A pharmacodynamic study of the P-glycoprotein antagonist CBT-1® in combination with paclitaxel in solid tumors.

BACKGROUND: This pharmacodynamic trial evaluated the effect of CBT-1® on efflux by the ATP binding cassette (ABC) multidrug transporter P-glycoprotein (Pgp/MDR1/ABCB1) in normal human cells and tissues. CBT-1® is an orally administered bisbenzylisoquinoline Pgp inhibitor being evaluated clinically. Laboratory studies showed potent and durable inhibition of Pgp, and in phase I studies CBT-1® did not alter the pharmacokinetics of paclitaxel or doxorubicin. METHODS: CBT-1® was dosed at 500 mg/m2 for 7 days; a 3-hour infusion of paclitaxel at 135 mg/m2 was administered on day 6. Peripheral blood mononuclear cells (PBMCs) were obtained prior to CBT-1® administration and on day 6 prior to the paclitaxel infusion. (99m)Tc-sestamibi imaging was performed on the same schedule. The area under the concentration-time curve from 0-3 hours (AUC(0-3)) was determined for (99m)Tc-sestamibi. RESULTS: Twelve patients were planned and enrolled. Toxicities were minimal and related to paclitaxel (grade 3 or 4 neutropenia in 18% of cycles). Rhodamine efflux from CD56+ PBMCs was a statistically significant 51%-100% lower (p < .0001) with CBT-1®. Among 10 patients who completed imaging, the (99m)Tc-sestamibi AUC(0-3) for liver (normalized to the AUC(0-3) of the heart) increased from 34.7% to 100.8% (median, 71.9%; p < .0001) after CBT-1® administration. Lung uptake was not changed. CONCLUSION: CBT-1® is able to inhibit Pgp-mediated efflux from PBMCs and normal liver to a degree observed with Pgp inhibitors studied in earlier clinical trials. Combined with its ease of administration and lack of toxicity, the data showing inhibition of normal tissue Pgp support further studies with CBT-1® to evaluate its ability to modulate drug uptake in tumor tissue. DISCUSSION: Although overexpression of ABCB1 and other ABC transporters has been linked with poor outcome following chemotherapy efforts to negate that through pharmacologic inhibition have generally failed. This is thought to be a result of several factors, including (a) failure to select patients with tumors in which ABCB1 is a dominant resistance mechanism; (b) inhibitors that were not potent, or that impaired drug clearance; and (c) the existence of other mechanisms of drug resistance, including other ABC transporters. Although an animal model for Pgp has been lacking, recent studies have exploited a Brca1(-/-); p53(-/-) mouse model of hereditary breast cancer that develops sporadic tumors similar to cancers in women harboring BRCA1 mutations. Treatment with doxorubicin, docetaxel, or the poly(ADP-ribose) polymerase inhibitor olaparib brings about shrinkage, but resistance eventually emerges. Overexpression of the Abcb1a gene, the mouse ortholog of human ABCB1, has been shown to be a mechanism of resistance in a subset of these tumors. Treating mice with resistant tumors with olaparib plus the Pgp inhibitor tariquidar resensitized the tumors to olaparib. Although results in this animal model support a new look at Pgp as a target, in this era of "targeted therapies," trial designs that directly assess modulation of drug uptake, including quantitative nuclear imaging, should be pursued before clinical efficacy assessments are undertaken. Such assessment should be performed with compounds that inhibit tissue Pgp without altering the pharmacokinetics of chemotherapeutic agents. This pharmacodynamic study demonstrated that CBT-1®, inhibits Pgp-mediated efflux from PBMCs and normal liver.

Cardiac studies in patients treated with depsipeptide, FK228, in a phase II trial for T-cell lymphoma.

