Lescol scientific update |
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Leuk Res. 2006 Sep 20;
Baulch-Brown C, Molloy TJ, Yeh SL, Ma D, Spencer A.
Myeloma Research Group, Department of Clinical Haematology and Bone Marrow Transplantation, Ground Floor, South Block, Alfred Hospital, Commercial Road, Melbourne, Vic. 3004, Australia.
Inhibitors of the mevalonate pathway as potential therapeutic agents in multiple myeloma.
Clinical studies have suggested that bisphosphonates may prolong the survival of sub-sets of myeloma patients. Newer nitrogen containing bisphosphonates such as zoledronate act, at least in part, by inhibiting farnesyl diphosphate synthase and subsequent protein prenylation, furthermore, limited data suggests that zoledronate exerts a direct anti-tumour effect against human myeloma cell lines. We therefore investigated the anti-myeloma potential of zoledronate in comparison to, and in combination with, two other inhibitors of the mevalonate pathway: the HMGCoA reductase inhibitor fluvastatin and the farnesyl transferase inhibitor SCH66336. We found that fluvastatin was able to inhibit the proliferation of myeloma cells more effectively than zoledronate or SCH66336 and that combinations of zoledronate and fluvastatin, but not zoledronate and SCH66336 acted synergistically. Our data indicated that the anti-proliferative effect of mevalonate pathway inhibitors is mediated principally via prevention of geranylgeranylation and is the result of both cell cycle arrest and apoptosis induction. Microarray and quantitative real-time PCR analyses further demonstrated that genes related to apoptosis, cell cycle control, and the mevalonate pathway were particularly affected by zoledronate and fluvastatin, and that some of these genetic effects were synergistic. We conclude that the mechanisms of geranylgeranylation inhibition mediated anti-myeloma effects warrant further evaluation and may provide novel targets for future therapeutic development.
Cleve Clin J Med. 2003 Jun;70(6):561-6.
Messerli AW, Aronow HD, Sprecher DL.
Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, OH 44195, USA.
The Lescol Intervention Prevention Study (LIPS): start all patients on statins early after PCI.
The Lescol Intervention Prevention Study (LIPS) was the first randomized trial to show a significant reduction in the risk of cardiac events in patients started on fluvastatin immediately after a successful percutaneous coronary intervention. The benefit was independent of baseline cholesterol levels. The results suggest that all patients should be discharged on lipid-lowering therapy after a percutaneous coronary intervention. Currently, this is seldom done.
Metabolism. 2004 Jun;53(6):733-9.
Shimabukuro M, Higa N, Asahi T, Oshiro Y, Takasu N.
Second Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
Fluvastatin improves endothelial dysfunction in overweight postmenopausal women through small dense low-density lipoprotein reduction.
Small dense low-density lipoprotein (sdLDL), which are often associated with obesity, are considered as the most atherogenic and have been shown to impair endothelial function. It is not known whether reduction of sdLDL by pharmacological intervention can improve endothelial function. Thirty-four consecutive postmenopausal women with >/=5.70 mmol/L total cholesterol were placed into either an overweight (body mass index [BMI] >/= 25.0, n = 22) or a normal-weight (BMI < 25.0, n = 12) group, and forearm blood flow (FBF) was measured using strain-gauge plethysmography during reactive hyperemia before and after fluvastatin treatment. At baseline, the peak FBF during reactive hyperemia in the overweight group was less than that in the normal-weight group (mean +/- SD, 13.6 +/- 4.4 v 22.2 +/- 4.0 mL/min/100 mL, P <.01). The maximal FBF after nitroglycerin was similar in both groups. In the stepwise multiple regression analysis, only the concentration of sdLDL was the predictor for peak FBF (standard coefficient = -0.517, P =.0115). The nonsignificant parameters for the correlations in the model were age, BMI, systolic blood pressure, the homeostasis model assessment of insulin resistance (HOMA-IR), hemoglobin A(1c) (HbA(1c)), and LDL-cholesterol. Fluvastatin treatment was associated with the recovery of the peak FBF in the overweight group but it did not influence that of the normal-weight group. Changes in sdLDL fractions by fluvastatin correlated well with the peak FBF recovery. These results suggested that an increased sdLDL was linked to endothelial dysfunction in overweight postmenopausal women and fluvastatin treatment improved endothelial dysfunction by decreasing the atherogenic sdLDL fraction in this population.
Am J Cardiol. 2004 Jun 1;93(11):1419-21, A10.
Fujimoto K, Hozumi T, Watanabe H, Shimada K, Takeuchi M, Sakanoue Y, Shimizu N, Ostuka R, Kawase Y, Sakamoto K, Yoshiyama M, Baba Y, Haze K, Yoshikawa J.
Department of Internal Medicine and Cardiology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
Effect of fluvastatin therapy on coronary flow reserve in patients with hypercholesterolemia.
Coronary flow reserve was evaluated using transthoracic Doppler echocardiography before and after 3 months of fluvastatin therapy in patients with hypercholesterolemia. Coronary flow reserve increased significantly after lipid-lowering therapy, and coronary microcirculation was improved in patients with hypercholesterolemia.
BJU Int. 2005 Jan;95(1):110-6.
Giuliano F, Donatucci C, Montorsi F, Auerbach S, Karlin G, Norenberg C, Homering M, Segerson T, Eardley I; Vardenafil Study Group.
Department of Urology, CHU de Bicetre, AP-HP, 78 rue du General Leclerc, 94272 Le Kremlin Bicetre Cedex, France.
Vardenafil is effective and well-tolerated for treating erectile dysfunction in a broad population of men, irrespective of age.
OBJECTIVES: To assess the efficacy and safety of vardenafil in the treatment of erectile dysfunction (ED) in men of different age groups. PATIENTS AND METHODS: In a retrospective pooled subgroup analysis of randomized, double-blind, placebo-controlled studies, men from the general population with ED received either placebo or vardenafil 5, 10 or 20 mg over 12 weeks. Efficacy variables included the erectile function (EF) domain score from The International Index of Erectile Function, diary response rates to questions on vaginal penetration and maintenance of erection, and positive responses to the Global Assessment Question (GAQ) "Has the treatment you have been taking over the past 4 weeks improved your erections?'. The 1385 men were grouped by age (< 45, 45-64 and > or =65 years). RESULTS: At 12 weeks the EF domain scores approached 20 with vardenafil and 14 with placebo in men aged > or = 65 years (P < 0.03 vardenafil 5 mg vs placebo, P < 0.001 vardenafil 10 and 20 mg vs placebo). The corresponding scores were 22 and 14 in men aged 45-64 years and up to 24 and 16 in those aged <45 years (P < 0.03 vardenafil 5 mg vs placebo, P < 0.001 vardenafil 10 and 20 mg vs placebo). Vardenafil generated positive GAQ responses in approximately 71%, 76% and 85% of men aged <45, 45-64 and > or = 65 years (P < or = 0.001 vardenafil vs placebo). The corresponding placebo rates were 23%, 25% and 34%. The most common treatment-emergent adverse events were headache, rhinitis, flushing and dyspepsia, which were mild to moderate, transient and unrelated to age. CONCLUSION: Vardenafil is an effective and generally well-tolerated treatment for ED, irrespective of age.
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Drug category:Antilipemic agents
 Lescol scientific update
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