Combination of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma: results from a phase I extension trial.

Sorafenib, an oral multikinase inhibitor, shows efficacy in renal cell and hepatocellular carcinoma (HCC) and is well tolerated when combined with doxorubicin in other solid tumours. Eighteen patients with inoperable HCC received doxorubicin 60 mg/m(2) IV for up to six 3-week cycles. Sorafenib 400mg bid was administered continuously starting day 4. Patients discontinuing doxorubicin were eligible for sorafenib monotherapy. The most frequent grade 3-4 drug-related adverse events were neutropaenia (61%), leukopaenia (45%) and diarrhoea (17%, grade 3). Seven of eight patients who completed six cycles of doxorubicin continued treatment with sorafenib for at least 3 months. Doxorubicin moderately increased AUC (21%) and C(max) (33%) when administered with sorafenib. The disease control rate for 16 evaluable patients was 69%. Sorafenib plus doxorubicin appears to be well tolerated and more effective in the treatment of HCC than doxorubicin alone. Follow-up with single-agent sorafenib in these patients also appears to be well tolerated.

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.

The architecture of Mourera fluviatilis (Podostemaceae): developmental morphology of inflorescences, flowers, and seedlings.

Mourera fluviatilis from northern South America is a spectacular member of the Podostemaceae (river-weeds). Its raceme-like inflorescences are up to 64 cm long and have 40-90 flowers arranged in two opposite rows. Inflorescence development starts with the initiation of a double-sheathed (dithecous) bract in a terminal position. All lateral bracts (again dithecous) are initiated in basipetal order along the two flanks of the inflorescence. Each gap between two neighboring bracts contains a single flower. The flowers are bisexual, each with a whorl of 16-20 ligulate tepals and 14-40 stamens, which are arranged in one or two whorls. Floral development starts with the formation of a girdling primordium rim around a two-lobed primordial gynoecium. Stamen and tepal initiation is centrifugal on the girdling primordium. The anthers are introrse or extrorse, depending on stamen position. Seedlings develop two entire, threadlike cotyledons, followed by forked filamentous leaves, which arise from the plumular pole. The radicular pole of the hypocotyl develops into a claw-shaped holdfast that fixes the young plant to the rock. The developmental morphologies of Mourera fluviatilis and other members of the Mourera group (including Lonchostephus and Tulasneantha) fit well with the Podostemoideae bauplan known from other New World genera, such as Apinagia and Marathrum.

Bioactive chromenes from Rhyncholacis penicillata.

Investigation of the aerial parts of Rhyncholacis penicillata afforded the new chromenes, 7-hydroxy-6-(3-methylbutyryl)-5-oxymethyl-chromene (rhynchonin A) and 7-hydroxy-6-(2-methylbutyryl)-6-oxymethylchromene (rhynchonin B). Structures were elucidated by spectroscopic methods and independent synthesis. Rhynchonin A showed broad insecticidal, acaricidal and nematicidal potency including strong biological activity against Heliothis zea.

A comparative calorimetric study on tRNA unfolding.

The heat effects involved in thermal unfolding of five tRNAs with different primary structures have been determined by direct differential scanning microcalorimetry. The overall molar values of the transition enthalpy (delta Ht) are 1150 kJ/mol for tRNA Lys2 (yeast), 1250 kJ/mol for tRNA Phe (yeast), 1350 kJ/mol for tRNA Val (yeast), 1490 kJ/mol for tRNA Val (E. coli) and 1630 kJ/mol for tRNA Tyr (E. coli). The tRNAs differ in their melting behaviour as can be shown by a comparison of the calorimetric curves. The calorimetrically measured delta Ht values are about 350 kJ/mol higher than the transition enthalpy values for the cloverleaf arrangement, which were estimated using the known parameters for G.C and A.U base pairs.