Rocaglamide derivatives are potent inhibitors of NF-kappa B activation in T-cells.

Crude extracts from different Aglaia species are used as anti-inflammatory remedies in the traditional medicine of several countries from Southeast Asia. Because NF-kappaB transcription factors represent key regulators of genes involved in immune and inflammatory responses, we supposed that the anti-inflammatory effects of Aglaia extracts are mediated by the inhibition of NF-kappaB activity. Purified compounds of Aglaia species, namely 1H-cyclopenta[b]benzofuran lignans of the rocaglamide type as well as one aglain congener were tested for their ability to inhibit NF-kappaB activity.

Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency.

Background: Intravenous pulse administration of cyclophosphamide (CYC) has been successfully used for the treatment of various autoimmune diseases. These patients often present with impaired renal function or even end-stage renal failure. Nevertheless, data concerning pharmacokinetics of CYC in renal insufficiency (RI) and on hemodialysis (HD) are rare and contradictory.

New insecticidal rocaglamide derivatives and related compounds from Aglaia oligophylla.

Organic-soluble extracts of the twigs of Aglaia oligophylla collected in Vietnam yielded four insecticidal cyclopentatetrahydrobenzofurans of the rocaglamide type including one new natural product (compound 4). Moreover, two cyclopentatetrahydrobenzopyran derivatives, belonging to the aglain and aglaforbesin types, respectively, were also isolated. The aglaforbesin derivative 6 proved likewise to be a new natural product.

[Pharmacokinetics of cyclophosphamide, adriamycin and adriamycin prodrug (HMR 1928) using an ex vivo isolated perfused human lung model (IHLP)].

Background: Today knowledge about pharmacokinetics of anticancer drugs in human malignant tumors is poor. Data from in vivo studies are limited and difficult to obtain due to ethical aspects. An ex vivo isolated perfused and ventilated human lung model however allows pharmacological studies of human bronchial carcinoma inside their host organ, the lung, under physiological conditions without compromising the patient.

Insecticidal rocaglamide derivatives from Aglaia spectabilis (Meliaceae).

Bark of Aglaia spectabilis collected on the island of Phu Quoc (Vietnam) yielded insecticidal cyclopentatetrahydrobenzofurans of the rocaglamide type including four new natural products. Structure elucidation of the new compounds is described. All rocaglamide derivatives isolated exhibited strong insecticidal activity towards neonate larvae of the polyphagous pest insect Spodoptera littoralis when incorporated into an artificial diet.

1H-cyclopenta[b]benzofuran lignans from Aglaia species inhibit cell proliferation and alter cell cycle distribution in human monocytic leukemia cell lines.

Thirteen naturally occurring 1H-cyclopenta[b]benzofuran lignans of the rocaglamide type as well as one naturally occurring aglain congener all of them isolated from three Aglaia species (Aglaia duperreana, A. oligophylla and A. spectabilis) collected in Vietnam were studied for their antiproliferative effects using the human monocytic leukemia cell lines MONO-MAC-1 and MONO-MAC-6.

Human CYP2B6: expression, inducibility and catalytic activities.

Human cytochrome (CYP)2B6 cDNA was cloned and expressed in bacteria and in yeast. Its expression in Saccharomyces cerevisiae enabled us to obtain, at a high level, an active yeast-expressed CYP2B6 protein, so as to assess its role in the metabolism of ethoxyresorufin, pentoxyresorufin, benzyloxyresorufin, ethoxycoumarin, testosterone and cyclophosphamide. Kinetic analysis showed that human CYP2B6 preferentially metabolized benzyloxyresorufin and pentoxyresorufin, although other CYPs also metabolized these substrates in human liver microsomes.

Investigation of the major human hepatic cytochrome P450 involved in 4-hydroxylation and N-dechloroethylation of trofosfamide.

Trofosfamide and its congeners ifosfamide and cyclophosphamide are cell-cycle-nonspecific alkylating agents that undergo bioactivation catalyzed by liver cytochrome P450 (CYP) enzymes. Two NADPH-dependent metabolic routes for the anticancer drug trofosfamide, i.e.

