Spontaneous recovery of renal function after resection of contralateral hypernephroma.

We report a case of nonfunction of an anatomically normal kidney associated with a contralateral hypernephroma. X-ray and radionuclide imaging suggested a disturbance of the contralateral renal blood flow at the microvascular level. Normal function resumed after tumor resection. The implications for management are discussed.     

Collateral susceptibility of adriamycin-, melphalan- and cisplatin-resistant human ovarian tumor cells to bleomycin

Three cell lines resistant to adriamycin, melphalan and cisplatin were established in vitro from human ovarian cancer cell line A2780. Each subline showed a resistance to its inducing drug of 75-fold in the case of adriamycin, 6-fold in the case of melphalan and 11-fold in the case of cisplatin. However, all of these sublines showed collateral sensitivity to bleomycin. Approximately a 2-fold higher susceptibility to bleomycin was observed generally. The biochemical mechanisms of this collateral sensitivity are not clear at present, but the higher concentration of glutathione in these resistant tumor cell lines might be related to the high susceptibility of these resistant cells to bleomycin.     

Kinetics of N-[(4-chlorophenyl)amino]carbonyl-2,3-dihydro-1H-indene-5-sulfonamide (LY186641) in humans

The metabolism and disposition of LY186641, a diarylsulfonylurea with antineoplastic activity identified in preclinical tests, was determined in 21 patients who received 23 courses of orally administered drug. A linear correlation was found between the dose of drug administered and LY186641 peak plasma concentrations and LY186641 area under the curve measurements. Clearance (135 +/- 36 ml/h/m2), terminal half-life (31 +/- 11 h), and volume of distribution (10.2 +/- 2.8 liters) were independent of drug dose. No LY186641 was excreted in urine. Hydroxy and keto metabolites of LY186641 were identified in plasma and urine samples. Urinary excretion of these metabolites during the initial 48 h following drug administration accounted for 20% of LY186641 disposition. Plasma half-life of the hydroxy and keto metabolites was longer than that of parent drug (3.3 and 3.1 days, respectively). Plasma concentrations of parent drug correlated with the presence of methemoglobinemia, the dose-limiting toxicity found with LY186641.     

Paraben preservatives but not succinylcholine are cerebral vasodilators in vitro

Since the increase in intracranial pressure produced by succinylcholine is temporally associated with intravenous administration, we investigated in vitro a possible direct cerebrovascular effect of this nicotinic drug. Isometric responses were recorded from dog and guinea pig basilar artery rings suspended in modified Krebs' solution at 37 degrees C. After precontracting with a voltage (KCl)- or a receptor (5-hydroxytryptamine)-mediated agonist, cumulative concentration-relaxation curves were established for: pure succinylcholine; Quelicin from multidose vials containing 20 mg/ml succinylcholine, 1.8 mg/ml methylparaben, and 0.2 mg/ml propylparaben; Anectine from single-dose vials containing 20 mg/ml succinylcholine; multidose Anectine containing 20 mg/ml succinylcholine and 1.0 mg/ml methylparaben; and methylparaben and propylparaben alone. When required, the endothelium of dog artery was removed by gentle mechanical rubbing and the response to the drugs reevaluated. Both Quelicin and multidose Anectine produced statistically significant (P less than 0.05) relaxation; Quelicin was the more potent of the two. Methylparaben and propylparaben produced relaxation in an additive manner and completely accounted for the relaxation produced by Quelicin and multidose Anectine. The vascular relaxation was found to be independent of the presence of a functional endothelium. Consistent with a nicotinic induced contraction, pure succinylcholine maintained vessel tone. It is concluded that the pharmaceutically ubiquitous preservatives methylparaben and propylparaben but not pure succinylcholine have vasoactive properties in vitro.     

Isolation and characterisation of Indian Ocean ciguatoxin.

We report the isolation and initial characterisation of Indian Ocean ciguatoxin (I-CTX) present in toxic lipid soluble extracts isolated from ciguateric fishes collected off the Republic of Mauritius in the Indian Ocean. Following i.p. injection of this extract, mice displayed symptoms that were similar, though not identical, to those produced by Pacific and Caribbean ciguatoxins (P-CTXs and C-CTXs). Using a radiolabelled brevetoxin (PbTx) binding assay and mouse bioassay guided fractionation, I-CTX was purified by Florisil, Sephadex LH-20 and TSK HW-40S chromatography with good recovery. Isolation to purity was not possible by preparative reversed phase high-performance liquid chromatography (HPLC) due to significant losses of toxicity. However, analytical reversed phase HPLC coupled to an electrospray mass spectrometry detector identified a [M + H](+) ion at m/z 1141.58 which co-eluted with activity that displaced [3H]-PbTx binding to rat brain. This mass corresponded to C-CTX-1, but the fragmentation pattern of I-CTX showed a different ratio of pseudo molecular and product ions. I-CTX was found to elute later than P-CTX-1 but was practically indistinguishable from C-CTX-1 on reversed phase HPLC, while the TSK HW-40S column chromatography differentiated I-CTX from the later eluting C-CTX-1. Taken together, these results indicate that I-CTX is a new ciguatoxin (CTX) responsible for ciguatera caused by reef fish in the Indian Ocean.