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Biomedical subjects

D A August

Publications and source records attributed to D A August.

At least 19 recordsLinked to original sources
PubMed2001

Effects of purified green and black tea polyphenols on cyclooxygenase- and lipoxygenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues.

The effects of green and black tea polyphenols on cyclooxygenase (COX)- and lipoxygenase (LOX)-dependent arachidonic acid metabolism in normal human colon mucosa and colon cancers were investigated. At a concentration of 30 microg/mL, (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), and (-)-epicatechin-3-gallate (ECG) from green tea and theaflavins from black tea inhibited LOX-dependent activity by 30-75%. The formation of 5-, 12-, and 15-LOX metabolites was inhibited to a similar extent. Tea polyphenols also inhibited COX-dependent arachidonic acid metabolism in microsomes from normal colon mucosa, with ECG showing the strongest inhibition. The formation of thromboxane (TBX) and 12-hydroxyheptadecatrienoic acid (HHT) was decreased to a greater extent than other metabolites. The inhibitory effects of tea polyphenols on COX activity, however, were less pronounced in tumor microsomes than in normal colon mucosal microsomes. Theaflavins strongly inhibited the formation of TBX and HHT, but increased the production of prostaglandin E(2) (PGE(2)) in tumor microsomes. The enhancing effect of theaflavins on PGE(2) production was related to the COX-2 level in the microsomes. Although theaflavin inhibited ovine COX-2, its activity in the formation of PGE(2) was stimulated by theaflavin when ovine COX-2 was mixed with microsomes, suggesting that theaflavin affects the interaction of COX-2 with other microsomal factors (e.g. PGE synthase). The present results indicate that tea polyphenols can affect arachidonic acid metabolism in human colon mucosa and colon tumors, and this action may alter the risk for colon cancer in humans.

Antioxidants↗
PubMed2000

Hepatic enzyme induction with phenobarbital and doxorubicin metabolism and myelotoxicity in the rabbit.

Doxorubicin (DOX) undergoes extensive liver metabolism. This study was designed to compare the pharmacokinetic and myelotoxicity profiles of DOX and metabolites with and without phenobarbital-associated hepatic enzyme induction. DOX was administered i.v. to eight rabbits with and without 7 prior days of oral phenobarbital, with venous blood samples collected between 0 and 72 hr for determination of plasma DOX and metabolite concentrations by high-performance liquid chromatography and complete blood counts obtained on days 1, 5, 7, 8, and 9. DOX AUC infinity, t1/2 beta and CLT values were significantly reduced by phenobarbital induction (PBI), while only the formation clearance of DOX metabolites was significantly changed. PBI had no effect on nadir neutrophil counts but was associated with significantly accelerated neutrophil recovery. Hepatic enzyme induction with phenobarbital significantly reduces plasma DOX exposure while increasing the rate of metabolite formation. These effects result in significant acceleration of neutrophil recovery.

Animals↗
PubMed1999

Temporal sequence compression by an integrate-and-fire model of hippocampal area CA3.

Cells in the rat hippocampus fire as a function of the animal's location in space. Thus, a rat moving through the world produces a statistically reproducible sequence of "place cell" firings. With this perspective, spatial navigation can be viewed as a sequence learning problem for the hippocampus. That is, learning entails associating the relationships among a sequence of places that are represented by a sequence of place cell firing. Recent experiments by McNaughton and colleagues suggest the hippocampus can recall a sequence of place cell firings at a faster rate than it was experienced. This speedup, which occurs during slow-wave sleep, is called temporal compression. Here, we show that a simplified model of hippocampal area CA3, based on integrate-and-fire cells and unsupervised Hebbian learning, reproduces this temporal compression. The amount of compression is proportional to the activity level during recall and to the relative timespan of associativity during learning. Compression seems to arise from an alteration of network dynamics between learning and recall. During learning, the dynamics are paced by external input and slowed by a low overall level of activity. During recall, however, external input is absent, and the dynamics are controlled by intrinsic network properties. Raising the activity level by lowering inhibition increases the rate at which the network can transition between previously learned states and thereby produces temporal compression. The tendency for speeding up future activations, however, is limited by the temporal range of associations that were present during learning.

