A dose-ranging study of the pharmacokinetics and pharmacodynamics of the selective apoptotic antineoplastic drug (SAAND), OSI-461, in patients with advanced cancer, in the fasted and fed state.

PURPOSE: To evaluate the safety, pharmacokinetics and determine the recommended dose of the selective apoptotic antineoplastic drug, OSI-461 administered on a twice-daily regimen to patients with advanced solid malignancies. METHODS: In this phase I trial, 33 patients were treated with OSI-461 doses ranging from 400 to 1,200 mg given twice daily in 4-week cycles. Pharmacokinetic studies were performed to characterize the plasma disposition of OSI-461 and the effect of food intake on OSI-461 absorption. Secondary biomarker studies were performed to assess the biologic activity of OSI-461 including the measurement of pGSK-3beta, a PKG substrate, and pharmacogenetic studies to identify polymorphisms of CYP3A that influence drug metabolism and of ABCG2, involved in drug resistance. RESULTS: Thirty-three patients were treated with 86 courses of OSI-461. The dose-limiting toxicities were grade 3 abdominal pain, found in one patient at the 1,000 mg BID fed dose level and all patients at the 1,200 mg BID fed dose level. There was also one episode each of grade 3 fatigue and grade 3 constipation at the 1,000 and 1,200 mg BID fed dose levels, respectively. Other common toxicities included mild to moderate fatigue, nausea, anorexia and mild elevation in bilirubin. Pharmacokinetic studies of OSI-461 revealed approximately a twofold increase in AUC(0-24) when OSI-461 was administered with food. An increase in pGSK-3beta post-dose was seen in the majority of patients and was greater at higher dose levels. No patients exhibited CYP3A4 polymorphisms, while 100% of patients were found to have the CYP3A5*3/CYP3A5*3 polymorphism. Two known polymorphisms of the ABCG2 gene, G34 --> A34 and C421 --> A421, occurred at frequencies of 11.76 and 29%, respectively. CONCLUSIONS: Toxicity and pharmacodynamic data show that the recommended oral dose of OSI-461 is 800 mg twice daily administered with food. The drug appears to be well-tolerated, and overall bioavailability appears to be markedly increased when the drug is administered with food. These results support further disease-directed evaluations of OSI-461 at a dose of 800 mg BID in combination with other chemotherapeutic agents.

Assessment of the biological and pharmacological effects of the alpha nu beta3 and alpha nu beta5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors.

BACKGROUND: Cilengitide, an antiangiogenic agent that inhibits the binding of integrins alpha(nu)beta(3) and alpha(nu)beta(5) to the extracellular matrix, was studied at two dose levels in cancer patients to determine the optimal biological dose. PATIENTS AND METHODS: The doses of cilengitide were 600 or 1200 mg/m(2) as a 1-h infusion twice weekly every 28 days. A novel dose escalation scheme was utilized that relied upon the biological activity rate. RESULTS: Twenty patients received 50 courses of cilengitide with no dose-limiting toxic effects. The pharmacokinetic (PK) profile revealed a short elimination half-life of 4 h, supporting twice weekly dosing. Of the six soluble angiogenic molecules assessed, only E-selectin increased significantly from baseline. Analysis of tumor microvessel density and gene expression was not informative due to intrapatient tumor heterogeneity. Although several patients with evaluable tumor biopsy pairs did reveal posttreatment increases in tumor and endothelial cell apoptosis, these results did not reach statistical significance due to the aforementioned heterogeneity. CONCLUSIONS: Cilengitide is a well-tolerated antiangiogenic agent. The biomarkers chosen in this study underscore the difficulty in assessing the biological activity of antiangiogenic agents in the absence of validated biological assays.

A phase I safety, pharmacological and biological study of the farnesyl protein transferase inhibitor, tipifarnib and capecitabine in advanced solid tumors.

BACKGROUND: To evaluate the toxicity and pharmacological and biological properties of the farnesyl protein transferase (FPTase) inhibitor, tipifarnib (R115777, ZARNESTRAtrade mark) and capecitabine administered for 14 days every 3 weeks. PATIENTS AND METHODS: Patients with advanced cancers received twice daily tipifarnib (100-500 mg) and capecitabine (1000-1125 mg/m(2)) for 14 days every 3 weeks. Pharmacokinetics of tipifarnib, capecitabine and 5-fluorouracil (5-FU) were determined. Peripheral blood mononuclear cells were analyzed for farnesylation of the HDJ2 chaperone protein and FPTase activity. RESULTS: Forty-one patients received 185 courses of treatment. Diarrhea and palmar-plantar erythrodysesthesia were dose limiting at 300 mg tipifarnib/1125 mg/m(2) capecitabine b.i.d. When the capecitabine dose was fixed at 1000 mg/m(2) b.i.d., neutropenia was dose limiting at 400 and 500 mg b.i.d. of tipifarnib. Capecitabine did not affect the pharmacology of tipifarnib at 100-300 mg b.i.d., although tipifarnib significantly increased the C(max) of 5-FU at 400 mg b.i.d. HDJ2 farnesylation and FPTase activity decreased between 200 and 400 mg b.i.d. doses of tipifarnib, without a dose-response relationship. Five patients demonstrated partial remissions and 11 patients maintained prolonged stable disease. CONCLUSIONS: Tipifarnib and capecitabine are well tolerated at 300 mg/1000 mg/m(2) b.i.d., respectively, resulting in biologically relevant plasma concentrations and antitumor activity. The recommended dose for further disease-focused studies is 300 mg b.i.d. tipifarnib and 1000 mg/m(2) b.i.d. capecitabine, given for 14 days every 3 weeks.

