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The clinical pharmacokinetic behavior of paclitaxel (Taxol) is distinctly nonlinear, with disproportional increases in systemic exposure with an increase in dose. We have recently shown that Cremophor EL, the formulation vehicle used for i.v. administration of paclitaxel, alters drug distribution as a result of micellar entrapment of paclitaxel, and we speculated that the free drug fraction (fu) is dependent on dose and time-varying concentrations of Cremophor EL in the central plasma compartment. To test this hypothesis, a reproducible equilibrium dialysis method has been developed for the measurement of paclitaxel fu in plasma. Equilibrium dialysis was performed at 37 degrees C in a humidified atmosphere of 5% CO(2) using 2.0-ml polypropylene test tubes. Experiments were carried out with 260-microliter aliquots of plasma containing a tracer amount of [G-(3)H]paclitaxel with high-specific activity against an equal volume of 0.01 M phosphate buffer (pH 7.4). Drug concentrations were measured by both reversed-phase HPLC and liquid scintillation counting. Using this method, fu has been measured in three patients receiving three consecutive 3-weekly courses of paclitaxel at dose levels of 135, 175, and 225 mg/m(2) and found to range between 0.036 and 0.079. The method was also used to define concentration-time profiles of unbound drug, estimated from the product of the total plasma concentration and fu.

The purpose of this study was to develop and validate limited-sampling strategies for prediction of the area under the plasma-concentration time curves (AUCs) of the lactone and total (i. e., lactone plus carboxylate) forms of the novel topoisomerase-I inhibitor 9-amino-20(S)-camptothecin (9-AC). Complete pharmacokinetic curves for both drug species were obtained from 32 patients who received the drug orally in a clinical phase I setting at dose levels ranging from 0.25 to 1.10 mg/m2. The concentrations of the lactone and carboxylate forms of 9-AC in plasma were measured by HPLC. Using data from 20 randomly selected patients, forward-stepwise multivariate regression analysis was used to generate modeling strategies incorporating data from one, two, or three plasma samples. The simultaneous optimal prediction of both 9-AC lactone and 9-AC total AUCs was obtained with sample time points at 0.33, 3.0, and 11.0 h after drug dosing. Validation of the models on an independent data set comprising data of the remaining 12 patients demonstrated that 9-AC lactone and 9-AC total AUCs could be predicted sufficiently unbiased and precise using one and two time points: [AUC (ng. h/ml) = 7.103*C3 + 4.333] for 9-AC lactone and [AUC (ng. h/ml) = 9.612*C3 + 13.77*C11 - 44.11] for 9-AC total, where C3 and C11 represent the 9-AC plasma concentrations in ng/ml at 3 and 11 h after drug dosing. Application of the proposed models will be valuable in the determination of 9-AC population pharmacokinetics and permits treatment optimization for patients on the basis of individual pharmacokinetic characteristics through restricted drug monitoring in clinical routines.

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The chemosensitizing potency of dexniguldipine hydrochloride (B8509-035) on epidoxorubicin was assessed in a multidrug-resistant (MDR) tumour model, the intrinsic MDR rat colon carcinoma CC531. In vitro in the sulphorhodamine B cell-viability assay the cytotoxicity of epidoxorubicin was increased approximately 15-fold by co-incubation with 50 ng/ml dexniguldipine. In vivo concentrations of dexniguldipine 5 h after a single oral dose of 30 mg/kg were 72 (±19 SD) ng/ml in plasma and 925 (±495 SD) ng/g in tumour tissue. Levels of the metabolite of dexniguldipine, M-1, which has the same chemosensitizing potential, were 26 (±6 SD) ng/ml and 289 (±127 SD) ng/g respectively. The efficacy of treatment with 6 mg/kg epidoxorubicin applied intravenously combined with 30 mg kg-1 day-1 dexniguldipine administered orally for 3 days prior to epidoxorubicin injection was evaluated on tumours grown under the renal capsule. Dexniguldipine alone did not show antitumour effects in vivo. Dexniguldipine modestly, but consistently, potentiated the tumour-growth-inhibiting effect of epidoxorubicin, reaching statistical significance in two out of four experiments. In conclusion, these experiments show that dexniguldipine has potency as an MDR reverter in vitro and in vivo in this solid MDR tumour model.

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In 77 women (Ø 41 week, <7 days before delivery) we compared the resistance index (RI) in the umbilical artery (UA), descending aorta (DA) and intracranial artery (ICA) with an oxytocin challenge test (OCT) and a non stress test (NST). Proof criterias were asphyxia resulting in operative deliveries and metabolic acidosis. The sensitivity in predicting metabolic acidosis was low in all tests, but a high and comparable specificity could be achieved in both the RI and OCT. In predicting fetal asphyxia the RI in the ICA had a high sensitivity, the RI in the UA and DA had the highest specificity of all tests. Centralisation and increased brain perfusion seem to detect fetal asphyxia as a result of placental insufficiency.