PURPOSE: The histone deacetylase inhibitor depsipeptide (FK228) has activity in patients with cutaneous or peripheral T-cell lymphoma. Electrocardiogram abnormalities, thought to be a class effect, were observed in preclinical animal studies and phase I testing and led to the incorporation of intensive cardiac monitoring in an ongoing efficacy trial. PATIENTS AND METHODS: This report summarizes the cardiac monitoring of 42 patients enrolled and treated on a phase II trial with depsipeptide. Cardiac evaluations included serial electrocardiograms to evaluate T-wave, ST segment, and QT interval effects and serial serum cardiac troponin I levels and left ventricular ejection fraction (LVEF) evaluations to exclude myocardial damage. RESULTS: Cardiac studies from 282 cycles and 736 doses of depsipeptide included 2,051 electrocardiograms and 161 LVEF evaluations. Although T-wave flattening (grade 1) or ST segment depression (grade 2) was observed in more than half of the electrocardiograms obtained posttreatment, these electrocardiogram abnormalities were not associated with elevation of cardiac troponin I or with altered left ventricular function. No significant changes in LVEF were observed, even in 16 patients treated for >or=6 months and regardless of prior anthracycline exposure. Posttreatment electrocardiograms had a mean heart rate-corrected QT interval prolongation of 14.4 milliseconds compared with baseline. Electrolyte replacement has been instituted to mitigate potential untoward effects. CONCLUSION: The data obtained in this study show that the administration of depsipeptide is not associated with myocardial damage or impaired cardiac function. The potential effect of heart rate-corrected QT interval prolongation remains under study.

Use of backscattered electron detector arrays for forming backscattered electron images in the scanning electron microscope.

The backscattered electron (BSE) signal in the scanning electron microscope (SEM) can be used in two different ways. The first is to give a BSE image from an area that is defined by the scanning of the electron beam (EB) over the surface of the specimen. The second is to use an array of small BSE detectors to give an electron backscattering pattern (EBSP) with crystallographic information from a single point. It is also possible to utilize the EBSP detector and computer-control system to give an image from an area on the specimen--for example, to show the orientations of the grains in a polycrystalline sample ("grain orientation imaging"). Some further possibilities based on some other ways for analyzing the output from an EBSP detector array, are described.

Sleep history is neglected diagnostic information. Challenges for primary care physicians.

Sleep problems are treatable causes of morbidity and mortality, but little is known about how often the history fundamental to diagnosis is obtained. We recorded the frequency of sleep histories during encounters with simulated patients by 20 experienced primary care practitioners, 23 uninstructed medical interns, and 22 interns who had previous instruction about sleep disorders. Sleep histories were uncommonly obtained by uninstructed physicians (0% of practitioners, 13% of interns), but trained interns more often (81.8%) asked about sleep. If sleep problems are to be prioritized, major changes in physician education and behaviors are essential. Focused instruction about sleep influences physician behavior.

The role of antepartum surveillance in the management of gastroschisis.

OBJECTIVE: To evaluate the perinatal morbidity and mortality of fetuses diagnosed with gastroschisis at our Fetal Diagnosis and Treatment Center. METHODS: A retrospective review of a regional prenatal diagnostic center. Twenty-nine cases of gastroschisis which were diagnosed, managed, delivered and had corrective surgeries through the Fetal Diagnosis and Treatment Center were identified from 1985 to 1994. Perinatal morbidity and mortality were reviewed. Antepartum testing schemes were reviewed when available to determine whether morbidity or mortality could have potentially been prevented. RESULTS: Meconium occurrence, intrauterine growth retardation (IUGR) and oligohydramnios complicated 79%, 41% and 36% of the cases, respectively. The perinatal mortality of this series was 241/1000. Significant differences in perinatal mortality were noted when fetal testing was incorporated (200/1000 vs. 286/1000, P < or = 0.001). CONCLUSION: Gastroschisis is associated with a high incidence of IUGR, meconium, oligohydramnios and high perinatal mortality. Antenatal testing appears to significantly lower perinatal mortality in pregnancies complicated by gastroschisis.

