ABSTRACT
BACKGROUND: Eribulin mesylate is a synthetic macrocyclic ketone analogue of Halichondrin B that has demonstrated high antitumor activity in preclinical and clinical settings. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics in combination with cisplatin (CP) in patients with advanced solid tumours. METHODS: Thirty-six patients with advanced solid tumours received eribulin mesylate 0.7-1.4 mg m(-2) and CP 60-75 mg m(-2). Eribulin mesylate was administered on days 1, 8, and 15 in combination with CP day 1 every 28-day cycle. The protocol was amended after dose level 4 (eribulin mesylate 1.4 mg m(-2), CP 60 mg m(-2)) when it was not feasible to administer eribulin mesylate on day 15 because of neutropenia; the treatment schedule was changed to eribulin mesylate on days 1 and 8 and CP on day 1 every 21 days. RESULTS: On the 28-day schedule, three patients had DLT during the first cycle: grade (G) 4 febrile neutropenia (1.0 mg m(-2), 60 mg m(-2)); G 3 anorexia/fatigue/hypokalemia (1.2 mg m(-2), 60 mg m(-2)); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m(-2), 60 mg m(-2)). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m(-2), 60 mg m(-2)); G 4 mucositis (1.4 mg m(-2), 60 mg m(-2)); and G 3 hypokalemia (1.2 mg m(-2), 75 mg m(-2)). The MTD and recommended phase II dose was determined as eribulin mesylate 1.2 mg m(-2) (days 1, 8) and CP 75 mg m(-2) (day 1), on a 21-day cycle. Two patients had unconfirmed partial responses (PR) (pancreatic and breast cancers) and two had PR (oesophageal and bladder cancers). CONCLUSIONS: On the 21-day cycle, eribulin mesylate 1.2 mg m(-2), administered on days 1 and 8, in combination with CP 75 mg m(-2), administered on day 1 is well tolerated and showed preliminary anticancer activity.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Ethers, Cyclic/therapeutic use , Macrolides/therapeutic use , Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Cisplatin/adverse effects , Ethers, Cyclic/administration & dosage , Ethers, Cyclic/adverse effects , Furans/administration & dosage , Furans/adverse effects , Humans , Ketones/administration & dosage , Ketones/adverse effects , Macrolides/administration & dosage , Macrolides/adverse effects , Middle Aged , Young AdultABSTRACT
This set of experiments examined the effects of prenatal buprenorphine (BUP) exposure on three measures of sexual differentiation in rats. Pregnant female rats were divided into four treatment groups: 0.6 mg/kg BUP, 0.3 mg/kg BUP, a pair-fed control (PFC), and an untreated control (UTC). Drugs were injected starting on gestation day (GD) 6 and continuing through GD 20 with a 48-h interval between drug administrations. Three variables were examined in the offspring: anogenital (AG) distance on postnatal day (PND) 1, spontaneous parental behavior on PNDs 23-28, and saccharin consumption on PNDs 42-55. Whereas prenatal BUP exposure had no effect on AG distance, spontaneous parental behavior was impaired in the 0.6-mg/kg-exposed offspring on two measures: pup-retrieval latencies and pup-directed behaviors. Furthermore, although both control groups and the 0.3-mg/kg-exposed offspring showed the expected sex difference in consumption of a 0.25% saccharin solution, this difference was not displayed by the 0.6-mg/kg-exposed offspring. These findings suggest that exposure to relatively high doses of buprenorphine during development may have long-term effects on behavior.
