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CNS & Neurological Disorders Drug... Oct 2023Aneurysmal subarachnoid hemorrhage (aSAH) is a type of non-traumatic SAH that can have detrimental effects on the central nervous system, resulting in severe disability...
INTRODUCTION
Aneurysmal subarachnoid hemorrhage (aSAH) is a type of non-traumatic SAH that can have detrimental effects on the central nervous system, resulting in severe disability or death.
METHODS
Early nimodipine is currently the only strongly recommended pharmacological treatment that has shown efficacy in improving neurological/functional outcomes in aSAH patients. Whether statin treatment is of benefit to aSAH patients is an issue that has generated considerable interest and debate. In the present scoping review, we mapped and analyzed the available literature on metaanalyses of randomized clinical trials (RCTs) examining the effect of statins on aSAH. Seventeen meta-analyses of RCTs, published between 2008 and 2023, were identified.
RESULTS
Treatments in included meta-analyses were based on various regimens of simvastatin, pravastatin, pitavastatin or atorvastatin for up to 21 days. Eleven of the included reports indicated some beneficial effect of statin treatment, reducing rates of at least one of the following: cerebral vasospasm, delayed cerebral ischemia/delayed ischemic neurologic deficit, mortality or functional/ neurological outcome. In contrast, six meta-analyses, showed no such effects.
CONCLUSION
The limitations reported by several meta-analyses, included low patient numbers or disproportionate representation of patients from certain RCTs, differences in drug treatment, patient diagnostic criteria and outcome evaluation between RCTs, as well as poor data quality or lack of RCTs data. Knowledge of the reported limitations may aid the design of future clinical trials and/or their meta-analyses.
PubMed: 37855296
DOI: 10.2174/0118715273270503230928100141 -
Cancer Drug Resistance (Alhambra,... 2023This study aimed to decipher the molecular mechanism underlying the synergistic effect of inhibitors of the mevalonate-cholesterol pathway (i.e., statins) and...
This study aimed to decipher the molecular mechanism underlying the synergistic effect of inhibitors of the mevalonate-cholesterol pathway (i.e., statins) and aminopeptidase inhibitors (APis) on APi-sensitive and -resistant acute myeloid leukemia (AML) cells. U937 cells and their sublines with low and high levels of acquired resistance to (6S)-[(R)-2-((S)-Hydroxy-hydroxycarbamoyl-methoxy-methyl)-4-methyl-pentanoylamino]-3,3 dimethyl-butyric acid cyclopentyl ester (CHR2863), an APi prodrug, served as main AML cell line models. Drug combination effects were assessed with CHR2863 and non-toxic concentrations of various statins upon cell growth inhibition, cell cycle effects, and apoptosis induction. Mechanistic studies involved analysis of Rheb prenylation required for mTOR activation. A strong synergy of CHR2863 with the statins simvastatin, fluvastatin, lovastatin, and pravastatin was demonstrated in U937 cells and two CHR2863-resistant sublines. This potent synergy between simvastatin and CHR2863 was also observed with a series of other human AML cell lines (e.g., THP1, MV4-11, and KG1), but not with acute lymphocytic leukemia or multiple solid tumor cell lines. This synergistic activity was: (i) specific for APis (e.g., CHR2863 and Bestatin), rather than for other cytotoxic agents; and (ii) corroborated by enhanced induction of apoptosis and cell cycle arrest which increased the sub-G1 fraction. Consistently, statin potentiation of CHR2863 activity was abrogated by co-administration of mevalonate and/or farnesyl pyrophosphate, suggesting the involvement of protein prenylation; this was experimentally confirmed by impaired Rheb prenylation by simvastatin. These novel findings suggest that the combined inhibitory effect of impaired Rheb prenylation and CHR2863-dependent mTOR inhibition instigates a potent synergistic inhibition of statins and APis on human AML cells.
PubMed: 37842233
DOI: 10.20517/cdr.2023.20 -
Asian Biomedicine : Research, Reviews... Jun 2023Statins are the most widely used lipid-lowering agents for patients with hyperlipidemia. However, interindividual variations in efficacy and risk of adverse drug... (Review)
Review
BACKGROUND
Statins are the most widely used lipid-lowering agents for patients with hyperlipidemia. However, interindividual variations in efficacy and risk of adverse drug reactions to statin treatment have been widely reported. Ethnicity is well known to be one of the contributing factors to this variation, particularly among Asians.
