Treatment of a patient with advanced esophageal cancer with a combination of mitomycin C and capecitabine: activation of the thymidine phosphorylase as active principle?

BACKGROUND: Both capecitabine, an oral prodrug of 5-fluorouracil (5-FU), and mitomycin C (MMC) have demonstrated activity as single agents in patients with gastrointestinal cancer. Furthermore, a combination of MMC with infusional 5-FU can induce tumor remission even in patients pretreated with 5-FU. Capecitabine and MMC act synergistically due to an upregulation of the thymidine phosphorylase activity by MMC in a human xenograft model. PATIENT: We sought to exploit these preclinically observed effects in a patient with esophageal cancer who was progressive after a first-line radiochemotherapy with 5-FU and cisplatin. He was treated with a combination of MMC and capecitabine on a compassionate use basis. A rapid remission lasting for about 6 months was observed. CONCLUSION: This is the first report on a combination therapy with capecitabine and MMC. The remission observed in our patient suggests that the preclinically observed synergy has clinical impact. This combination should be further investigated in prospective clinical trials.     

Pharmacokinetic/Pharmacodynamic Evaluation of Deflazacort in Comparison to Methylprednisolone and Prednisolone

Purpose. The pharmacokinetics and pharmacodynamics of deflazacort after oral administration (30 mg) to healthy volunteers were determined and compared with those of 20 mg of methylprednisolone and 25 mg of prednisolone. Methods. Methylprednisolone, prednisolone and the active metabolite of deflazacort, 21-desacetyldeflazacort, were measured in plasma using HPLC. For the assessment of pharmacodynamics, differential white blood cell counts were obtained over 24 hours. An integrated pharmacokinetic-pharmacodynamic (PK-PD) model was applied to link corticosteroid concentrations to the effect on lymphocytes and granulocytes. Results. Deflazacort is an inactive prodrug which is converted rapidly to the active metabolite 21-desacetyldeflazacort. Maximum concentrations of 21-desacetyldeflazacort averaged 116 ng/ml and were observed after 1.3 h. The average area under the curve was 280 ng/ml · h, and the terminal half-life was 1.3 h. 21-Desacetyldeflazacort was cleared significantly faster than both methylprednisolone and prednisolone. The PK-PD-model was suitable to describe time course and magnitude of the observed effects. The results were consistent with reported values for glucocorticoid receptor binding affinities for the investigated compounds. Conclusions. Due to the short pharmacokinetic half-life of its active metabolite, pharmacodynamic effects of deflazacort are of shorter duration than those of methylprednisolone and prednisolone. The PK-PD model allows good prediction of pharmacodynamic effects based on pharmacokinetic and receptor binding data.     

Analysis of leucine enkephalin by high-performance liquid chromatography using enzymatic derivatization by tyrosinase and electrochemical or fluorescence detection

Two tyrosine specific, HPLC methods with either electrochemical (HPLC-ED) or fluorescence (HPLC-FL) detection are described for leucine-enkephalin (LE) in cerebrospinal fluid (CSF). Both approaches involve the hydroxylation of the Tyr¹-moiety of LE by mushroom tyrosinase. Production of a catechol permitted the selective clean-up of the analyte using boronate gels and produced species which were more readily oxidizable than the LE. The controlled oxidation of the catechol to corresponding chinones enabled the reaction with 1,2-diamino-1,2-diphenylethane (DPE) and subsequent quantification by HPLC-FL. The HPLC-ED and HPLC-FL yielded limits of detection for LE in CSF of 360 and 500 fmol per injection, respectively. Inter-day variability of calibration curve samples was lower than 20% for the HPLC-ED with slightly higher variability for the HPLC-FL assay.     

