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Clinical and Translational Science Nov 2023Ziritaxestat, an autotaxin inhibitor, was under development for the treatment of idiopathic pulmonary fibrosis. It is a substrate of cytochrome P450 3A4 (CYP3A4) and...
Ziritaxestat, an autotaxin inhibitor, was under development for the treatment of idiopathic pulmonary fibrosis. It is a substrate of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein and a weak inhibitor of the CYP3A4 and OATP1B1 pathways. We developed a physiologically based pharmacokinetic (PBPK) network interaction model for ziritaxestat that incorporated its metabolic and transporter pathways, enabling prediction of its potential as a victim or perpetrator of drug-drug interactions (DDIs). Concurrently, we evaluated CYP3A4 autoinhibition, including time-dependent inhibition. In vitro information and clinical data from healthy volunteer studies were used for model building and validation. DDIs with rifampin, itraconazole, voriconazole, pravastatin, and rosuvastatin were predicted, followed by validation against a test dataset. DDIs of ziritaxestat as a victim or perpetrator were simulated using the final model. Predicted-to-observed DDI ratios for the maximum plasma concentration (C ) and the area under the plasma concentration-time curve (AUC) were within a two-fold ratio for both the metabolic and transporter-mediated simulated DDIs. The predicted impact of autoinhibition/autoinduction or time-dependent inhibition of CYP3A4 was a 12% decrease in exposure. Model-based predictions for ziritaxestat as a victim of DDIs with a moderate CYP3A4 inhibitor (fluconazole) suggested a 2.6-fold increase in the AUC of ziritaxestat, while multiple doses of a strong inhibitor (voriconazole) would increase the AUC by 15-fold. Efavirenz would yield a three-fold decrease in the AUC of ziritaxestat. As a perpetrator, ziritaxestat was predicted to increase the AUC of the CYP3A4 index substrate midazolam by 2.7-fold. An overarching PBPK model was developed that could predict DDI liability of ziritaxestat for both CYP3A4 and the transporter pathways.
Topics: Humans; Cytochrome P-450 CYP3A; Voriconazole; Models, Biological; Area Under Curve; Drug Interactions
PubMed: 37667518
DOI: 10.1111/cts.13622 -
Frontiers in Pharmacology 2023Preterm birth rates and maternal and neonatal mortality remain concerning global health issues, necessitating improved strategies for testing therapeutic compounds...
Preterm birth rates and maternal and neonatal mortality remain concerning global health issues, necessitating improved strategies for testing therapeutic compounds during pregnancy. Current 2D or 3D cell models and animal models often fail to provide data that can effectively translate into clinical trials, leading to pregnant women being excluded from drug development considerations and clinical studies. To address this limitation, we explored the utility of in silico simulation modeling and microfluidic-based organ-on-a-chip platforms to assess potential interventional agents. We developed a multi-organ feto-maternal interface on-chip (FMi-PLA-OOC) utilizing microfluidic channels to maintain intercellular interactions among seven different cell types (fetal membrane-decidua-placenta). This platform enabled the investigation of drug pharmacokinetics in vitro. Pravastatin, a model drug known for its efficacy in reducing oxidative stress and inflammation during pregnancy and currently in clinical trials, was used to test its transfer rate across both feto-maternal interfaces. The data obtained from FMi-PLA-OOC were compared with existing data from in vivo animal models and ex vivo placenta perfusion models. Additionally, we employed mechanistically based simulation software (Gastroplus®) to predict pravastatin pharmacokinetics in pregnant subjects based on validated nonpregnant drug data. Pravastatin transfer across the FMi-PLA-OOC and predicted pharmacokinetics in the in silico models were found to be similar, approximately 18%. In contrast, animal models showed supraphysiologic drug accumulation in the amniotic fluid, reaching approximately 33%. The results from this study suggest that the FMi-PLA-OOC and in silico models can serve as alternative methods for studying drug pharmacokinetics during pregnancy, providing valuable insights into drug transport and metabolism across the placenta and fetal membranes. These advanced platforms offer promising opportunities for safe, reliable, and faster testing of therapeutic compounds, potentially reducing the number of pregnant women referred to as "therapeutic orphans" due to the lack of consideration in drug development and clinical trials. By bridging the gap between preclinical studies and clinical trials, these approaches hold great promise in improving maternal and neonatal health outcomes.