OBJECTIVES
To identify genetic variants associated with statin treatment responses among Asian populations with a focus on four commonly prescribed statins: atorvastatin, rosuvastatin, simvastatin, and pravastatin.
METHODS
A literature search was conducted in Medline and Embase databases. Studies published from 2008 to 2021 were included. The title and abstract of each article were screened by two reviewers and verified by another two reviewers. Data charted include information on authors, year of study, study population, statin studied, gene studied, study findings, and data of significant statistical value.
RESULTS
A total of 35 articles were included from the 1,939 original studies related to treatment efficacy and 5 articles out of the 284 original studies related to adverse effects. Genetic variants in transmembrane transporters, cytochrome P450 isoenzymes, and apolipoproteins are the most extensively studied among Asian populations, with a main focus on ethnic Chinese. However, Asia consists of genetically different populations, and the results of this review indicated that there is a paucity of studies on other ethnic groups within Asia.
CONCLUSIONS
Considering the ethnicity of patients could provide a potential value to personalized medicine in statin therapy.
PubMed: 37818163
DOI: 10.2478/abm-2023-0050 -
Biotechnic & Histochemistry : Official... Nov 2023We investigated the effects of pravastatin (PRAVA) on isoprenaline (ISP) induced cardiac fibrosis using four groups of mice: untreated control, PRAVA, ISP, ISP + PRAVA...
We investigated the effects of pravastatin (PRAVA) on isoprenaline (ISP) induced cardiac fibrosis using four groups of mice: untreated control, PRAVA, ISP, ISP + PRAVA groups. ISP, 20 mg/kg, was administered subcutaneously daily for 14 days. PRAVA, 20 mg/kg, was administered orally daily for 14 days. Mice were sacrificed on day15 and heart and blood samples were collected to investigate cardiac injury markers. The mean body weight for the ISP group on day 15 was decreased significantly compared to day 0; PRAVA increased the mean body weight slightly on day 15 of treatment compared to day 0. The heart:body weight ratio was increased in the ISP group compared to the control group, but the ratio was returned to near control ratio in the PRAVA + ISP group. The serum creatine kinase-myocardial band (CK-MB) level was reduced significantly in the PRAVA + ISP group compared to the ISP group. Serum triglyceride level was decreased significantly in ISP + PRAVA group compared to the ISP group. PRAVA administration significantly reduced tissue collagen I and III levels in the ISP + PRAVA group compared to the ISP group. Lipid oxidation was decreased and reduced glutathione activity was increased in the PRAVA + ISP group compared to the ISP group. , α, , and gene expressions were decreased in the PRAVA + ISP group compared to the ISP group. We found fewer inflammatory cells and less fibrosis in heart tissue in the PRAVA + ISP group compared to the ISP group. PRAVA decreased ISP induced cardiac fibrosis by reducing oxidative stress, collagen deposition and inflammation, as well as by decreasing expression of , and genes.
Topics: Mice; Animals; Isoproterenol; Pravastatin; Fibrosis; Collagen; Transforming Growth Factor beta; Body Weight
PubMed: 37814775
DOI: 10.1080/10520295.2023.2260303 -
Evidence-based Complementary and... 2023[This retracts the article DOI: 10.1155/2022/9666963.].
[This retracts the article DOI: 10.1155/2022/9666963.].
PubMed: 37808121
DOI: 10.1155/2023/9841947 -
Mikrochimica Acta Oct 2023A sol-gel Carbowax 20 M/3-[(3-Cholamidopropyl) dimethyl ammonio]-1-propanesulfonate composite sorbent-based capsule phase microextraction device has been fabricated and...
Fabricating a designer capsule phase microextraction platform based on sol-gel Carbowax 20M-zwitterionic ionic liquid composite sorbent for the extraction of lipid-lowering drugs from human urine samples.