Animals↗
PubMed1999

Ingestion of green tea rapidly decreases prostaglandin E2 levels in rectal mucosa in humans.

The objective of this Phase I/II study was to assess the potential for green tea to be used as a colorectal cancer chemopreventive agent. This study measured the dose-related biological effects of administration of a single dose of green tea on the rectal mucosa of normal volunteers. Volunteers were admitted to the Robert Wood Johnson Medical School Clinical Research Center for 24 h. Baseline blood and rectal biopsy samples were obtained before the volunteers drank 0.6, 1.2, or 1.8 g of green tea solids dissolved in warm water. Blood samples were taken 2, 4, 8, and 24 h after the tea administration. Rectal biopsies were obtained at 4, 8, and 24 h. Prostaglandin E2 (PGE2) levels were analyzed by ELISA. Tea polyphenol levels in the blood, urine, and rectal tissue were measured by high-performance liquid chromatography using a Coulochem electrode array detection system. Statistical comparisons were made using ANOVA. Decreased levels of PGE2 in rectal mucosa were observed at 4 and 8 h after consumption of green tea. There was no correlation between inhibition of PGE2 and tissue or plasma levels of tea polyphenols. Ten of 14 subjects demonstrated a response to green tea, as evidenced by at least a 50% inhibition of PGE2 levels at 4 h. We conclude that green tea constituents have biological activity in inhibiting PGE2 synthesis. Given the 71% "response rate," we believe these data support the study of green tea as a colorectal chemopreventive agent in more long-term Phase II trials.

Administration, Oral↗
PubMed1998

Augmentation of hepatic doxorubicin extraction with extracorporeal filtration avoids the dose-dependent, nonlinear increase in AUC observed with systemic administration.

PURPOSE: Regional therapy of primary or metastatic liver cancer with low hepatic extraction ratio drugs such as doxorubicin is constrained by development of systemic toxicity. To examine the effect of augmentation of hepatic drug extraction, a swine model of hepatic artery infusion (HAI) with minimally invasive hepatic venous isolation and hepatic venous drug extraction (HVDE) was developed to study the comparative pharmacokinetic profiles of regional and systemically administered doxorubicin. METHODS: Doxorubicin 0.5-9 mg/kg was administered to 31 pigs over 90 min either by HAI with simultaneous HVDE or by standard systemic vein infusion. Systemic artery and hepatic vein plasma samples were collected periodically (0 to 240 min) for determination of doxorubicin concentrations by high-performance liquid chromatography. Pharmacokinetic profiles were modeled with PCNONLIN 4.2. RESULTS: Concentration-time data were best described in all pigs by a two-compartment open model of elimination. Independent of the route of administration, AUC and Cmax values increased with dose. Mean systemic AUC and Cmax values were consistently lower with regional administration, with statistically significant decreases at the 0.5 and 3 mg/kg doses, whereas there was no relationship between hepatic vein parameters and route of administration. There was a linear relationship between mean systemic AUC values and dose in pigs receiving doxorubicin via HAI with HVDE, whereas mean systemic AUC values increased exponentially at doses of 5 mg/kg or above with systemic vein administration. CONCLUSIONS: Administration of doxorubicin by HAI with simultaneous HVDE significantly decreases systemic exposure in comparison with standard systemic vein drug infusion, and may protect against nonlinear increases in exposure at higher doses.

Animals↗
PubMed1997

Parenteral zinc supplementation in adult humans during the acute phase response increases the febrile response.

The acute phase response (APR) that follows injury or infection is characterized by a decrease in serum zinc concentrations, which we hypothesized benefits the host. Additionally, we proposed that preventing this decline by supplementing zinc would result in an exaggerated APR as indicated by elevated temperatures, increased serum cytokine concentrations, interleukin 6 and the acute phase protein (ceruloplasmin). A prospective, randomized, double-blinded, clinical trial was conducted. Patients on home parenteral nutrition with a diagnosis of catheter sepsis and patients with a diagnosis of pancreatitis, also on total parenteral nutrition (TPN), were recruited for the study. Following enrollment, block randomization was used to assign patients to receive 0 mg (n = 23) or 30 mg (n = 21) of zinc per day for the first 3 d of TPN. Blood samples for measurement of serum zinc, copper, ceruloplasmin and interleukin-6 were obtained upon enrollment and on d 1 through 3 of TPN. The highest temperatures reported on these days in the medical record were also recorded. Repeated measures ANOVA was used to determine differences in the primary outcome variables over time. No significant differences between groups were observed in serum interleukin-6 or ceruloplasmin concentrations. A significantly higher (P = 0.035) temperature was observed in the zinc-supplemented group compared with the control group on d 3 of parenteral nutrition. We conclude that parenteral zinc supplementation in patients experiencing a mild APR resulted in an exaggerated APR as evidenced by a significantly higher febrile response.

