L-menthol to lung membranes was found to be time-dependent becoming fully associated to its site within 40 min, and half-maximum association occurred within 8 min (t1/2=8 min). [3H]-L-menthol was fully dissociated from its binding site within 8 min, (t1/2=2 min). 3. Inhibition studies presented a pharmacological profile of the 'L-menthol site'. Capsaicin, capsazepine, D-menthol, eugenol, SCH23390 and camphor were all found to displace [3H]-L-menthol binding. In contrast WS3, noradrenaline, 5-hydroxytryptamine, spiperone, flunarazine, bepridil and nicardipine were without effect. 4. We have identified a L-menthol binding site in the guinea-pig, which may represent a site common to a variety of compounds.

Animals↗

PubMed1998

Exogenous NPY modulation of cardiac autonomic reflexes and its pressor effect in the conscious rabbit.

1. Neuropeptide Y (NPY) may inhibit sympathetic and vagal transmission via presynaptic Y2 receptors and cause vasoconstriction via postsynaptic Y1 receptors. We examined the effects of NPY and related peptides on cardiovascular parameters and autonomic reflexes in the conscious rabbit. Further, the postjunctional effects of NPY and related peptides were assessed on acetylcholine (ACh) and isoprenaline agonist dose-chronotropic response curves. 2. In conscious rabbits the cardiac baroreceptor-heart rate reflex (baroreflex), Bezold-Jarisch like and nasopharyngeal reflexes were assessed in control, propranolol-treated or methscopolamine-treated (baroreflex only) groups, before and 30 min after i.v. administration of NPY (10 microg kg[-1] + 5 microg kg[-1] min[-1]) or vehicle (saline, 10 ml h[-1]). The effects of equivalent pressor doses of [Leu31, Pro34]NPY or methoxamine on the baroreflex were also examined. In separate animals, dose-heart rate (HR) response curves to isoprenaline or ACh were constructed before and 15 min after administration of NPY, [Leu31,Pro34]NPY (ACh only) or [Leu31,Pro34]NpY + sodium nitroprusside (ACh only). 3. Administration of NPY-receptor agonists caused sustained bradycardia (in the absence of methscopolamine) and rightward shifts of the barocurves in all 3 groups. The range of sympathetically-mediated tachycardia was significantly decreased by NPY or [Leu31,Pro34]NPY in the methscopolamine-treated group. However, these changes in the baroreflex were no different from those elicted by equipressor doses of methoxamine. There was no vagal inhibition by any NPY-receptor agonist in all three autonomic reflexes examined. ACh or isoprenaline dose-HR response curves were not affected by NPY peptide administration. 4. We conclude that in the conscious rabbit, at a single dose that elicits a significant pressor response, exogenous NPY has no direct effect on modulation of cardiac and autonomic reflexes. Non-specific effects of exogenous NPY on the baroreflex may be fully explained by its pressor action. There was no effect of NPY on postjunctional ACh or isoprenaline agonist dose-response curves. Therefore, it is unlikely that endogenous NPY has a functional role in directly modulating cardiac autonomic neurotransmission in the rabbit.

Adrenergic beta-Agonists↗