Doxorubicin (DOX) is an anthracycline derivative antibiotic that still frequently used in the treatment of solid tumors and hematological malignancies. The clinical use of DOX is largely restricted ...due to acute and chronic renal, cardiac, hematological, and testicular toxicities. Previous studies have indicated that oxidative stress, lipid peroxidation, and apoptosis in germ cells are the main factors in DOX-induced testicular toxicity, but the entire molecular mechanisms that responsible for DOX-induced testicular damage are not yet fully understood. Fluvastatin is a cholesterol-lowering agent that acts by inhibiting hydroxylmethyl glutaryl coenzyme A, the key enzyme for cholesterol biosynthesis. In addition to its cholesterol-lowering effect, fluvastatin showed an antioxidant effect by cleaning hydroxyl and superoxide radicals and this drug could have a protective effect by acting on the mammalian target of rapamycin (mTOR) signal pathway in testicular damage caused by obesity. This study aimed to investigate the possible protective and therapeutic effects of fluvastatin on the DOX-induced testicular toxicity model by histochemical, immunohistochemical, biochemical, and real-time polymerase chain reaction analyses. The present study indicates that fluvastatin may have a protective and therapeutic effect by removing reactive oxygen species and by regulating the mTOR, connexin 43, and matrix metalloproteinase 9 protein and messenger ribonucleic acid expressions, which play an important role in regulating the blood–testis barrier. On the other hand, the use of fluvastatin as a protective/prophylactic agent was found to be more effective than the use of this drug for treatment. In light of this information, fluvastatin may be a candidate agent that can be used to prevent testicular toxicity observed in men receiving DOX treatment.
Background
Sirtuins (SIRTs) are NAD
+
-dependent deacetylases that play various roles in numerous pathophysiological processes, holding promise as therapeutic targets worthy of further investigation. ...Among them, the SIRT2 subtype is closely associated with tumorigenesis and malignancies. Dysregulation of SIRT2 activation can regulate the expression levels of related genes in cancer cells, leading to tumor occurrence and metastasis.
Methods
In this study, we used computer simulations to screen for novel SIRT2 inhibitors from the FDA database, based on which 10 compounds with high docking scores and good interactions were selected for in vitro anti-pancreatic cancer metastasis testing and enzyme binding inhibition experiments. The results showed that fluvastatin sodium may possess inhibitory activity against SIRT2. Subsequently, fluvastatin sodium was subjected to molecular docking experiments with various SIRT isoforms, and the combined results from Western blotting experiments indicated its potential as a SIRT2 inhibitor. Next, molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations were performed, revealing the binding mode of fluvastatin sodium at the SIRT2 active site, further validating the stability and interaction of the ligand–protein complex under physiological conditions.
Results
Overall, this study provides a systematic virtual screening workflow for the discovery of SIRT2 activity inhibitors, identifies the potential inhibitory effect of fluvastatin sodium as a lead compound on SIRT2, and opens up a new direction for developing highly active and selectively targeted SIRT2 inhibitors.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Malignant melanoma is a highly aggressive skin cancer, and the overall median survival in patients with metastatic melanoma is only 6–9 months. Although molecular targeted therapies have recently ...been developed and have improved the overall survival, melanoma patients may show no response and acquisition of resistance to these drugs. Thus, other molecular approaches are essential for the treatment of metastatic melanoma. In the present study, we investigated the effect of cotreatment with dacarbazine and statins on tumor growth, metastasis, and survival rate in mice with metastatic melanomas. We found that cotreatment with dacarbazine and statins significantly inhibited tumor growth and metastasis via suppression of the RhoA/RhoC/LIM domain kinase/serum response factor/c‐Fos pathway and enhanced p53, p21, p27, cleaved caspase‐3, and cleaved poly(ADP‐ribose) polymerase 1 expression in vivo. Moreover, the cotreatment significantly improved the survival rate in metastasis‐bearing mice. Importantly, treatment with dacarbazine plus 100 mg/kg simvastatin or fluvastatin prevented metastasis‐associated death in 4/20 mice that received dacarbazine + simvastatin and in 8/20 mice that received dacarbazine + fluvastatin (survival rates, 20% and 40%, respectively). These results suggested that cotreatment with dacarbazine and statins may thus serve as a new therapeutic approach to control tumor growth and metastasis in melanoma patients.