PubMed: 37663251
DOI: 10.3389/fphar.2023.1241815 -
Journal of Pharmaceutical Health Care... Aug 2023Difficulty in taking solid medicines is a common issue particularly for the elderly because of a decline in swallowing function, also known as dysphagia. For patients...
BACKGROUND
Difficulty in taking solid medicines is a common issue particularly for the elderly because of a decline in swallowing function, also known as dysphagia. For patients with such a dysfunction, a simple suspension method, in which solid medicines are disintegrated and suspended using warm water, has been developed and widely used in Japanese clinical settings. However, there is little information on drug stability in the simple co-suspension of multiple formulations especially including acidic or alkaline ones. In this study, the chemical stability of typical cholesterol-lowering drugs was investigated in a simple co-suspension with alkaline magnesium oxide (MgO) which is frequently used as a laxative or antacid in Japan.
METHODS
A cholesterol-lowering drug (one tablet) was soaked with or without MgO in warm water (55°C), and the vessel was left at room temperature for 10 min or 5 h. The suspensions prepared were then analyzed by high-performance liquid chromatography. Degradation products were analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry for the structural elucidation.
RESULTS
In the simple co-suspension with MgO, no significant degradation was observed for atorvastatin or pravastatin, while a significant decrease of the recovery from the co-suspension was observed for rosuvastatin after 5 h. On the other hand, simvastatin and ezetimibe co-suspended with MgO were partially degraded to simvastatin acid and a pyran compound, respectively.
CONCLUSIONS
A simple co-suspension with MgO is feasible for atorvastatin, pravastatin, and rosuvastatin, although the rosuvastatin tablet should not be left soaking for a long time. Further it is inadvisable to suspend simvastatin or ezetimibe together with MgO because of their partial degradation.
PubMed: 37644559
DOI: 10.1186/s40780-023-00301-1 -
Balkan Medical Journal Sep 2023Anticoagulants are the mainstay of treatment for venous thromboembolism (VTE). Studies have shown conflicting results regarding statins ability to reduce the incidence... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Anticoagulants are the mainstay of treatment for venous thromboembolism (VTE). Studies have shown conflicting results regarding statins ability to reduce the incidence of VTE.
AIMS
To perform a network meta-analysis to determine which lipid-lowering agent was more efficacious in and had more evidence regarding reducing the VTE risk.
STUDY DESIGN
Network meta-analysis of the randomized controlled trials (RCTs).
METHODS
RCTs that assessed the effectiveness and safety of statins or fibrates and compared them to a placebo or another statin were eligible for the study. The outcomes examined in the study were deep vein thrombosis, pulmonary embolism, and/or VTE. We conducted a comprehensive search of the Medline database from 1966 to February 2017, using specific search terms related to VTE and statins. Additionally, we screened, and cross-checked relevant systematic reviews and meta-analyses. We performed a network meta-analysis to compare the different lipid-lowering agents to each other and the placebo and their effectiveness.
RESULTS
Twenty-seven RCTs were included in the network meta-analysis (n = 137,940). Pairwise meta-analysis revealed a statistically significant lower incidence of VTE with statins than with placebos (0.79% vs 0.99%, respectively; risk ratios: 0.87, 0.77-0.98; = 0.022). Rosuvastatin had the most favorable effect in reducing VTE risk than the other statins, fenofibrate, and placebo. Fenofibrate was ranked the worst drug choice, because it increased risk of VTE when compared with the other statins. Rosuvastatin was the best choice for reducing the VTE risk when compared with the placebo (OR: 0.56, 0.42-0.75), atorvastatin (OR: 0.64, 0.44-0.95), pravastatin (OR: 0.50, 0.34-0.74), simvastatin (OR: 0.60, 0.42-0.86) and fenofibrate (OR: 0.37, 0.25-0.56). Compared with a placebo, rosuvastatin reduced the VTE risk by around 45% and fenofibrate increased the risk by 65%.