Acute-Phase Reaction↗
PubMed1997

Using simulation to improve the operational efficiency of a multi-disciplinary clinic.

A recent trend in health care is to provide patients with the benefits of multi-disciplinary care during a single clinic visit. The University of Michigan Breast Care Center is a leading example of a multi-disciplinary clinic which has served the Midwest United States since 1985. A hallmark of the Breast Care Center operation is a patient care conference immediately following the clinical evaluation sessions, where each case is discussed by a group of experts for immediate evaluation and generation of recommendations. The Center has experienced significant increases in the number of patient visits over the nine years since its inception. The patient mix, initially all new patients, has matured, and returning patients are now a significant portion of the clinic load. Unfortunately, the success of the Breast Care Center strained its smooth operation. Physicians were unable to attend the patient care conference because the clinical evaluation sessions were too busy, and this undermined the quality of the care recommendations generated. Patients were complaining about long waits in the Breast Care Center and delays in getting their next appointment. To examine these operational problems and to suggest corrective actions, a simulation study was conducted. This paper reports the results of this study. Our findings provide interesting insights into the operation and management of multi-disciplinary clinics.

Appointments and Schedules↗
PubMed1996

Carotenoids, vitamin A, and estrogen receptor status in breast cancer.

Among patients with breast cancer, tumors that contain estrogen receptors (ER) are associated with improved survival and better response to hormone therapy than those not expressing these receptors. The purpose of these case comparison studies was to examine the relationship between carotenoids, vitamin A, and the tumor ER status in women at diagnosis of primary breast cancer. The focus of the first study was the relationship between dietary intake and ER status, and the focus of the second study was the relationship between ER status and the plasma carotenoid, retinol, and tocopherol concentrations. We evaluated tumor ER status and self-reported dietary intake in 142 women and plasma concentrations of carotenoids, retinol, and tocopherols in 149 women, at diagnosis of breast cancer, before any medical or surgical treatment. In the first study the overall odds of ER-positive status were increased in relation to number of mammograms in the past five years, number of breast-fed babies, dietary carotenoid intake, and more frequent intake of yellow and green vegetables. Overall odds of ER-positive status were decreased in relation to years of oral contraceptive use and preformed vitamin A intake. In the second study older women, women with higher plasma lutein concentration, and women not using beta-carotene supplements were more likely to be ER positive, when data were adjusted for body mass index and factors that may influence breast cancer risk or hormonal status. Significant independent relationships between plasma retinol or tocopherol concentrations and ER status were not observed. The strong and independent relationships between carotenoid intake, plasma lutein concentration, and ER status may relate to observations linking a carotenoid-rich diet with improved prognosis after diagnosis of breast cancer.

Adolescent↗
PubMed1996

A simple spike train decoder inspired by the sampling theorem.

Reconstructing a time-varying stimulus estimate from a spike train (Bialek's "decoding" of a spike train) has become an important way to study neural information processing. In this paper, we describe a simple method for reconstructing a time-varying current injection signal from the simulated spike train it produces. This technique extracts most of the information from the spike train, provided that the input signal is appropriately matched to the spike generator. To conceptualize this matching, we consider spikes as instantaneous "samples" of the somatic current. The Sampling Theorem is then applicable, and it suggests that the bandwidth of the injected signal not exceed half the spike generator's average firing rate. The average firing rate, in turn, depends on the amplitude range and DC bias of the injected signal. We hypothesize that nature faces similar problems and constraints when transmitting a time-varying waveform from the soma of one neuron to the dendrite of the postsynaptic cell.

