Investigating the potential role of multi-drug resistance protein (MRP) transporters in fetal to maternal glyburide efflux in the human placenta.

Glyburide, a drug used to treat gestational diabetes has previously been shown not to be measurable in fetal blood, and to be transferred from the fetal to the maternal circulation against a concentration gradient. The objective of the study is to determine whether indomethacin, an inhibitor of the multi-drug resistance family (MRP) of transporters is involved in the active efflux of glyburide from the fetus to the mother. Using the dually perfused human placental cotyledon model, 12 perfusions were performed of both glyburide and indomethacin concomitantly. The rate of transfer of glyburide in the presence of inhibitor was not different from the rate of transfer of glyburide in the absence of inhibitor. Furthermore, our study suggests that MRP1, 2 or 3 may be only minimally involved in the transport of glyburide across the human placenta. These results pose other ABC transporters, such as likely candidates for the placental transfer of glyburide.

Delayed administration of a potent cyclin dependent kinase and glycogen synthase kinase 3 beta inhibitor produces long-term neuroprotection in a hypoxia-ischemia model of brain injury.

We compared the neuroprotective efficacy of a potent and CNS-penetrant cyclin dependent kinase (CDK) and glycogen synthase kinase 3 beta (GSK3beta) inhibitor (Compound 1) in juvenile (postnatal day 21; P21) and adult C57Bl/6 mice (postnatal day 60; P60) using a model of hypoxic-ischemic brain injury (HI). Neuronal cell counts and density measures from brain sections stained with Cresyl Violet revealed that exposure of P21 mice to 60 min of HI resulted in extensive damage to the ipsilateral cornu ammonis 1 (CA1) region of the hippocampus (40% cell loss) and striatum (30% cell loss) 7 days later. Exposure of P60 mice to 40 min of HI produced a similar pattern of cell loss. Intraperitoneal administration of Compound 1 (3 mg/kg) 1, 5 and 9 h after 60 min of HI did not reduce brain injury in P21 mice relative to vehicle controls. By contrast, in P60 mice, this treatment significantly decreased cell loss in the ipsilateral hippocampus (10% cell loss) and striatum (15% loss) relative to vehicle controls. Terminal uridine deoxynucleotidyl transferase (TUNNEL) positive cell counts and infarct volume were also substantially reduced in P60 mice treated with Compound 1. A motor coordination test performed twice weekly until 5 weeks post-HI confirmed that Compound 1 produced long lasting functional recovery. Our results indicate that Compound 1 produced long lasting neuroprotective effects in adult but not juvenile mice suggesting that inhibition of the CDKs and GSK3beta plays a distinct neuroprotective role in the juvenile and adult brain.

Pharmacokinetic studies in pregnant women.

Prescription and over-the-counter drug use during pregnancy is necessary for many women today. A study of US and Canadian women found that, on average, 2.3 drugs were used during pregnancy; however, 28% reported using more than 4. For some women, this is because they become pregnant with preexisting conditions that require ongoing or intermittent pharmacotherapy. For others, this is because pregnancy itself can give rise to new medical conditions such as gestational diabetes and preeclampsia. The principal concern of prescribing physicians is whether or not agents will harm the fetus (i.e., have teratogenic effects). This concern rose to prominence primarily as a result of the thalidomide disaster. Marketed for use in morning sickness, thalidomide was found to be a potent teratogen capable of producing a variety of birth defects relating to development. Consequently, determining the teratogenicity of new drugs currently dominates the objectives of pregnancy-relevant experiments conducted throughout drug development. This often comes at the expense of valuable pharmacokinetic (PK) studies, which are seldom performed pre-market. Sex differences in PK parameters have been demonstrated in animals and humans since the 1930s. It is, therefore, not surprising that differences also arise in pregnancy. A wide array of physiological and hormonal changes occur during pregnancy; most begin early in the first trimester and increase linearly until parturition. Physicians lacking adequate PK information typically prescribe the standard adult dose in pregnancy, and this can be either inadequate or excessive depending on a variety of factors. The purpose of this report is to highlight this issue and illustrate how current methods used to obtain PK data in pregnancy are insufficient. The steps that are being taken to address this issue will also be discussed.