CONCLUSION
Rosuvastatin is significantly reduces the risk of VTE when compared with a placebo, other statin subtypes, and fibrate. Furthermore, fenofibrate increased the VTE risk when compared with a placebo and statins.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Venous Thromboembolism; Rosuvastatin Calcium; Fenofibrate; Network Meta-Analysis; Atorvastatin
PubMed: 37519020
DOI: 10.4274/balkanmedj.galenos.2023.2023-5-26 -
Cell Death & Disease Jul 2023Cell-to-cell propagation of protein aggregates has been implicated in the progression of neurodegenerative diseases. However, the underlying mechanism and modulators of...
Cell-to-cell propagation of protein aggregates has been implicated in the progression of neurodegenerative diseases. However, the underlying mechanism and modulators of this process are not fully understood. Here, we screened a small-molecule library in a search for agents that suppress the propagation of α-synuclein and mutant huntingtin (mHtt). These screens yielded several molecules, some of which were effective against both α-synuclein and mHtt. Among these molecules, we focused on simvastatin and pravastatin. Simvastatin administration in a transgenic model of synucleinopathy effectively ameliorated behavioral deficits and α-synuclein accumulation, whereas pravastatin had no effect. Because only simvastatin enters the brain effectively, these results suggest that inhibition of brain cholesterol synthesis is important in simvastatin effects. In cultured cells, accumulation of intracellular cholesterol, induced by genetic ablation of the NPC1 gene or by pharmacological treatment with U18666A, increased α-synuclein aggregation and secretion. In contrast, lowering cholesterol using methyl-β-cyclodextrin or statins reversed α-synuclein aggregation and secretion in NPC1-knockout cells. Consistent with these observations, feeding a high-fat diet aggravated α-synuclein pathology and behavioral deficits in the preformed fibril-injected mouse model, an effect that was also reversed by simvastatin administration. These results suggest that statins suppress propagation of protein aggregates by lowering cholesterol in the brain.
Topics: Animals; Mice; alpha-Synuclein; Cholesterol; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pravastatin; Protein Aggregates; Simvastatin
PubMed: 37500624
DOI: 10.1038/s41419-023-05977-9 -
Pharmacogenetics and Genomics Sep 2023The association of SLCO1B1 c.521T>C with simvastatin-induced muscle toxicity is well characterized. However, different statins are subject to metabolism and transport...
OBJECTIVE
The association of SLCO1B1 c.521T>C with simvastatin-induced muscle toxicity is well characterized. However, different statins are subject to metabolism and transport also by other proteins exhibiting clinically meaningful genetic variation. Our aim was to investigate associations of SLCO1B1 c.521T>C with intolerance to atorvastatin, fluvastatin, pravastatin, rosuvastatin, or simvastatin, those of ABCG2 c.421C>A with intolerance to atorvastatin, fluvastatin, or rosuvastatin, and that of CYP2C9*2 and *3 alleles with intolerance to fluvastatin.
METHODS
We studied the associations of these variants with statin intolerance in 2042 patients initiating statin therapy by combining genetic data from samples from the Helsinki Biobank to clinical chemistry and statin purchase data.
RESULTS
We confirmed the association of SLCO1B1 c.521C/C genotype with simvastatin intolerance both by using phenotype of switching initial statin to another as a marker of statin intolerance [hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.08-3.25, P = 0.025] and statin switching along with creatine kinase measurement (HR 5.44, 95% CI 1.49-19.9, P = 0.011). No significant association was observed with atorvastatin and rosuvastatin. The sample sizes for fluvastatin and pravastatin were relatively small, but SLCO1B1 c.521T>C carriers had an increased risk of pravastatin intolerance defined by statin switching when compared to homozygous reference T/T genotype (HR 2.11, 95% CI 1.01-4.39, P = 0.047).