A sol-gel Carbowax 20 M/3-[(3-Cholamidopropyl) dimethyl ammonio]-1-propanesulfonate composite sorbent-based capsule phase microextraction device has been fabricated and characterized for the determination of four statins (pravastatin, rosuvastatin, pitavastatin, and atorvastatin) in human urine. The presence of ionizable carboxyl functional groups in statins requires pH adjustment of the sample matrix to ensure that the target molecules are in their protonated form (pH should be 2 units below their pK values) which not only is cumbersome but also risks unintended contamination of the sample. This challenge was addressed by introducing zwitterionic ionic liquid in addition to neutral, polar Carbowax 20 M polymer in the sol-gel-derived composite sorbent. As such, the composite zwitterionic multi-modal sorbent can simultaneously extract neutral, cationic, and anionic species. This particular attribute of the composite sorbent eliminates the necessity of the matrix pH adjustment and consequently simplifies the overall sample preparation workflow. Various experimental parameters such as the sample amount, extraction time, salt addition, stirring rate, and elution solvent type that may affect the extraction performance of the statins were investigated using a central composite design and the one-parameter-at-a-time approach. The analytes and the internal standard were separated on a Ccolumn with gradient elution using phosphate buffer (20 mM, pH 3) and acetonitrile as mobile phase. The analytes were detected at 237 nm. The method was validated, and linearity was observed in the range 0.10-2.0 μg mL for all compounds. The method precision was better 9.9% and 10.4% for intra-day and inter-day, respectively, while the relative recoveries were acceptable, ranging between 83.4 and 116% in all cases. Method greenness was assessed using the ComplexGAPI index. Finally, the method's applicability was demonstrated in the determination of the statins in authentic human urine after oral administration of pitavastatin and rosuvastatin-containing tablets.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Polyethylene Glycols; Ionic Liquids; Rosuvastatin Calcium; Lipids
PubMed: 37796344
DOI: 10.1007/s00604-023-05998-3 -
BioRxiv : the Preprint Server For... Sep 2023The incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease.
BACKGROUND
The incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease.
OBJECTIVES
Determine if irradiation causes chronic vascular injury and whether short-term administration of statins during and after irradiation is sufficient to prevent chronic injury compared to long-term administration.
METHODS
C57Bl/6 mice were pretreated with pravastatin for 72 hours and then exposed to 12 Gy x-ray head-and-neck irradiation. Subsequently, they received pravastatin either for one additional day or for one year. Carotid arteries were tested for vascular reactivity and altered gene expression one year after irradiation.
RESULTS
Treatment with pravastatin for 24 hours reduced the loss of endothelium-dependent vasorelaxation and protected against enhanced vasoconstriction after IR. It reduced the expression of some markers associated with inflammation and oxidative stress and modulated that of subunits of the voltage and Ca activated K (BK) channel in the carotid artery one year after irradiation. Treatment with pravastatin for one year completely reversed the changes caused by irradiation.
CONCLUSIONS
In mice, short-term administration of pravastatin is sufficient to reduce chronic vascular injury after irradiation. Long-term administration eliminates the effects of irradiation. These findings suggest that a prospective treatment strategy involving statins could be effective in patients undergoing radiation therapy. The optimal duration of treatment in humans has yet to be determined.
PubMed: 37790532
DOI: 10.1101/2023.09.20.558723 -
Toxicology Mechanisms and Methods Feb 2024An increased risk of new-onset diabetes mellitus has been recently reported for statin therapy, and experimental studies have shown reduced glucose-stimulated insulin...
An increased risk of new-onset diabetes mellitus has been recently reported for statin therapy, and experimental studies have shown reduced glucose-stimulated insulin secretion (GSIS) and mitochondrial dysfunction in beta cells with effects differing among agents. Organic anion transporting polypeptide (OATP) 2B1 contributes to hepatic uptake of rosuvastatin, atorvastatin and pravastatin, three known substrates. Since OATP2B1 is present in beta cells of the human pancreas, we investigated if OATP2B1 facilitates the local accumulation of statins in a rat beta cell model INS-1 832/13 (INS-1) thereby amplifying statin-induced toxicity. OATP2B1 overexpression in INS-1 cells adenoviral transduction showed 2.5-, 1.8- and 1.4-fold higher cellular retention of rosuvastatin, atorvastatin and pravastatin, respectively, relative to LacZ control, while absolute intracellular concentration was about twice as high for the lipophilic atorvastatin compared to the more hydrophilic rosuvastatin and pravastatin. After 24 h statin treatment at high concentrations, OATP2B1 enhanced statin toxicity involving activation of intrinsic apoptosis (caspase 3/7 activation) and mitochondrial dysfunction (NADH dehydrogenase activity) following rosuvastatin and atorvastatin, which was partly reversed by isoprenoids. OATP2B1 had no effect on statin-induced reduction in GSIS, mitochondrial electron transport chain complex expression or caspase 9 activation. We confirmed a dose-dependent reduction in insulin secretion by rosuvastatin and atorvastatin in native INS-1 with a modest change in cellular ATP. Collectively, our results indicate a role of OATP2B1, which is abundant in human beta cells, in statin accumulation and statin-induced toxicity but not insulin secretion of rosuvastatin and atorvastatin in INS-1 cells.