Antiinflammatory and analgesic activity of an inhibitor of neuropeptide amidation.

4-Phenyl-3-butenoic acid (PBA) has been shown in vitro to be a turnover-dependent inactivator of peptidylglycine alpha-monooxygenase (PAM), the rate-limiting enzyme involved in the formation of amidated neuropeptides from their glycine-extended precursors. In the studies reported herein, we have shown that PBA produces a dose-dependent (50-500 mg/kg s.c.) inhibition of serum PAM activity in normal rats without affecting peptidylamidoglycolate lyase activity. Because amidated neuropeptides such as substance P and calcitonin gene-related peptide are involved in acute inflammation, we evaluated the effects of PBA on carrageenan-induced inflammation in rats. The acute administration of PBA (s.c. or i.p.) produced a dose-related inhibition of edema with maximum inhibition (67%) observed at 2 hr postphlogistic agent. In addition, the continuous administration of PBA to animals over a 7-day period using osmotic pumps not only inhibited hind paw swelling induced by carrageenan but also inhibited serum PAM activity and reduced tissue levels of substance P in hind paws. These results demonstrate for the first time a correlation between the antiinflammatory activity produced by an inhibitor of peptide amidation with its ability to inhibit serum PAM activity and lower endogenous tissue levels of substance P. Moreover, these results confirm our contention that PAM is an excellent pharmacological target for controlling the acute inflammatory response. We also demonstrate the ability of PBA to inhibit phenyl-p-quinone and acetylcholine-induced writhing in mice without affecting the spinally mediated tail immersion assay in rats. Because this analgesic effect was extremely rapid (within 15 min), PBA may be producing this effect by a mechanism other than peptide amidation.

Distribution and behaviour of radiocaesium in Scottish freshwater loch sediments.

The distribution and behaviour of radiocaesium have been studied in the sediments of two contrasting freshwater lochs: Round Loch of Glenhead, an acidified loch in south-west Scotland, with organic-rich sediments (≈20%C) and Loch Lomond, 35 km north-west of Glasgow, where sediments are low in organic matter (1-6%C, southern basin), but with a relatively high clay content.In the sediments of Scottish freshwater lochs,(137)Cs [half life (t1/2) = 30.23 yr] originates from fallout from nuclear weapons' testing (1950s and 1960s) and from the Chernobyl reactor accident in 1986, which is also the source of the shorter-lived(134)Cs [half life (t1/2) = 2.05 yr]. Use of the characteristic(134)Cs/(137)Cs activity ratio of radiocaesium emitted from Chernobyl enables resolution of sedimentary radiocaesium profiles into the two component sources.In the organic-rich sediment of Round Loch, downward diffusion of radiocaesium in porewaters obscures its pattern of input to the loch. In the more clay-rich sediments of Loch Lomond, separate radiocaesium concentration peaks, related to atmospheric deposition maxima, are clearly discernible, although an influence of partial mixing is apparent. While the derived Chernobyl fallout inventory of radiocaesium in Round Loch sediments is broadly comparable with that for Loch Lomond, the corresponding weapons testing inventory is an order of magnitude lower than in Loch Lomond. Although Round Loch is situated in an area of known elevated Chernobyl deposition, the inventory is much lower than literature values of atmospheric deposition, indicating significant loss of radiocaesium from this loch. The weapons testing inventory in Round Loch is also lower than reported estimates, whereas in Loch Lomond the established inventories from both sources are similar to, or greater than, fallout deposition. The differences between the distribution and inventories in the two lakes confirms that radiocaesium is much less efficiently bound and is correspondingly much more mobile in the organic sediments of Round Loch of Glenhead than in the more clay-rich sediments of Loch Lomond.

Single lung transplantation. Factors in postoperative cytomegalovirus infection.

Thirty-one single lung transplantations were performed between March 17, 1988, and November 1, 1990. Postoperative infection, especially with cytomegalovirus, has been the major cause of morbidity and mortality. Eighteen of the 31 patients were receiving prednisone before transplantation. Every patient was prepared preoperatively with oral cyclosporine 5 mg/kg and azathioprine (Imuran) 2 mg/kg. Every patient received methylprednisolone for 3 days postoperatively, followed by prednisone 1.0 mg/kg/day, oral cyclosporine, and azathioprine. Ten patients additionally had cytolytic therapy with OKT3 and 12 with antilymphocyte globulin. Nine patients had no cytolytic therapy. Cytolytic therapy was chronologic, not randomized. Postoperative infection occurred in 20 patients, 13 of whom had cytomegalovirus infection. Preoperative use of prednisone did not correlate with postoperative infection, cytomegalovirus, or death. Postoperative infection occurred in 17 of 22 patients with cytolytic therapy compared with three of nine without cytolytic therapy (p = 0.035). Cytomegalovirus infection occurred in 13 of 22 with cytolytic therapy and in none of the nine without cytolytic agents (p = 0.003). Therefore preoperative prednisone does not appear to be a contraindication to single lung transplantation. Cytolytic therapy with either OKT3 or antilymphocyte globulin increases the prevalence of postoperative infection with cytomegalovirus and should not be used in patients undergoing lung transplantation.