Breast cancer resistance protein: mediating the trans-placental transfer of glyburide across the human placenta.

Members of the ATP-binding cassette (ABC) efflux transporter family, including P-glycoprotein (PGP), the multidrug resistance-associated proteins (MRPs) and the breast cancer resistance protein (BCRP) have been shown to be highly expressed in the human placenta. Recent studies documented that the oral hypoglycemic glyburide does not cross the human placenta to an appreciable extent. Furthermore, the trans-placental transfer of glyburide has been shown not to be affected by either the presence of PGP inhibitor, verapamil or MRP inhibitor, indomethacin. Therefore, our objective was to identify other human placental ABC transporters potentially involved in limiting the trans-placental transfer of glyburide to the fetus. [(3)H]-glyburide transport was examined in brush border human placental vesicles in the presence or absence of specific inhibitors. Prepared vesicles were 70% oriented right-side-out and demonstrated 25-27 fold enrichment as compared to whole placenta. Functional studies demonstrated significant increases in the intra-vesicular accumulation of [(3)H]-glyburide in vesicles treated with the BCRP inhibitor, novobiocin. In contrast, PGP inhibition as well as MRP inhibition did not affect [(3)H]-glyburide accumulation. This is the first evidence to clearly indicate that glyburide is preferentially transported by BCRP, in the brush border of the human placenta. Our study also indicates that BCRP likely effluxes substrates in the fetal to maternal direction in the human placenta.

Induced current measurements in whole body exposure condition to radio frequency electric fields.

The current induced in a human exposed to radio frequency electric fields has been studied by the use of a stripline, in which whole body exposure to vertical electric fields (3-27 MHz) can be produced. We have examined two different techniques to measure the induced current; parallel plate meters and current probes. When the subject has good connection to the ground, the choice of measurement technique is not crucial, since there are only minor differences in readings between the instruments. But when the subject is wearing shoes and/or standing on a wooden plate, the difference between the instruments increases considerably. The difference can mainly be explained by the capacitive coupling between the parallel plate meters and the ground; therefore, the current probes are preferred when the subject does not have perfect contact with the ground. Since the International Commission on Non-Ionizing Radiation Protection guidelines demand measurements of induced current in humans exposed to radio frequency fields in the range of 10-110 MHz, the importance of finding an appropriate measurement procedure becomes apparent.

Successful treatment and re-treatment of resistant B-cell chronic lymphocytic leukemia with the monoclonal anti-CD 20 antibody rituximab.

We report on two patients with chemoresistant B-cell chronic lymphocytic leukemia who were treated successfully with the monoclonal anti-CD 20 antibody rituximab. Both patients suffered from severe thrombocytopenia requiring platelet transfusions over a period of several months. Neither chemotherapy nor immunosuppressive agents (corticoids, immunoglobulins) were effective. After four doses of rituximab (375 mg/m2 weekly), both patients recovered within a few weeks to hematological partial remission. One patient was re-treated successfully three times after relapses. Both patients were premedicated with prednisone (100 mg) 30 min prior to the infusion to prevent cytokine release and the antibody infusions were well tolerated.

Bendamustine as salvage treatment in patients with advanced progressive breast cancer: a phase II study.

A phase II pilot study of bendamustine as salvage treatment in patients with advanced breast cancer was performed to determine the objective response rates and make further observations on the toxicity of this drug. A group of 37 patients, pretreated with chemotherapy for advanced disease, entered the trial. Treatment consisted of 150 mg/m2 bendamustine on days 1 and 2 of a 4-week treatment course. Patients continued to receive treatment until complete remission and then two further courses, until tumour progression or unacceptable toxicity ensued. A total of 36 patients received at least one treatment course and were assessable for toxicity; 33 patients were evaluable for treatment results. Dose-limiting grade 3 and 4 WHO toxicity occurred in 5 and 3 patients respectively; 27% of patients entered complete or partial tumour remission. The median time to tumour progression was 2 months with a range of 1-14 months. The efficacy of bendamustine was apparently independent of pretreatment with anthracyclines, suggesting a lack of cross-resistance between bendamustine and anthracyclines. It can be concluded that bendamustine in the dose and application schedule used here is active in the salvage therapy of women with advanced breast cancer. The toxicity was acceptable. Future studies have to confirm the data of this pilot trial and to define the role of bendamustine in the combination chemotherapy of metastatic breast cancer that has been suggested by previous trials.

