E.A. De Bruijn

Pharmacokinėtics of intravenous and oral cyclophosphamide in the presence of methotrexate and fluorouracil

Cyclophosphamide was administered to 12 breast cancer patients in combination with methotrexate and fluorouracil. Doses prescribed were cyclophosphamide 75 mg/m2, methotrexate 30 mg/m2 and fluorouracil 500 mg/m2 (per square meter body surface). Cyclophosphamide was administered intravenously and orally in aqueous solutions and in tablets in a randomized cross-over trial. Methotrexate and fluorouracil were administered intravenously, methotrexate was given first and then fluorouracil. Assays of cyclophosphamide in blood plasma were performed by capillary gas chromatography. Data of mean bioavailability of cyclophosphamide administered by tablets were suggestive of sufficient absorption. In 2 patients, however, a lower bioavailability of cyclophosphamide was demonstrated. Intra-individual differences in the terminal slope of the plasma decay curves after intravenous and oral administration in some patients decreased the calculated bioavailability of cyclophosphamide, if these values were included in the calculation of cyclophosphamide bioavailability. Compared with the administration of the solutions peak times, lag-times and mean absorption times of cyclophosphamide given in tablets were markedly prolonged. It is concluded that interactions between cyclophosphamide and methotrexate and/or fluorouracil after oral dosing as tablets are different from interactions observed after intravenous administration of cyclophosphamide.

The nicotinergic receptor as a target for cognitive enhancement in schizophrenia: Barking up the wrong tree?

RationaleCognitive symptoms have increasingly been recognized as an important target in the development of future treatment strategies in schizophrenia. The nicotinergic neurotransmission system has been suggested as a potentially interesting treatment target for these cognitive deficits. However, previous research yielded conflicting results, which may be explained by several methodological limitations, such as the failure to include both a group of smoking and non-smoking schizophrenic patients, the use of only a single nicotine dose, and the inclusion of a very limited cognitive battery.ObjectivesThe present study aims at investigating the cognitive effects of nicotine in schizophrenia while addressing these methodological issues.MethodsIn a double-blind placebo-controlled randomized crossover design, cognitive effects are assessed in smoking (nu2009=u200916) and non-smoking (nu2009=u200916) schizophrenic patients after receiving active (1 or 2xa0mg) or placebo oromucosal nicotine spray.ResultsA modest improving effect of nicotine on attention in the smoking but not the non-smoking group was found. No enhancing effects were found on measures of visual memory, working memory, processing speed, psychomotor speed, or social cognitive functioning in either patient group.ConclusionsThese findings suggest that the nicotinic receptor only has limited value as a cognitive treatment target in schizophrenia.

Bioanalysis of suramin in human plasma by ion-pair high-performance liquid chromatography.

A liquid chromatographic method is described that can be used for the determination of suramin in plasma samples from cancer patients treated with this drug. The chromatographic system is based on the use of tetrabutylammonium bromide as an ion-pairing agent, while ultraviolet detection is applied. The sample pretreatment is a simple deproteination step by an organic solvent. The same counter-ion as used in the phase system is added in order to increase the recovery of the almost complete protein-bound suramin. The minimum detectable concentration in plasma is ca. 0.1 microgram/ml, thus allowing the monitoring of patients treated with this drug. One example of a plasma concentration-time course after administration of suramin is given.

Structural characterization of cisplatin analogues by fast atom bombardment (FAB) and laser microprobe mass spectrometry (LAMMA)

The present study is concerned with the investigation of the potentials and limitations of fast atom bombardment (FAB) and laser microprobe mass spectrometry (LAMMA) for the structural characterization of a series of cisplatin analogues. The limiting factors for obtaining good quality FAB spectra are the solubility and the stability of the organometallic platinum complexes in the FAB matrix. In the case of a suitable matrix being found, molecular weight information is derived from the (M + H)+ and/or (M - H)- ions. Drawbacks of the application of FAB are (i) the low signal intensities of the molecular ion-like species as compared to the matrix signals and (ii) the scarcity of fragmentation necessary for structure determination. Combination of FAB with tandem mass spectrometry was used to overcome these problems. LAMMA provides a valuable alternative for the direct mass spectral analysis of cisplatin analogues. For some compounds, LAMMA results in useful mass spectra, whereas FAB fails. The abundant fragmentation yields structural information which is complementary for positive and negative ions. The laser power density applied to the sample is of critical importance for the quality of the spectra.