Topics: Humans; Rats; Animals; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Rosuvastatin Calcium; Pravastatin; Mitochondrial Diseases
PubMed: 37771097
DOI: 10.1080/15376516.2023.2262568 -
Journal of Clinical Medicine Sep 2023Throughout the history of medicine, preeclampsia has remained an enigmatic field of obstetrics. In 2023, despite its prevalence and impact, preeclampsia's exact cause... (Review)
Review
Throughout the history of medicine, preeclampsia has remained an enigmatic field of obstetrics. In 2023, despite its prevalence and impact, preeclampsia's exact cause and effective treatment remain elusive; the current options are limited to delivery. The purpose of this review is to summarize the knowledge of the possible novel prophylactic therapies and screening methods for preeclampsia, thereby providing valuable insights for healthcare professionals and researchers. Aspirin and LMWH have already been widely used; meanwhile, calcium, vitamin D, and pravastatin show promise, and endothelin receptor antagonists are being explored. Stress reduction, dietary changes, and lifestyle modifications are also being investigated. Another interesting and fast-growing area is AI- and software-based screening methods. It is also key to find novel biomarkers, which, in some cases, are not only able to predict the development of the disease, but some of them hold promise to be a potential therapeutic target. We conclude that, while a definitive cure for preeclampsia may not be eligible in the near future, it is likely that the assessment and enhancement of preventive methods will lead to the prevention of many cases. However, it is also important to highlight that more additional research is needed in the future to clarify the exact pathophysiology of preeclampsia and to thus identify potential therapeutic targets for more improved treatment methods.
PubMed: 37762960
DOI: 10.3390/jcm12186020 -
Immunopharmacology and Immunotoxicology Feb 2024The study investigated the prognostic and immune predictive potential of major histocompatibility complex class I (MHC-I) in lung adenocarcinoma (LUAD).
OBJECTIVES
The study investigated the prognostic and immune predictive potential of major histocompatibility complex class I (MHC-I) in lung adenocarcinoma (LUAD).
MATERIALS AND METHODS
With The Cancer Genome Atlas (TCGA)-LUAD and Gene Expression Omnibus datasets (GSE26939, GSE72094) as the training and validation sets, respectively, we used Cox regression analysis to construct a prognostic model, and verified independence of riskscore. The predictive capacity of the model was assessed in both sets using the receiver operating characteristic curve and Kaplan-Meier survival curves. Immune analysis was performed by using ssGSEA. Additionally, immune checkpoint blockade therapy was assessed by using immunophenoscore, Tumor Immune Dysfunction and Exclusion score. Based on the cMAP database, effective small molecule compounds were predicted.
RESULTS
A prognostic model was established based on 8 MHC-I-related genes, and the predictive capacity of the model was accurate. Immune analysis results revealed that patients classified as high-risk had lower levels of immune cell infiltration and impaired immune function. The low-risk group possessed a better response to immune checkpoint blockade therapy. Theobromine and pravastatin were identified as having great potential in improving the prognosis of LUAD.
CONCLUSION
Overall, the study revealed MHC-I-related molecular prognostic biomarkers as robust indicators for LUAD prognosis and immune therapy response.
Topics: Humans; Prognosis; Immune Checkpoint Inhibitors; Adenocarcinoma of Lung; Lung Neoplasms; Immunity
PubMed: 37728543
DOI: 10.1080/08923973.2023.2261146