Proton electron-nuclear double-resonance spectra of molybdenum(V) in different reduced forms of xanthine oxidase.

Electron-nuclear double-resonance (ENDOR) spectra of protons coupled to molybdenum(V) in reduced xanthine oxidase samples have been recorded. Under appropriate conditions these protons may be studied without interference from protons coupled to reduced iron-sulfur centers. Spectra have been obtained for the molybdenum(V) species known as Rapid, Slow, Inhibited, and Desulfo Inhibited. Resonances corresponding to at least nine protons or sets of protons are observed for all four species, with coupling constants in the range 0.08-4 MHz. Most of these protons do not exchange when 2H2O is used as solvent. Additional protons giving couplings up to 40 MHz are also detected. These correspond to EPR-detectable protons studied in earlier work. The strongly coupled protons may be replaced by 2H, through appropriate use of 2H2O or of 2H-substituted substrates, with consequent disappearance of the 1H resonances. In most cases the corresponding 2H ENDOR features have also been observed. The nature of the various coupled protons is briefly discussed. Results permit specific conclusions to be drawn about the structures of the Inhibited and Desulfo Inhibited species. In particular, the data indicate that the aldehyde residue of the Inhibited species has been oxidized and that the four protons derived from the ethylene glycol molecule in the Desulfo Inhibited species are not all equivalent. Recent assignments [Edmondson, D.E., & D'Ardenne, S.C. (1989) Biochemistry 28, 5924-5930] of the weakly coupled protons in the latter species appear not to be soundly based. The possibility of obtaining more detailed structural information from the spectra is briefly considered.(ABSTRACT TRUNCATED AT 250 WORDS)

[Thirty years of hemodialysis treatment at Martin Luther University in Halle-Wittenberg]. / Dreissig Jahre Hämodialysebehandlung an der Martin-Luther-Universität Halle-Wittenberg.

An artificial kidney has been taken into operation in the clinic for surgery of the University of Halle-Wittenberg since 1959. This was the second clinical arrangement in the DDR. The indication of the application evolved by the acute renal failure, about the chronic renal insufficiency, within to the hemodialysis as an additive for kidney transplantation. Coworkers of our clinic were engaged vigorously in the technical development of this method in the GDR.

[Erythrocyte ferritin in patients with normal and abnormal iron metabolism]. / Erythrozytenferritin bei Patienten mit normalem und abnormalem Eisenstoffwechsel.

Erythrocyte and serum ferritin was determined in 36 patients with different pictures of diseases and under bleeding therapy in idiopathic haemochromatosis (IH). With latent iron deficiency there was no significant difference in the ferritin content of erythrocytes in comparison with the control group. The intraerythrocyte ferritin content in idiopathic haemochromatosis is always increased and will normalize under bleeding therapy as well serum ferritin. After disrupting the therapy the ferritin content in erythrocytes will more rapidly increase again than in the serum. Increased erythrocyte ferritin could be identified in patients with anaemia due to ineffective erythropoiesis.

Reduced fibrinolytic potential in patients with arterial occlusive disease (AOD) in comparison with normal subjects.