Determination of the new anticancer agent KW 2149, 7-N-[2-((2-(γ-l-glutamylamino)ethyl)dithio)ethyl]mitomycin C, an analogue of mitomycin C

The new mitomycin 7-N-[2-[2-(gamma-L-glutamylamino)ethyl)dithio)ethyl] mitomycin C (KW 2149) (I) proved to be active against a wide variety of experimental tumours. In order to perform pharmacokinetic studies with the new drug in Phase I sessions, a fast and reliable method has been developed based on the data of previous assays for mitomycin C. XAD-2 was preferred for isolation of I from blood plasma. The recovery of I was 50% whereas that of mitomycin C was 85%. Optimal separation was obtained on octadecyl silica columns with methanol-water (45:55, v/v) as mobile phase, while ultraviolet absorbance detection was performed at 375 nm. The assay enabled determination of I in a plasma concentration range of 20-1000 ng/ml using porfiromycin as internal standard.

969 Erythrocytes and the distribution of mitomycin C (MMC)

The E is an important component of whole blood and can act as a transporter and bioreactor. We have recently described an instrument allowing the improved separation and simultaneous analysis of E and plasma (P) fractions †. We report a study of these fractions in 6 patients who received MMC 6xa0mg m –2 (9 to 12xa0mg) as an intravenous bolus for the treatment of NSCLC. Blood was sampled regularly, and E and P separated immediately using the MESED instrument (Fabre, Kelmis, Belgium). MMC concentrations were determined using HPLC. Mean P C 0 was 591xa0ng/ml (SD 40) and mean P t l/2 SO minutes (SD 8). In most samples, MMC levels in E were less than those in P, but concentration time profiles were of a similar shape (E/P ratio 0.77 [SD 0.25]), until approx. 80 minutes after injection, when MMC was no longer detected in E, despite significant quantities in P. This may reflect loss from E, by redistribution, or transformation within E; investigation of this phenomenon is continuing. † Clin Biochem; 27: 195–196 (1994).

942 Uptake of ifosfamide (IF) and its metabolites by erythrocytes (E)

IF is a prodrug requiring activation to isophosphoramide mustard (IPM), but the main site of formation of IPM and its circulating transport form are not certain. We have recently described an instrument (MESED) † allowing the separation and simultaneous analysis of E and plasma(P) fractions, and present the results of such an analysis in two patients receiving an infusion of IF 3xa0g m −2 over 6xa0hours. Blood was sampled until approx. 24xa0hrs after the infusion; E and P fractions were separated immediately using MESED; and IF and its metabolites measured with GC-MS. High mean E/P Cmax ratios were seen for IPM (5.94), Carboxyifosfamide (4.28), Ketoifosfamide (2.87) and IF (2.26), and lower ratios for 2- and 3-Dechloroethylifosfamide, Chloroethylamine and 1,3-Oxazolidine-2-one (1.17–1. 83). E/P AUC ratios showed a similar trend. Therefore, there is significant uptake of IF and its metabolites, particularly IPM, by E, which may be important in the transfer and delivery of these compounds.

763 Continuous low dose, oral doxifluridine (DFURI, 5’-deoxy-5-fluorouridine) for the generation of non-toxic 5FU levels in colorectal cancer

Fluoropyrimidines are one of the few treatment options for colerectal cancer. We describe the use of oral dFUrd (a 5FU prodrug) administration in order to generate low, stable 5FU concentrations and to avoid toxic side-effects. dFUrd (Dxa0=xa0600–1000xa0mg/m 2 ) was given to 6 colerectal patients. Daily doses resulted in continuous systemic levels between 1–5xa0μg/ml which could be maintained during several weeks without any side-effects at all. The biovailability was 32–45%. Renal excretion (3.2–46%) was dose dependent and related with changes of 5FU metabolism. One patient had a partial remission and one a stable disease at 1000xa0mg/m 2 , illustrating the known activity of fluoropyrimidines in the treatment of colerectal cancers. It is concluded that continuous, low dose oral dFUrd results in continuous, non-toxic levels of dFUrd up to 5xa0μg/ml for several days. These findings are supplementary to the sensitizing influence of ras (frequently mutated in colerectal cancer) for dFUrd activity. 1 But also the possible drag carrier function of dFUrd (enhanced anthracycline uptake in cell lines after dFUrd exposure, non-related to multidrug resistance) makes the further study of continuous, low dose oral dFUrd administration warranted as non-toxic (adjuvant) treatment for colerectal cancer. 2