Pharmacokinetic/Dynamic Correlation of Pulmonary and Cardiac Effects of Fenoterol in Asthmatic Patients After Different Routes of Administration

Pulmonary and cardiac effects of the ₂-adrenergic drug fenoterol were studied in 27 asthmatic patients using an integrated pharmacokinetic/dynamic (PK/PD) approach. Airway resistance (R _f), intrathoracic gas volume (IGV), heart rate, and plasma levels were monitored after placebo, injection (12.5 and 25 µg), nasal instillation (400 µg), inhalation (200 and 400 µg), and infusion (200 µg/180 min with or without loading dose). The pharmacokinetics were best described by an open three-compartment model with a terminal half-life of 200 min ( = 0.23 ± 0.08 L/hr), a volume of distribution at steady state of 1.9 ± 0.8 L/kg, and a clearance of 0.86 ± 0.32 L/hr/kg, with 14 and 9% absorbed after nasal and pulmonary administration, respectively. For the noninhalation regimens, a PK/PD correlation linked the concentration in the shallow pharmacokinetic compartment to the investigated effects via an E_max relationship, resulting in three to five times higher EC₅₀ values (concentration necessary to achieve half-maximal effect) for the heart rate than for the ₂ mediated effects on IGV and R _f. In contrast, pulmonary effects after inhalation could not be incorporated into the correlation, indicating that these effects are induced locally after inhalation. Intrapatient variability for EC₅₀ and E_max was approximately 90%.     

Die megakaryozytäre Myelose — Klinik,Morphologie und Plättchenfunktion

Summary The study reviews 22 patients, aged between 19 to 73 years, with megakaryocytic myelosis. In the course of the disease 11 patients presented haemorrhagic manifestations, 12 patients thrombotic complications, and 6 patients the association of haemorrhage and thrombosis. The maximum platelet counts ranged from 524 to 2700×10⁹/l. The bone marrow showed a conspicuous megakaryocytic proliferation with polyploidy of the nuclei, giant forms and clusters. Marked alterations of erythro- and granulopoiesis were excluded. There was no evidence for a reactive thrombocytosis in any case.Patients with thrombocythaemia due to megakaryocytic myelosis (n=14), with secondary thrombocytosis of various origin (n=16), and a control group of healthy donors (n=20) were investigated with respect to the aggregation behaviour and the total calcium content of blood platelets. In 9 of 14 patients with megakaryocytic myelosis platelet rich plasma did not respond to epinephrine (15 µmol/l), a concentration which induced at least weak aggregation in 14 of 16 patients with secondary thrombocytosis and also in healthy subjects. In patients with megakaryocytic myelosis the mean extent of aggregation induced by epinephrine, collagen or adenosine diphosphate was significant lower as compared to controls whereas in patients with secondary thrombocytosis in most cases this parameter did not differ significantly from that of controls. The total calcium content of platelets was significantly lower in both groups of patients as compared to controls. In 14 patients with megakaryocytic myelosis the concentration of the glycoprotein (GP) IIb-IIIa complex was estimated by crossed- and rocket-immunoelectrophoresis and found to be decreased in 8 of them. The amount of GP IIb-IIIa correlated inversely with the platelet count (r=–0,66). The results may contribute to better pathophysiological understanding of the megakaryocytic myelosis, thrombocythaemias in myeloproliferative disorders and their complications.

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Abkürzungen ADP Adenosindiphosphat - T_max maximale Transmissionsänderung - GP Glycoprotein - mM megakaryozytäre Myelose - PAF plättchenaktivierender Faktor - PAP plättchenarmes Plasma - PRP plättchenreiches Plasma - ST sekundäre Thrombozytose Herrn OMR Prof. Dr. sc. med. G. Panzram zum 65. Geburtstag gewidmet     

Results of comprehensive geriatric assessment effect survival in patients with malignant lymphoma

Purpose  

The prevalence of elderly and comorbid patients (pts) with malignant lymphoma (ML) will steadily increase in future. Elderly patients comprise a heterogeneous population. Comprehensive geriatric assessment (CGA) is an established diagnostic tool in geriatric medicine. However, the prognostic value in patients with ML is unclear. We sought to establish a relationship between results of CGA and survival time in patients with ML.