When combining angioplasty and local lysis with urokinase (UK) in treatment of peripheral arterial occlusions we have observed marked differences in the individual patient's response irrespective of the age of the thrombus. The extensive arteriosclerotic changes revealed by angiography in some of these patients suggest a reduced fibrinolytic potential depending on the underlying disease. In the standard in vitro test system we measured the UK-dependent thrombolysis in blood samples from 10 normal controls at UK concentrations of 150, 200, and 300 IU/ml of whole blood. In comparison we determined the whole blood thrombolysis time (WBTT) of 10 patients with AOD using UK concentrations of 150, 200, and 300 IU/ml of whole blood. The mean WBTT values for normal controls obtained at UK concentrations of 150 IU/ml, 200 IU/ml, and 300 IU/ml, respectively, amounted to 9.5, 5.5, and 3.5 minutes, respectively, while in patients mean values of 20.7, 8.1, and 5.5 minutes, respectively, were found. Studies on plasma samples had shown that the lysis time could be shortened in a dose-dependent manner by addition of lys-plasminogen (LYS-PLASMINOGEN Steam Treated) and to some extent also glu-plasminogen. Since lys-plasminogen gave clearly superior results we tried to improve the lytic potential in terms of a shortening of the WBTT by adding different doses of lys-plasminogen (0.14-0.56 CU/ml whole blood) to each patient sample. Although the individual response varied, the addition of lys-plasminogen to the patient samples resulted in a clear dose-dependent improvement of pathologically prolonged lysis times.(ABSTRACT TRUNCATED AT 250 WORDS)

[Value of carcinoembryonic antigen (CEA) in assessing therapeutic success in small cell bronchial cancer]. / Stellenwert des karzinoembryonalen Antigens (CEA) bei der Therapieerfolgseinschätzung des kleinzelligen Bronchialkarzinoms.

UNLABELLED: The determination of the carcino-embryonal antigen (CEA) for the assessment of the therapeutic success and course in colorectal tumours is at present an established diagnostic method. In other solid tumours, e.g. in bronchial carcinomas, the therapy monitoring by means of CEA was less tested. 92 Patients were examined, 31 of them with limited disease (l. d.) and 61 with extensive disease (e. d.). The determination of the CEA was performed before and during the combined radiation therapy and polychemotherapy with 2 different protocols of treatment: ACO (adriblastin, vincristine, cyclophosphamide), FOMC (5-fluoruracil, methotrexate, vincristine, cyclophosphamide) with the OPIDI-radioimmunoassay. Normal values: 0-10 micrograms/l. Limiting area: 11-20 micrograms/l. Pathological area: greater than 20 micrograms/l. RESULTS: patients with limited disease: 8 normal, 14 in the limiting area, 9 in the pathological area (29%). Patients with extensive disease: 17 normal, 19 in the limiting area, 25 in the pathological area (42%) before the beginning of the therapy. With 54 and 60 micrograms/l, respectively, the mean values of the two groups, however, did not differ significantly. Altogether 39 of the 92 patients examined (42%) showed changes of the CEA-values during the course of the disease. For the 31 patients with limited disease 26 (84%) achieved a CR. Of these 26 patients the CEA-values were increased in 7 patients, 5 of them showed a clear decrease, in 3 patients a normalization of the CEA appeared with further existing remission, which lasts for 28, 24 and 14 months. In the remaining 2 patients in the CEA-values decreased into the limiting area.(ABSTRACT TRUNCATED AT 250 WORDS)

[Staging of inoperable small cell bronchial cancer]. / Stadieneinteilung beim inoperablen kleinzelligen Bronchialkarzinom.

This paper compares two staging regimes for the inoperable small-cell carcinoma of the lung. It reveals that at present the differentiation in two classes of the Veterans Administration Lung Cancer Study Group (VALCSG) is preferred to the TNM-classification of the World Health Organization (WHO), as it includes an orientation of prognosis and enables consequences of therapy relevant to practice. If studies of therapy of the small-cell carcinoma of the lung are compared, the uniform application of the classification should be considered.

[Internal medicine aspects of oncology]. / Internistische Onkologie.

Internal oncology is described as an interdisciplinary field of internal medicine and its subspecialties for the diagnostics, therapy and care of patients with tumours. It is based on the close connection of various specialties at different levels of care. The consultation is the decisive instrument for the planning of diagnosis and therapy.

[Paraneoplastic endocrinopathies]. / Paraneoplastische Endokrinopathien.

After the presentation of the definition and of several historical data the present pathophysiological imaginations concerning the problems of the ectopic hormone production are sketched which nowadays not yet have accepted a definitive form. A survey of the at present ascertained paraneoplastic endocrinopathies and several own findings allow a valuation of the significance of these phenomena in practice, taking into consideration the literature.