Determination of tetrahydrothiophene formation as a probe of in vitro busulfan metabolism by human glutathione S-transferase A1-1: use of a highly sensitive gas chromatographic-mass spectrometric method.

A method for the sensitive determination of tetrahydrothiophene (THT) in cytosolic incubation mixtures was developed. Busulfan conjugation with glutathione was predominantly catalysed by glutathione S-transferase A1-1 (GST A1-1) and THT was released from the primary metabolite by alkalization. After liquid-liquid extraction using n-pentane separation and quantification of the product was performed by gas chromatography with a mass-selective detector.

Structure activity relationships of antiproliferative rocaglamide derivatives from Aglaia species (Meliaceae).

Eleven rocaglamide derivatives (cyclopentatetrahydrobenzofurans) and one structurally related aglain congener all isolated from different Aglaia species (Meliaceae) were tested for growth inhibiting properties using the human cancer cell lines MONO-MAC-6 and MEL-JUSO. Proliferation of both cell lines was efficiently inhibited in a dose and compound dependent manner. Applying MTT-Assay, the IC50 of the most active compound didesmethyl-rocaglamide (1) was observed at 0.

In vitro cleavage of paracetamol glucuronide by human liver and kidney beta-glucuronidase: determination of paracetamol by capillary electrophoresis.

A capillary electrophoresis (CE) method was developed using paracetamol glucuronide as a novel probe for human beta-glucuronidase activity. Using UV detection without prior sample clean-up procedures, fast and reliable quantitation of the released paracetamol was possible. The method showed good precision, accuracy and sensitivity with a limit of detection of 0.

Fractionated administration of high-dose cyclophosphamide: influence on dose-dependent changes in pharmacokinetics and metabolism.

Purpose: The alkylating agent cyclophosphamide (CP) is a prodrug that is metabolized to both cytotoxic and inactive compounds. We have previously shown that following dose escalation from conventional-dose (CD) to high-dose (HD) levels; the fraction of the dose cleared by bioactivation is significantly decreased (66% versus 48.5%) in favor of inactivating elimination pathways when the HD is given as a single 1-h infusion.

Dose escalation of cyclophosphamide in patients with breast cancer: consequences for pharmacokinetics and metabolism.

Purpose: The alkylating anticancer agent cyclophosphamide (CP) is a prodrug that undergoes a complex metabolism in humans producing both active and inactive metabolites. In parallel, unchanged CP is excreted via the kidneys. The aim of this study was to investigate the influence of dose escalation on CP pharmacokinetics and relative contribution of activating and inactivating elimination pathways.

High-performance liquid chromatographic determination of acrolein as a marker for cyclophosphamide bioactivation in human liver microsomes.

A high-performance liquid chromatographic method for the quantification of acrolein following incubation of cyclophosphamide (CP) with human liver microsomes was developed. Based on the formation of the fluorescent derivative 7-hydroxyquinoline by condensation of acrolein with 3-aminophenol quantitation was performed without prior extraction or other sample cleanup procedures. The method showed sufficient sensitivity with a limit of detection of 5 ng/ml and a limit of quantification of 10 ng/ml.

Characterization of the cytochrome P450 involved in side-chain oxidation of cyclophosphamide in humans.

Objective: Cyclophosphamide (CP) is an antineoplastic prodrug which requires bioactivation (4-hydroxylation) by the cytochrome P450 (CYP) enzymes in human liver. In parallel, P450-mediated side-chain oxidation (N-dealkylation) leads to the formation of the non-alkylating dechloroethylcyclophosphamide (DCI-CP) and chloroacetaldehyde, the latter being a potential neurotoxic agent. The enzyme responsible for side-chain oxidation has not been identified yet.

Direct gas chromatographic determination of dechloroethylcyclophosphamide following microsomal incubation of cyclophosphamide.

A method for the sensitive determination of dechloroethylcylclophosphamide (3-DCl) in microsomal incubation mixtures was developed. 3-DCl, a side-chain oxidation product of cyclophosphamide (CP), was isolated by extraction with acetic acid ethyl ester following solid-phase extraction on C8 cartridges. Quantification of the metabolite was performed by direct capillary gas chromatography with a nitrogen-phosphorus detector without prior derivatization.