Action Potentials↗
PubMed1996

Theoretic and experimental aspects of regional liver infusion.

Pharmacokinetic theory of hepatic arterial infusion chemotherapy predicts that parameters, such as hepatic blood flow, hepatic drug extraction, and extrahepatic drug clearance, may potentially be manipulated to enhance the selectivity of hepatic artery drug administration. In practice, diminution of hepatic blood flow through the use of degradable starch microspheres or gelatin sponge embolization has been accomplished and has improved drug selectivity. Likewise, augmentation of hepatic drug extraction improves the pharmacokinetic advantages of regional chemotherapy for liver tumors. Development of optimal hepatic infusion chemotherapy approaches can be undertaken rationally and in an expeditious fashion by applying pharmacokinetic principles to create innovative treatment regimens and by testing them in preclinical and phase I investigations.

Antineoplastic Agents↗
PubMed1995

Pharmacokinetic evaluation of percutaneous hepatic venous isolation for administration of regional chemotherapy.

Hepatic artery infusion (HAI) chemotherapy has been used to treat patients with unresectable liver tumours. We report a preclinical study of the pharmacokinetics of HAI combined with hepatic venous drug extraction (HVDE) for regional administration of doxorubicin. HVDE was aided by a double balloon catheter inserted via femoral vein cutdown into the inferior vena cava to collect all hepatic vein blood. Pigs received doxorubicin 0.5-9.0 mg kg-1 over 90 min via HAI or systemic infusion (SYSI). HVDE was performed for 240 min. SYSI pigs underwent hepatic venous isolation without drug filtration. Doxorubicin levels were assayed using high-pressure liquid chromatography (HPLC). HAI/HVDE reduced systemic exposure to doxorubicin with equivalent hepatic exposure at all doses. Pharmacokinetic enhancement ranged from 7.0 to 22.3 for peak concentration, 8.8-23.2 for the area under the curve and 2.9-4.2 for tissue concentration. HAI/HVDE also prevented the mortality which was observed with SYSI administration of high-dose (5.0 and 9.0 mg kg-1) doxorubicin. We conclude that HAI/HVDE reduces systemic exposure to doxorubicin as compared with SYSI of equivalent doses. Pharmacokinetic enhancement indices suggest that HAI/HVDE may allow equivalent hepatic drug exposure with reduced systemic exposure. This method may be applicable to other drugs and to other anatomic settings in which enhanced regional drug delivery is desirable.

Animals↗
PubMed1995

An evaluation of hepatic extraction and clearance of doxorubicin.

A swine model was developed to study quantitatively the pharmacokinetics of hepatic extraction and clearance of doxorubicin (DOX). Systemic and hepatic artery infusions of DOX (0.5-9 mg kg-1) were administered to 34 pigs. Pharmacokinetic analysis was simplified by use of a double-balloon catheter in the inferior vena cava to collect hepatic venous effluent. During hepatic artery infusion only, DOX in hepatic venous blood was extracted using activated carbon filters to prevent drug recirculation. Hepatic extraction and clearance of DOX were independent of dose and route of administration. Extraction ratios varied from 0.75 to 0.91 during hepatic artery infusion and from 0.50 to 0.72 during systemic infusion. Clearance results were analogous. After cessation of drug infusions, hepatic extraction and clearance of DOX was negative, suggesting that the liver serves as a drug reservoir during DOX infusion and subsequently is a net source of unmetabolised drug. Liver extraction and clearance of DOX in pigs are substantial. During either systemic or hepatic artery infusion of DOX, the liver serves as a drug reservoir. Subsequent mobilisation of this hepatic pool of DOX may cause prolonged systemic exposure to drug.

Animals↗
PubMed1995

Patient evaluation of care within a multidisciplinary breast care center.

To understand patient perceptions of multidisciplinary medical care, a survey instrument was developed to poll 1,023 consecutive visitors to the University of Michigan Breast Care Center (BCC). Factors influencing patient satisfaction included staff concern for patients, one-stop shopping, medical thoroughness, and length of waiting in the reception area (negative correlation). These factors are well addressed by a multidisciplinary approach to medical care. Similar models of multidisciplinary care can probably be implemented at other institutions and in other clinical settings.

Adult↗