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Biomedical subjects

R A Hilger

Publications and source records attributed to R A Hilger.

At least 19 recordsLinked to original sources
PubMed2006

Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors.

BACKGROUND: Sorafenib (BAY 43-9006), a novel, oral multi-kinase inhibitor, blocks serine/threonine and receptor tyrosine kinases in the tumor and vasculature. Sorafenib demonstrated single-agent activity in Phase I studies, and was tolerated and inhibited tumor growth in combination with doxorubicin in preclinical studies. This Phase I dose-escalation study determined the safety, pharmacokinetics and efficacy of sorafenib plus doxorubicin. PATIENTS AND METHODS: Thirty-four patients with refractory, solid tumors received doxorubicin 60 mg/m(2) on Day 1 of 3-week cycles, and oral sorafenib from Day 4 of Cycle 1 at 100, 200 or 400 mg bid. RESULTS: Common drug-related adverse events were neutropenia (56%), hand-foot skin reaction (44%), stomatitis (32%), and diarrhea (32%). The maximum tolerated dose was not reached. One patient with pleural mesothelioma achieved a partial response (modified WHO criteria) and remained on therapy for 39.7 weeks. Fifteen patients (48%) achieved stable disease for >/=12 weeks. Doxorubicin exposure increased moderately with sorafenib 400 mg bid. The pharmacokinetics of sorafenib and doxorubicinol were not affected. CONCLUSION: Sorafenib 400 mg bid plus doxorubicin 60 mg/m(2) was well tolerated. The increased doxorubicin exposure with sorafenib 400 mg bid did not result in significantly increased toxicity; low patient numbers make the clinical significance of this unclear. These promising efficacy results justify further clinical investigation.

Adult↗
PubMed2005

Dose-escalated treosulphan in combination with cyclophosphamide as a new preparative regimen for allogeneic haematopoietic stem cell transplantation in patients with an increased risk for regimen-related complications.

Treosulphan has recently demonstrated antileukaemic activity and potent haematopoietic stem cell toxicity. Dose-escalated treosulphan (3 x 12 or 3 x 14 g/m2) combined with cyclophosphamide (Cy) was chosen for a new preparative regimen before allogeneic haematopoietic stem cell transplantation in 18 patients (median age 44, range 19-64 years) with haematological malignancies, considered ineligible for other myeloablative preparative regimens. Pharmacokinetic studies demonstrated rapid treosulphan plasma clearance and a dose-dependent increase of its maximum plasma concentrations and area under the concentration-time curves. Rapid and sustained white blood cell and platelet recovery and full donor chimerism was attained in all evaluable patients. Nonhaematological regimen-related CTC grades 3-4 adverse events were transient and predominantly consisted of cardiac (28%), gastrointestinal (39%), and hepatic (39%) toxicities. The 1-year nonrelapse mortality was 22%. Principal causes of transplant-related lethal events were infections in three of four affected patients. Only one patient died from regimen-related cardiac toxicity. The 1-year relapse estimate is 22%, overall and progression-free survival estimates are 67 and 56%, respectively. In conclusion, this new treosulphan and Cy combination is an effective, comparatively well-tolerated myeloablative preparative regimen even in patients with an increased risk for regimen-related toxic complications.

Adult↗
PubMed2003

Femoral head necrosis in three patients with relapsed ovarian cancer receiving high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation.

We report three patients with relapsed ovarian cancer who developed femoral head necrosis requiring endoprosthetic hip surgery 16-35 months after high-dose chemotherapy (HDC) with treosulfan (47 and 56 g/m(2) body-surface area (BSA)) given as 3-25 h infusions and followed by autologous peripheral blood stem cell (PBSC) transplantation. One woman received two courses of single agent treosulfan while the other two patients received one course of high-dose treosulfan either preceded or followed by high-dose carboplatin, etoposide and cyclophosphamide. A total of 30 women with ovarian cancer were treated with HDC at our unit and 21 of them received treosulfan-containing regimens. Femoral head necrosis was not observed in patients either receiving conditioning regimens without treosulfan (n=9) or when the total treosulfan dose was given over 3 consecutive days (n=3) or in patients with a diagnosis other than ovarian cancer and treated with high-dose treosulfan (n=10). We conclude that women with relapsed ovarian cancer receiving HDC with excessive single-dose treosulfan might be at an increased risk of developing bone necrosis.

Adenocarcinoma↗
PubMed2002

The Ras-Raf-MEK-ERK pathway in the treatment of cancer.

The mitogen activated protein kinases (MAPKs) are conserved proteins that regulate cell growth, division and death. Although activated in the cytosol, the MAPKs translocate to the nucleus upon activation and phosphorylate a large number of nuclear proteins. Investigating how Ras transmits extracellular growth signals, the MAPK pathway has emerged as the crucial route between membrane-bound Ras and the nucleus. The MAPK pathway represents a cascade of phosphorylation events including three pivotal kinases, namely Raf, MEK (MAP kinase kinase), and ERK (MAP kinase). These kinases present new opportunities for the development of novel anti-cancer drugs designed to be target-specific and probably less toxic than conventional chemotherapeutic agents. A number of drugs inhibiting Ras, Raf or MEK are currently under clinical investigation. This review addresses the rationale for targeting the MAP kinase pathway and the current status of various pharmacological approaches.

Animals↗
PubMed2000

Investigation of bioavailability and pharmacokinetics of treosulfan capsules in patients with relapsed ovarian cancer.

PURPOSE: Treosulfan (L-threitol-1,4-bis-methanesulfonate, Ovastat) is a prodrug of a bifunctional alkylating agent with activity in ovarian carcinoma and other solid tumors. In a pharmacologic study of the bioavailability of treosulfan in a capsule formulation, patients with relapsed ovarian carcinoma were treated with alternating doses of oral and intravenous (i.v.) treosulfan of 1.5 or 2.0 g daily for 5 to 8 days. METHODS: A sensitive method for the determination of treosulfan in plasma and urine by reversed-phase high-performance liquid chromatography had previously been developed. Pharmacokinetic analyses of treosulfan were carried on plasma and urine samples from 20 i.v. courses and 20 courses of oral administration. RESULTS: The bioavailability ratio (f) of oral to i.v. administration was calculated as 0.97 +/- 0.18 (mean +/- SD) using the values AUC oral = 82.1 +/- 39.4 microg/ml h and AUC i.v. = 85.4 +/- 30.3 microg/ml h. The peak plasma concentration cmax (29 +/- 14 microg/ml vs 65 +/- 23 microg/ml) was significantly (P < 0.01) higher after i.v. administration and the tmax after oral administration was 1.5 +/- 0.34 h. The terminal half-life of treosulfan was about 1.8 h. The mean urinary excretion of the parent compound was about 15% of the administered total dose over 24 h (range 6-26%). CONCLUSIONS: The high and relatively constant bioavailability of treosulfan indicates that capsules provide a satisfactory noninvasive treatment alternative. A feasible and reliable oral treosulfan formulation could provide the basis for the development of long-term low-dose outpatient treatment of patients with malignant diseases.

Administration, Oral↗