Doxorubicin (adriamycin) has a very wide antitumour spectrum, compared with other anticancer drugs; however, except for Hodgkin's disease, it is not associated with curative chemotherapy. Doxorubicin has been in clinical use for more than 2 decades, and only recently has it been recognised that the cytotoxic effect is produced at the cellular level by multiple mechanisms which have not yet been conclusively identified. Key factors are a combination of doxorubicin-induced free radical formation due to metabolic activation, deleterious actions at the level of the membrane, and drug-intercalation into DNA. Multiple aspects of the clinical pharmacokinetics of this drug have been described. Wide interpatient variations in plasma pharmacokinetics have been noted, but without firm relation to clinical outcome. An apparent volume of distribution of approximately 25 L/kg points to extensive uptake by tissues. Up to several weeks after administration, significant concentrations of doxorubicin have been found in haematopoietic cells and in several other tissues. The maximum cellular doxorubicin concentrations reached in vivo remain significantly below those at which all clonogenic leukaemic cells are killed in vitro. Doxorubicin has been administered as frequent (weekly) low doses, single high doses, and as a continuous infusion. The optimal schedule with respect to tumour cytotoxicity and dose-limiting side effects such as myelosuppression or cardiotoxicity, has never been investigated in a prospective, randomised manner. Clinical trials large enough to study optimal, and possibly individualised, doxorubicin chemotherapy need to be performed. This review summarises pharmacological and pharmacodynamic data of doxorubicin, and discusses these in relation to possible improvement of its therapeutic index. Furthermore, drug interactions, dose-response relationships, mechanisms of action, multidrug resistance, and treatment scheduling are discussed in the perspective of the development of novel treatment strategies.

No abstract

No abstract

No abstract

SUMMARY In a double-blind study we have compared the effect of 50 mg acarbose, 100 mg acarbose, 4.2 g pectin, a combination of 50 mg acarbose with 4.2 g pectin, and placebo on plasma glucose, plasma insulin, breath hydrogen and hypoglycaemic symptoms after a normal carbohydrate rich meal in nine patients with previous gastric surgery. Fifty milligrams acarbose, 100 mg acarbose and the combination of 50 mg acarbose with 4.2 g pectin significantly inhibited the postprandial peak glucose concentration (p<0.01); The lowest plasma glucose concentration, observed 60-150 minutes after ingestion of the meal, was significantly increased by the addition of 50 mg acarbose (p<0.01) and the combination of acarbose with pectin (p<005). The combination of acarbose with pectin was the only treatment that significantly inhibited the plasma insulin peak (p<005). Eight of nine patients had symptoms of hypoglycaemia on placebo, two on 50 mg acarbose (p<005), two on 100 mg acarbose (p<005), five on pectin (ns), and two on the combination of acarbose and pectin (p<005). All treatments with acarbose induced significant increases in breath hydrogen excretion (p<005).Postprandial reactive hypoglycaemia may occur in patients with previous gastric surgery.1-3 This postprandial hypoglycaemia is thought to be because of the rapid gastric emptying of a carbohydrate meal into the small intestine inducing rapid absorption of glucose followed by reactive hyperinsulinism and subsequent hypoglycaemia.1-3 It has been shown recently that 100 mg acarbose, an cx-glucoside hydrolase inhibitor (Bayer, BAY g 5421), induced a significant increase in the lowest plasma glucose concentration after an oral dose of 50 g sucrose in five patients with reactive hypoglycaemia after gastric surgery.4 Although not presented in that study, it is very likely that such a high dose of acarbose will induce serious side-effects due to malabsorption of carbohydrates.5,6 On the other hand, it has previously been reported that addition of 14.5 g of pectin to a 50 g oral glucose load prevented the occurrence of hypoglycaemic symptoms and induced a significant increase in the lowest postprandial glucose concentration in nine patients with previous gastric surgery.3 14.5 g of Address for correspondence to: Dr C Lamers. Division of Gastroenterology.St Radboud Hospital, 6500 HB Nijmegen, The Netherlands.Received for publication 12 November 1982 pectin is, however, an extremely high dose and it is very unlikely that this dose of pectin is tolerated by patients on chronic treatment.The present study was undertaken to determine whether a low dose of 50 mg acarbose is effective in reducing hypoglycaemic symptoms and influencing laboratory measurements after ingestion of a normal carbohydrate rich meal in patients with symptoms of postprandial reactive hypoglycaemia after gastric surgery, and to compare the effect of 50 mg acarbose with a higher dose of acarbose, with a relatively low dose of pectin and with the combination of acarbose with pectin. Therefore, we have compared in a...