The enhancement of antitumor effect of dacarbazine by statins.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A case of fluvastatin-induced rhabdomyolysis after coadministration of colchicine is reported. A 77 year old man with ischemic heart disease, chronic pericardial effusion, diabetes mellitus, ...dyslipidemia, arterial hypertension, chronic renal failure (stage 2 of classification of chronic kidney disease of National Kidney Foundation) and chronic gout presented with a generalized muscle pain. The patient had been taking 80 mg/day of fluvastatin for 4 years, and, for four weeks before presentation, he had also been taking a dose of colchicine (1.0 mg daily) for an exacerbation of gout. Investigations confirmed the diagnosis of rhabdomyolysis. Discontinuation of fluvastatin and colchicine therapy and adequate fluid administration resulted in the resolution of clinical and biochemical features of rhabdomyolysis. Although neuromuscular adverse effects of fluvastatin and colchicine are well recognized, rhabdomyolysis is rare, making this is only the second case reported of fluvastatin and colchicine co-administration induced rhabdomyolysis in literature.
The incidence of aging-related disorders may be decreased through strategies influencing the expression of longevity genes. Although numerous approaches have been suggested, no effective, safe, and ...easily applicable approach is yet available. Efficacy of low-dose fluvastatin and valsartan, separately or in combination, on the expression of the longevity genes in middle-aged males, was assessed. Stored blood samples from 130 apparently healthy middle-aged males treated with fluvastatin (10 mg daily), valsartan (20 mg daily), fluvastatin-valsartan combination (10 and 20 mg, respectively), and placebo (control) were analyzed. They were taken before and after 30 days of treatment and, additionally, five months after treatment discontinuation. The expression of the following longevity genes was assessed:
,
,
,
,
, and
. Treatment with fluvastatin and valsartan in combination significantly increased the expression of
(1.8-fold;
< 0.0001),
(1.5-fold;
= 0.262) and
(1.7-fold;
< 0.0001), but not
,
and
. Both fluvastatin and valsartan alone significantly, but to a lesser extent, increased the expression of
, and did not influence the expression of other genes. Five months after treatment discontinuation, genes expression decreased to the basal levels. In addition, analysis with previously obtained results revealed significant correlation between
and both increased telomerase activity and improved arterial wall characteristics. We showed that low-dose fluvastatin and valsartan, separately and in combination, substantially increase expression of
,
, and
genes, which may be attributed to their so far unreported pleiotropic beneficial effects. This approach could be used for prevention of ageing (and longevity genes)-related disorders.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Statins are prescribed for prevention and treatment of coronary artery disease. Statins have different cholesterol lowering abilities, with rosuvastatin and atorvastatin being the most effective, ...while statins like simvastatin and fluvastatin having lower effectiveness. Statins, in addition to their cholesterol lowering effects, can prevent isoprenylation of Rab-GTPase proteins, a protein family important for the regulation of membrane-bound protein trafficking. Here we show that endosomal localization of Rab-GTPases (Rab5, Rab7 and Rab11) was inhibited in a statin-specific manner, with stronger effects by fluvastatin, followed by simvastatin and atorvastatin, and with a limited effect by rosuvastatin. Fluvastatin inhibition of Rab5 has been shown to mediate cPKC-dependent trafficking regulation of the cardiac delayed rectifier KCNQ1/KCNE1 channels. We observed statin-specific inhibition of channel regulation consistent with statin-specific Rab-GTPase inhibition both in heterologous systems and cardiomyocytes. Our results uncover a non-cholesterol-reducing statin-specific effect of statins. Because Rab-GTPases are important regulators of membrane trafficking they may underlie statin specific pleiotropic effects. Therefore, statin-specificity may allow better treatment tailoring.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Purpose
To evaluate association of the dose-dependent effect of rifampicin, an OATP1B inhibitor, on the plasma concentration–time profiles among OATP1B substrates drugs and endogenous substrates.
...Methods
Eight healthy volunteers received atorvastatin (1 mg), pitavastatin (0.2 mg), rosuvastatin (0.5 mg), and fluvastatin (2 mg) alone or with rifampicin (300 or 600 mg) in a crossover fashion. The plasma concentrations of these OATP1B probe drugs, total and direct bilirubin, glycochenodeoxycholate-3-sulfate (GCDCA-S), and coproporphyrin I, were determined.
Results
The most striking effect of 600 mg rifampicin was on atorvastatin (6.0-times increase) and GCDCA-S (10-times increase). The AUC
0–24h
of atorvastatin was reasonably correlated with that of pitavastatin (
r
2
= 0.73) and with the AUC
0–4h
of fluvastatin (r
2
= 0.62) and sufficiently with the AUC
0–24h
of rosuvastatin (
r
2
= 0.32). The AUC
0–24h
of GCDCA-S was reasonably correlated with those of direct bilirubin (
r
2
= 0.74) and coproporphyrin I (r
2
= 0.80), and sufficiently with that of total bilirubin (
r
2
= 0.30). The AUC
0–24h
of GCDCA-S, direct bilirubin, and coproporphyrin I were reasonably correlated with that of atorvastatin (
r
2
= 0.54–0.70).