CONCLUSION
The current results can inform pharmacogenetic statin prescribing guidelines and show feasibility for the methodology to be used in larger future studies.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Rosuvastatin Calcium; Pravastatin; Cytochrome P-450 CYP2C9; Fluvastatin; Pharmacogenetics; Simvastatin; Liver-Specific Organic Anion Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Neoplasm Proteins
PubMed: 37490620
DOI: 10.1097/FPC.0000000000000504 -
BMC Pregnancy and Childbirth Jul 2023There are few medicines in clinical use for managing preterm labor or preventing spontaneous preterm birth from occurring. We previously developed two target product...
BACKGROUND
There are few medicines in clinical use for managing preterm labor or preventing spontaneous preterm birth from occurring. We previously developed two target product profiles (TPPs) for medicines to prevent spontaneous preterm birth and manage preterm labor. The objectives of this study were to 1) analyse the research and development pipeline of medicines for preterm birth and 2) compare these medicines to target product profiles for spontaneous preterm birth to identify the most promising candidates.
METHODS
Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched to identify candidate medicines (including drugs, dietary supplements and biologics) and populate the Accelerating Innovations for Mothers (AIM) database. This database was screened for all candidates that have been investigated for preterm birth. Candidates in clinical development were ranked against criteria from TPPs, and classified as high, medium or low potential. Preclinical candidates were categorised by product type, archetype and medicine subclass.
RESULTS
The AIM database identified 178 candidates. Of the 71 candidates in clinical development, ten were deemed high potential (Prevention: Omega-3 fatty acid, aspirin, vaginal progesterone, oral progesterone, L-arginine, and selenium; Treatment: nicorandil, isosorbide dinitrate, nicardipine and celecoxib) and seven were medium potential (Prevention: pravastatin and lactoferrin; Treatment: glyceryl trinitrate, retosiban, relcovaptan, human chorionic gonadotropin and Bryophyllum pinnatum extract). 107 candidates were in preclinical development.
CONCLUSIONS
This analysis provides a drug-agnostic approach to assessing the potential of candidate medicines for spontaneous preterm birth. Research should be prioritised for high-potential candidates that are most likely to meet the real world needs of women, babies, and health care professionals.
Topics: Infant, Newborn; Female; Humans; Premature Birth; Progesterone; Obstetric Labor, Premature; Fatty Acids, Omega-3
PubMed: 37464260
DOI: 10.1186/s12884-023-05842-9 -
Frontiers in Pharmacology 2023Elevated plasma levels of extracellular vesicles have been associated with impaired placentation, angiogenesis imbalance, intravascular inflammation, and endothelial...
Elevated plasma levels of extracellular vesicles have been associated with impaired placentation, angiogenesis imbalance, intravascular inflammation, and endothelial dysfunction in women with preeclampsia, thus suggesting that circulating vesicles may be a good therapeutic target for the treatment of the disease. Recently, statins have been considered a potential treatment for the prevention of preeclampsia because of their pleiotropic effects, including the improvement of endothelial dysfunction and inhibition of inflammatory responses. However, the effects of these drugs on circulating vesicles concentration in women at risk of preeclampsia have not been established. Herein, we aimed to assess the effects of pravastatin on circulating extracellular vesicle generation in women at high risk of term preeclampsia. In a sample of 68 singleton pregnant women participating in the multicenter, double-blind, placebo-controlled STATIN trial (Nº EducraCT 2016-005206-19 ISRCTN), 35 women received a placebo and 33 women received a 20 mg/day dose of pravastatin for approximately 3 weeks (from 35 to 37 weeks of gestation until delivery). Large extracellular vesicles were characterized and quantified by flow cytometry using annexin V and cell-specific antibodies directed against platelet, endothelial, leukocyte, and syncytiotrophoblast cell surface markers. In women who received the placebo, a significant increase in the plasma levels of large extracellular vesicles from platelets (34%, < 0.01), leukocytes (33%, < 0.01), monocytes (60%, < 0.01), endothelial cells (40%, < 0.05), and syncytiotrophoblast cells (22%, < 0.05) were observed. However, treatment with pravastatin significantly reduced the plasma levels of large extracellular vesicles from platelets (42%, < 0.001), leukocytes (25%, < 0.001), monocytes (61%, < 0.001), endothelial cells (69%, < 0.001), activated endothelial cells (55%, < 0.001), and syncytiotrophoblast cells (44%, < 0.001). These results indicate that pravastatin reduces the levels of activated cell-derived membrane vesicles from the maternal vasculature, blood, and placental syncytiotrophoblast of women at high risk of term preeclampsia, suggesting that this statin may be beneficial in reducing endothelial dysfunction and pro-inflammatory and pro-coagulatory state characteristics of the disease.