Elevated endoxin-like factor complicating a multifetal second trimester pregnancy: treatment with digoxin-binding immunoglobulin.

We report a case of a second trimester multifetal pregnancy with preeclampsia associated with an elevated digoxin-like immune factor. Due to the remoteness from viability the patient was offered therapy with digoxin-binding immunoglobulin. No untoward maternal effects were noted.

Abortion mortality, United States, 1972 through 1987.

OBJECTIVE: The aim of our study was to describe risk factors for legal abortion mortality and the characteristics of women who died of legal abortion complications for the period 1972 through 1987. STUDY DESIGN: We reviewed abortion mortality surveillance data collected by the Division of Reproductive Health, Centers for Disease Control and Prevention, and calculated rates by various demographic and reproductive health variables using the Center for Disease Control and Prevention's abortion surveillance data as denominators. Rates are reported as legal abortion deaths per 100,000 abortions. RESULTS: Between 1972 and 1987, 240 women died as a result of legal induced abortions. The case-fatality rate decreased 90% over time, from 4.1 deaths per 100,000 abortions in 1972 to 0.4 in 1987. Women > or = 40 years old had three times the risk of death as teenagers (relative risk 3.0, 95% confidence interval 1.5 to 6.0), and black women and those of other minority races had 2.5 times the risk of white women (relative risk 2.5, 95% confidence interval 1.9 to 3.2). Abortions at > or = 16 weeks were associated with a risk of death almost 15 times the risk of death from procedures at < or = 12 weeks' gestation. Women undergoing currettage procedures for abortion had a significantly lower risk of death than women undergoing other procedures. Whereas before 1977 infection and hemorrhage were the leading causes of death, during 1977 through 1982 anesthesia complications emerged as one of the leading causes of death and since 1983 have become the most frequent cause. CONCLUSIONS: Although legal induced abortion-related deaths are rare events, our findings suggest that more rigorous efforts are needed to increase the safety of anesthetic methods and anesthetic agents used for abortions and that efforts are still necessary to monitor serious complications of abortion aimed at further reducing risks of death associated with the procedure.

PIP: Abortion related mortality in the US between 1972 and 1987 amounted to 240 deaths from legal induced abortion and 88 deaths from illegal induced abortion in the US. The study aimed to describe risk factors for legal abortion related mortality based on Centers for Disease Control and Prevention abortion surveillance data. Mortality decreased by 90% from 4.1 deaths/100,000 legal induced abortions in 1972 to 0.4/100,000 in 1987. Reporting which included demographic data on abortion mortality included 29 states between 1983 and 1987. Three time periods were compared: 1972-76, 1977-82, and 1983-87 for age groups under 19 years, 20-29 years, and over 30 years. There were 667 reported deaths during 1972-87, of which 240 were due to legally induced abortion, 88 due to illegal abortions, and 172 due to spontaneous abortions. The case fatality rate for legal abortions during 1972-87 was 1.3 deaths/100,000 legal abortions. Abortion mortality was 2.5 times higher for Black and minority women: 2.3/100,000 compared to 0.9/100,000 for White women. This risk was partially attributed to the greater proportion of later abortions for Black women, which declined over time as did abortion-related mortality. In the Poisson regression analysis, Black race remained a significant risk factor. The risk tripled for women aged over 40 years (3.1/100,000), particularly for those women with 3 or more prior births. The risk by age declined over time and was not a significant risk factor between 1983 and 1987. The highest risk was among women with abortions beyond 20 weeks of gestation (10.4/100,000). About 20% of legal abortion-related deaths were attributed to each of the following causes: infection, embolism, hemorrhage, and anesthesia complications (82% of the 240 reported deaths). Over time, the primary remaining risk between 1983 and 1987 was from general anesthesia. Future abortions should be performed with special attention to choosing and administering anesthesia and to having emergency equipment available for complications from anesthesia.