Conclusion
These results suggest that direct bilirubin, GCDCA-S, and coproporphyrin I are promising surrogate probes for the quantitative assessment of potential OATP1B-mediated DDI.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Brown adipose tissue (BAT), an organ that burns energy through uncoupling thermogenesis, is a promising therapeutic target for obesity. However, there are still no safe anti-obesity drugs that target ...BAT in the market. In the current study, we performed large scale screening of 636 compounds which were approved by Food and Drug Administration (FDA) to find drugs that could significantly increase uncoupling protein 1 (
) mRNA expression by real-time PCR. Among those
activators, most of them were antibiotics or carcinogenic compounds. We paid particular attention to fluvastatin sodium (FS), because as an inhibitor of the cellular hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase, FS has already been approved for treatment of hypercholesteremia. We found that in the cellular levels, FS treatment significantly increased
expression and BAT activity in human brown adipocytes. Consistently, the expression of oxidative phosphorylation-related genes was significantly increased upon FS treatment without differences in adipogenic gene expression. Furthermore, FS treatment resisted to high-fat diet (HFD)-induced body weight gain by activating BAT in the mice model. In addition, administration of FS significantly increased energy expenditure, improved glucose homeostasis and ameliorated hepatic steatosis. Furthermore, we reveal that FS induced browning in subcutaneous white adipose tissue (sWAT) known to have a beneficial effect on energy metabolism. Taken together, our results clearly demonstrate that as an effective BAT activator, FS may have great potential for treatment of obesity and related metabolic disorders.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
T-cells orchestrate the inflammatory responses in atherosclerosis, and their function is modified by the lipoprotein milieu and complement activity. We investigated the effects of fluvastatin on the ...expression of complement decay-accelerating factor (DAF/CD55) antigen, and the levels of transcription factors in circulating T-cells in hypercholesterolemia. The hypercholesterolemic state was associated with the upregulation of DAF expression on circulating T-cells and increased levels nuclear factor kappa B (NF-kB) and interferon regulatory factor 4 (IRF4). Notably, the elevated levels of DAF and NF-kB expression persisted following treatment with fluvastatin. Therefore, the pleiotropic effects of fluvastatin are partially ascribed to its ability to mediate T-cell activation and regulate complement activity. Consequently, enhanced therapeutic interventions that targets complement-induced T-cell activation may be important in mitigating the development of atherosclerosis and major cardiovascular events in individuals with hypercholesterolemia.
•Hypercholesterolemia is associated with increased T-cell activation.•Fluvastatin regulates T-cell complement activity through the modulation of DAF (CD55) expression.•The levels of NF-kB and IRF4 were increased in circulatory T-cells following treatment with fluvastatin.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
FR&D scientists continuously try to increase the in vivo performance of low soluble and bioavailable drugs. Solid SMEDDS and liquisolid formulations are relatively simple to develop and fall within ...the novel drug delivery approaches. Here, a comparison is made to know relative superiority.
The study aimed to conduct comparative pharmacokinetic (PK) and pharmacodynamic (PD) studies of developed Fluvastatin (FLU) solid SMEDDS (SSMED) and liquisolid formulation (LS) for their relative in vivo efficacy.
FLU liquid SMEDDS were optimized by central composite design (CCD). Components, oil, surfactant and co-surfactant were selected as variables; particle size, self-emulsifying time and % drug release in 15min were selected as responses. L-SMEDDS with positive charge inducer were adsorbed on to porous carriers and characterized. Liquisolid formulations were prepared with Avicel PH-102 and Neusilin US2 as carriers.
Optimized L-SMEDDS contained 24.92 mg of oil, 45.18 mg of surfactant and 34.28 mg of cosurfactant. SSMEDs containing Syloid XDP (SSMED-XDP) as carrier was selected based on flow properties and liquid retention potential. The average particle size of SSMED-XDP was 154.30±1.10 nm, PDI was 0.311±0.03 and ZP was +19.57±1.34 mV after dilution. The drug release from SSMEDXDP and LS formulations was higher than FLU powder. The bioavailability of SSMEDs was increased by 3.00 fold and that of LS by 1.49 fold more than FLU-suspension. SSMEDs showed 12 h, while LS and suspension showed only 6 h lipid-lowering effect.
The development of solid SMEDDS resulted in superior performance in both PK and PD effects over the LS formulation.
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