PubMed: 37426825
DOI: 10.3389/fphar.2023.1166123 -
Frontiers in Cardiovascular Medicine 2023The incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease. However,...
BACKGROUND
The incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease. However, the mechanisms by which statins protect the vasculature from irradiation injury remain poorly understood.
OBJECTIVES
Identify the mechanisms by which the hydrophilic and lipophilic statins pravastatin and atorvastatin preserve endothelial function after irradiation.
METHODS
Cultured human coronary and umbilical vein endothelial cells irradiated with 4 Gy and mice subjected to 12 Gy head-and-neck irradiation were pretreated with statins and tested for endothelial dysfunction, nitric oxide production, oxidative stress, and various mitochondrial phenotypes at 24 and 240 h after irradiation.
RESULTS
Both pravastatin (hydrophilic) and atorvastatin (lipophilic) were sufficient to prevent the loss of endothelium-dependent relaxation of arteries after head-and-neck irradiation, preserve the production of nitric oxide by endothelial cells, and suppress the cytosolic reactive oxidative stress associated with irradiation. However, only pravastatin inhibited irradiation-induced production of mitochondrial superoxide; damage to the mitochondrial DNA; loss of electron transport chain activity; and expression of inflammatory markers.
CONCLUSIONS
Our findings reveal some mechanistic underpinnings of the vasoprotective effects of statins after irradiation. Whereas both pravastatin and atorvastatin can shield from endothelial dysfunction after irradiation, pravastatin additionally suppresses mitochondrial injury and inflammatory responses involving mitochondria. Clinical follow-up studies will be necessary to determine whether hydrophilic statins are more effective than their lipophilic counterparts in reducing the risk of cardiovascular disease in patients undergoing radiation therapy.
PubMed: 37404737
DOI: 10.3389/fcvm.2023.1133315 -
Current Medicinal Chemistry 2024Previous studies have found a potential role for statins in liver cancer prevention. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Previous studies have found a potential role for statins in liver cancer prevention.
OBJECTIVE
This study aimed to explore the effect of different types of statins on the incidence of liver cancer.
METHODS
Relevant articles were systematically retrieved from PubMed, EBSCO, Web of Science, and Cochrane Library databases from inception until July 2022 to explore the relationship between lipophilic statins or hydrophilic statins exposure and the incidence of liver cancer. The main outcome was the incidence of liver cancer.
RESULTS
Eleven articles were included in this meta-analysis. The pooled results showed a reduced incidence of liver cancer in patients exposed to lipophilic statins (OR=0.54, p < 0.001) and hydrophilic statins (OR=0.56, p < 0.001) compared with the non-exposed cohort. Subgroup analysis showed that both exposures to lipophilic (Eastern countries: OR=0.51, p < 0.001; Western countries: OR=0.59, p < 0.001) and hydrophilic (Eastern countries: OR=0.51, p < 0.001; Western countries: OR=0.66, p=0.019) statins reduced the incidence of liver cancer in Eastern and Western countries, and the reduction was most significant in Eastern countries. Moreover, atorvastatin (OR=0.55, p < 0.001), simvastatin (OR=0.59, p < 0.001), lovastatin (OR=0.51, p < 0.001), pitavastatin (OR=0.36, p=0.008) and rosuvastatin (OR=0.60, p=0.027) could effectively reduce the incidence of liver cancer, unlike fluvastatin, cerivastatin and pravastatin.
CONCLUSION
Both lipophilic and hydrophilic statins contribute to the prevention of liver cancer. Moreover, the efficacy was influenced by the region and the specific type of statins used.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Simvastatin; Lovastatin; Liver Neoplasms
PubMed: 37393552
DOI: 10.2174/0929867330666230701000400