Three aspects of electroreception in catfish were investigated and discussed. 1) The distribution of the electroreceptive small pit organs over the skin was mapped (Fig. 2). Small pit organs occur all over the body with the exception of the barbels. The total number of small pit organs per fish has to be estimated at several thousands. 2) Some examples of the potential pattern of the bioelectric field ofIctalurus are given (Fig. 4, 5). It was found that the opening or closing of the mouth, and contractions of the anal sphincter result in variations in this bioelectricfield, that might be of significance in behaviour. 3) The skin resistance of catfish proved to be constant in electric fields from d.c. to 10 Hz, and to behave frequency dependent from 10 Hz upwards. The resistive behaviour of the fish's body varies with the direction of the body axes. In dorso-ventral direction the insulating properties of the body are greatest, which suggest a greater electro-sensitivity in this direction than in others (Fig. 6, 7). The relatively small deformation of external homogeneous a.c. fields, caused by the insulating character of the swim bladder, suggests that a subdermal conductive layer screens the inner structures and might function as a potential reference.

An improved method is presented for preparing optically active cyanohydrins in high yield and high enantioselectivity, using R-oxynitrilase from almonds as the catalyst in a biphasic water-organic solvent system. Reaction conditions for two representative substates have been studied with respect to conversion, optical purity and enzyme stability.The suitability of the procedure for industrial use was substantiated by the possibility of reusing the enzyme-containing aqueous phase for the synthesis of R-mandelonitrile.

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Zusammenfassung Durch konsequente Weiterentwicklung derAbbeschen Theorie der mikroskopischen Abbildung konnteZernike zeigen, daß durch willkürliche Beeinflussung der Phase eines Teiles des Lichts eine Steigerung des Kontrastes im mikroskopischen Bild erreicht werden kann. Die theoretischen Grundlagen dieses Phasenkontrastverfahrens werden ausführlich besprochen und auf die Gründe für die Verwendung kreisringförmiger Phasenplättchen hingewiesen. An einigen Beispielen werden die prinzipiellen Unterschiede zwischen Hellfeld und Dunkelfeld und positivem und negativem Phasenkontrast besprochen. Es zeigt sich, daß in vielen Fällen das neue Verfahren dem Dunkelfeld und dem Hellfeld grundsätzlich überlegen ist; es liefert objektähnlichere Bilder als die bisherigen Methoden. Besonders erfolgreich können ungefärbte, auch lebende mikroskopische Präparate mit bisher nicht für möglich gehaltener Deutlichkeit beobachtet und photographiert werden.

Zusammenfassung: Das neue Phasenkontrastverfahren ist eine mikroskopische Beobachtungsmethode, die gegenber dem Hellfeld und dem Dunkelfeld eine Reihe von wichtigen Vorteilen bei der Untersuchung ungefrbter oder lebender Objekte bietet. Der Effekt kommt zustande durch knstliche Beeinflussung der Phase des Lichtes in der Austrittspupille des Mikroskopobjektivs. An einer Reihe von Beispielen wird der Nutzen und die berlegenheit des Verfahrens vor anderen Methoden gezeigt. So kann die seit langem fr abgeschlossen gehaltene Lichtmikroskopie einen neuen Fortschritt fr sich buchen, der auch im Zeitalter des Elektronenmikroskops das Interesse der Biologen und rzte erwecken wird.

Summary: 32 patients suffering from HELLP-syndrome (hemolysis, elevated liver enzymes, low platelets, [pains in the right epigastrium] were treated in the departments of Obstetrics and Gynecology, Universities of Gttingen and Munich (Rechts der Isar) during the last 2 years. The clinical management was the following:

Septic ovarian vein thrombosis is commonly the sequela of puerperal purulent endomyometritis. The incidence has been reported to be 1 in 600–6000 deliveries. The predominant location is the right ovarian vein according to the puerperal uterine drainage. The diagnostic and therapeutic experience in 9 cases is described. The leading symptoms were abdominal pain localized at the psoatic muscle and a tender, barrel-shaped tumor. Ultrasound and computed tomography (CT) added in the correct preoperative diagnosis. Antibiotic therapy and anticoagulation are recommended in an uneventful course; in complicated cases surgical intervention becomes mandatory.

Pregnancy induced hypertension is not associated with coagulation changes in the sense of hypercoagulability or chronic disseminated intravascular coagulation. Doppler flow measurements show an increased restistance index in the Arteria umbilicalis in 50% of our patients.

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From linearized two fluid hydrodynamics it is shown that there is a spatially constant temperature rise if a heat current is switched on in a channel of infinite length. This leads to a maximum possible heat current vanishing atTgl. In a spherical geometry there is a similar temperature rise, but it decays exponentially with time.

Mandelonitrile lyase as present in a crude extract of almond flour is tested for the synthesis of several chiral cyanohydrins such as (III).