Silibinin derivatives as anti-prostate cancer agents: Synthesis and cell-based evaluations.

This study aims to systematically explore the alkylation effect of 7-OH in silibinin and 2,3-dehydrosilibinin on the antiproliferative potency toward three prostate cancer cell lines. Eight 7-O-alkylsilibinins, eight 7-O-alkyl-2,3-dehydrosilibinins, and eight 3,7-O-dialkyl-2,3-dehydrosilibinins have been synthesized from commercially available silibinin for the in vitro cell-based evaluation. The WST-1 cell proliferation assay indicates that nineteen out of twenty-four silibinin derivatives have significantly improved antiproliferative potency when compared with silibinin. 7-O-Methylsilibinin (2) and 7-O-ethylsilibinin (3) have been identified as the most potent compounds with 98- and 123-fold enhanced potency against LNCaP human androgen-dependent prostate cancer cell line. Among 2,3-dehydrosilibinin derivatives, 7-O-methyl-2,3-dehydrosilibinin (10) and 7-O-ethyl-2,3-dehydrosilibinin (11) have been identified as the optimal compounds with the highest potency towards both androgen-dependent LNCaP and androgen-independent PC-3 prostate cancer cell lines. 7-O-Ethyl-2,3-dehydrosilibinin (11) was demonstrated to arrest PC-3 cell cycle at the G0/G1 phase and to induce PC-3 cell apoptosis. The findings in this study suggest that antiproliferative potency of silibinin and 2,3-dehydrosilibinin can be appreciably enhanced through suitable chemical modifications on the phenolic hydroxyl group at C-7 and that introduction of a chemical moiety with the potential to improve bioavailability through a linker to 7-OH in silibinin and 2,3-dehydrosilibinin would be a feasible strategy for the development of silibinin derivatives as anti-prostate cancer agents.

Clinical results of meniscus repair with the meniscus arrow: a 4- to 8-year follow-up study.

The short-term clinical results of meniscus repair with the meniscus arrow were promising. Unfavorable outcomes were reported in two studies, with longer follow-up, raising concerns about the efficacy of this device. We retrospectively reviewed 62 patients (mean age 23.7 years; range 14-37 years) that underwent all-inside meniscus repair, using the meniscus arrow. Seventeen patients had an isolated meniscus tear (ACL intact group) and 45 patients concomitant ACL rupture that was reconstructed at the same time with the meniscus repair (ACL reconstructed group). All patients followed a non-aggressive rehabilitation protocol. Follow-up was assessed by clinical examination, Lysholm and Tegner score, IKDC knee examination form and KT-2000 arthrometry for the anteroposterior laxity of the reconstructed knees. At an average follow-up of 73 months (range 49-96 months) there were three failures (4.8%), one from the ACL intact group and two from the ACL reconstructed group. One patient developed arthrofibrosis (ACL reconstructed group) that resolved conservatively. Soft tissue irritation at the repair site was noted in three patients. In two patients the symptoms were transient. In the third patient the arrow tip was cut off under local anaesthesia due to saphenous infrapatellar branch irritation and the symptoms resolved (inappropriate arrow size). KT-2000 arthrometry showed that sagittal knee laxity was less than 3 mm in all reconstructed knees. The mean Tegner activity score decreased from 6.7 (pretrauma) to 6.2 (postoperatively). The average Lysholm score was 96, with normal or nearly normal function of all success knees, according to the IKDC knee examination form. Our results show a high clinical success rate of meniscus repair with the meniscus arrow. We found this device both safe and effective.

Mid-term clinical results of medial meniscus repair with the meniscus arrow in the unstable knee.

The medial meniscus is a secondary stabilizer to anterior tibial translation and provides significant stability, especially in an ACL-deficient knee. The purpose of this study is to evaluate the clinical outcome of medial meniscus repair in the unstable knee. Between 1997 and 2002, 11 patients, with a mean age of 25.8 years (range 15-39 years), underwent all-inside medial meniscus repair, using the Meniscus Arrow, for unstable medial meniscus tear in ACL-deficient knees. For various reasons none of these patients underwent ACL reconstruction. The average follow-up was 73 months (range 52-91 months). There were three failures (27.3%) defined as the need for reoperation and partial meniscectomy. The mean Tegner activity score decreased from 6.75 (pretrauma) to 4.5 (postoperatively). The average Lysholm and subjective IKDC scores were 83 and 77.4, respectively. Two patients were graded as B (nearly normal) and six as C (abnormal), according to the IKDC knee evaluation form. KT-2000 arthrometry demonstrated that sagittal knee laxity was more than 5 mm in all knees (side to side difference). MRI demonstrated grade three signal alterations at the repair site of meniscus in three patients and signs of cartilage damage in two patients. All patients were asymptomatic during daily activities but seven out of eight reported pain or effusion after sports. Medial meniscus repair in the ACL-deficient knee is not contraindicated. The need of reducing the level of physical activity is essential.