No abstract

The renal clearance of melphalan and the fraction unbound in plasma were determined after intravenous infusion of 5 mg/m2 over 5 min in nine patients with cancer to obtain information regarding the mechanism of renal handling of melphalan. Four of the patients underwent bone marrow transplantation and also received an IV dose of 220 mg/m2. Total melphalan clearance after the 5 mg/m2 dose ranged from 66.0 to 272 ml/min per m2; the percentage of the dose excreted unchanged in urine, from 2.5% to 92.8%; renal clearance, from 4.1 to 188 ml/min per m2; the fraction unbound in plasma, from 0.0598 to 0.460; and t1/2 beta, from 39.4 to 84.3 min. Unbound melphalan clearance and renal clearance calculated from the unbound fraction in plasma for each patient ranged from 441 to 3356 ml/min per m2 and 15 to 961 ml/min per m2 respectively and were not related to serum albumin, serum creatinine or creatinine clearance. The percentage of the dose excreted and melphalan renal clearance were not related to urine flow. There was evidence of active secretion of melphalan in the kidney an possible reabsorption. There were no significant paired differences in melphalan disposition between the high- and low-dose studies. Highly variable renal clearance involving active secretion may contribute in part to large interpatient differences in the total plasma clearance of melphalan in patients with cancer.

A double Z pinch driving a cylindrical secondary hohlraum from each end has been developed which can indirectly drive intertial confinement fusion capsule implosions with time-averaged radiation fields uniform to 2%-4%. 2D time-dependent view factor and 2D radiation hydrodynamic simulations using the measured primary hohlraum temperatures show that capsule convergence ratios of at least 10 with average distortions from sphericity of /r200 MJ.

SinaryWe asessed factors which affect cisplatin concentrations in human surgical tumour specmen. al., 1994a;Stewart, 1994). For many chemotherapy drugs, only low concentrations are found in normal brain and cerebrospinal fluid (CSF), because of the BBB and blood-CSF barrier, but the barrier is often largely disrupted in patients with brain tumours (Blasberg and Groothuis, 1986). In animal models, the degree of BBB disruption varies from one type of tumour to another and between parts of the same tumour (Groothuis et al., 1981;Blasberg and Groothuis, 1986). Lower concentrations of chemotherapy drugs (Levin et al., 1972;Tator, 1976;Groothuis et al., 1981) and lower capillary permeability (Hasegawa et al., 1983) It has also been argued that resistance of IC tumours may be due in part to invasion of tumour cells into the brain adjacent to tumour (BAT), where the BBB is more intact, and where drug concentrations are lower than in the main body of the tumour (Levin et al., 1975). However, the importance in brain tumour chemotherapy of resistance of tumour cells in the BAT remains controversial. Since even small numbers of tumour cells may induce leakiness in local blood vessels (Stewart et al., 1987), small tumour deposits in the BAT could result in a very localised increase in drug concentrations, and it is uncertain how drug concentrations compare in individual tumour cells in BAT vs the main tumour body.We have studied several chemotherapy drugs with respect to the concentrations reached in human IC tumours (reviewed in Stewart et al., 1994a, Stewart, 1994. Concentrations in IC tumours appeared to be similar to those in EC tumours for cisplatin, phosphonacetyl-L-aspartate, 4'-(9-acridinylamino)-methanesulphon-m-aniside (AMSA), pentamethylmeamine, doxorubicin and vinblasine. Concentrations of etoposide and mitoxantrone in IC tumours were somewhat lower than in EC tumours. Since no EC tumour samples were available, comparisons were not possible for a variety of other agents, but for most of these drugs potentially cytotoxic concentrations were achieved in human IC tumours. Low drug concentrations in normal brain and CSF did not preclude high concentrations in IC tumours.In this paper, we report the results of further studies of human tumour accumulation of the chemotherapy drug cisplatin. These studies were done since our earliest studies of surgical specimens had looked only at IC tumours. While our later autopsy studies had looked at both IC and EC tumours, there were differences between patients with respect to drug doses, time from last treatment to death, concurrent drugs, etc. (reviewed in Stewart et al., 1994a; Stewart, 1994). Hence, we conducted the studies reported in this paper so that a companson could be made between IC and EC tumours

This paper considers ascertainment corrections for continuous phenotypes. Two main points are considered. The first is a discussion of what ascertainment corrections can be devised to ensure asymptotically unbiased parameter estimates when the nature of the ascertainment procedure is not known. The second is an analysis of the properties of various forms of ascertainment correction possible when the nature of the ascertainment procedure is known. Some ascertainment corrections are thus shown to be valid and others invalid.