Search Results (71)

The prostaglandin E2 receptor EP3 is emerging as a promising therapeutic target in cardiovascular diseases because of its involvement in vascular inflammation, platelet aggregation, and vasoconstriction. However, selective EP3 ligands with validated biological activities are scarce. In this study, we combined computational and experimental strategies to identify and validate novel EP3 receptor ligands with therapeutic potential. We implemented a high-throughput, structure- and ligand-based virtual screening pipeline, enabling efficient exploration of approved drugs and natural compounds from DrugBank and FooDB libraries. Top-scoring candidates were prioritised based on binding energy and pharmacophoric similarity. Selected hits were subjected to in silico ADME/Tox profiling using QikProp to identify molecules with favourable pharmacokinetic and safety parameters. TUCA, masoprocol, and pravastatin sodium have emerged as lead candidates and were validated in vitro using endothelial migration and platelet aggregation assays. TUCA exhibited the most consistent inhibitory effect on endothelial migration, whereas masoprocol and hydrocortisone significantly reduced platelet aggregation. These findings establish a multidimensional workflow for the rational identification of EP3 ligands and support their potential use in cardiovascular therapeutics. Full article

The assessment of surface water quality of the Danube River and Black Sea was performed taking into account the amounts determined for heavy metals (As, Cd, Cr, Cu, Hg, Mn, Ni, Pb, Zn), nutrients (compounds of N and P, chlorophyll a), emerging contaminants (CECs) (pharmaceutics and endocrine disruptors—19 quantified compounds, out of 30 targeted chemicals), heterotrophic bacteria and total coliforms, in thirty-two locations from the lower Danube sector (starting with km 375 up to the river mouths), the Danube Delta Biosphere Reserve (three Danube branches—Chilia, Sulina, and Sf. Gheorghe) and the Romanian coastal area of the Black Sea. The heavy metals levels were found in the following ranges: 3.0–6.5 μg/L As; 0.51–1.32 μg/L Cd; 21.6–61.2 μg/L Cr; 10.2–28.6 μg/L Cu; 196–351 μg/L Mn; 12.3–47.67 μg/L Ni; 5.2–15.5 μg/L Pb; 44–74 μg/L Zn; 0.01–0.08 μg/L Hg. The nutrient concentrations vary in the intervals: 0.04–0.45 mg/L N-NH₄; 0.01–0.06 mg/L N-NO₂; 0.07–1.9 mg/L N-NO₃; 1.0–3.2 mg/L N total; 0.01–0.05 mg/L P-PO₄; 0.02–0.27 mg/L P total, and 0.8–17.3 μg/L chlorophyll a. The concentrations of CECs from various classes (sulfamethoxazole, trimethoprim, ciprofloxacin, flumequine, amoxicillin, cefuroxime, dicloxacillin, carbamazepine, pravastatin, erythromycin, piroxicam, ketoprofen, diclofenac, naproxen, enilconazole (imazalil), clotrimazole, drospirenone, 17α-ethinylestradiol, and bisphenol A) were compared with values reported for European rivers and the Danube River water in various river sectors. The highest detection frequencies were registered for bisphenol A (100%), sulfamethoxazole (96%), carbamazepine and diclofenac (87%), trimethoprim (78%), pravastatin (46%), and imazalil (34%). Bisphenol A exhibited the largest concentrations (342 ng/L), followed by diclofenac (132 ng/L), carbamazepine (38 ng/L), and sulfamethoxazole (36 ng/L). For most of the contaminants, Black Sea coastal water showed lower concentrations than the Danube water and good ecological status for surface water. Correlations between CECs and total coliforms suggest insufficient treated wastewater effluents as a common contamination source and possible use of CECs as indirect fecal pollution indicator in aquatic systems. This is the first study carried out in the connected system Danube River–Danube Delta–Black Sea for a large palette of toxicants classes and microbial pollutants, which will serve as a baseline for future monitoring of water quality in the region. Full article

Background/Objectives: The increasing use of statins in people with cystic fibrosis (CF) necessitates the investigation of potential drug–drug interactions (DDI) of statins with cystic fibrosis transmembrane conductance regulator (CFTR) modulators, including elexacaftor, tezacaftor, and ivacaftor (ETI). The interactions may involve the potential inhibition of cytochrome P450 isoenzymes (CYPs), organic anion-transporting polypeptides (OATPs), and Breast Cancer Resistance Protein (BCRP) by ETI. This presents a therapeutic challenge in CF due to the potential for elevated statin levels, consequently heightening the risk of myopathy. This study aimed to predict potential DDIs between statins and ETI using a physiologically based pharmacokinetic (PBPK) modeling approach. Methods: We performed in vitro assays to measure the inhibitory potency of ETI against OATPs and CYP2C9 and incorporated these data into our PBPK models alongside published inhibitory parameters for BCRP and CYP3A4. Results: The PBPK simulation showed that atorvastatin had the highest predicted AUC ratio (3.27), followed by pravastatin (2.27), pitavastatin (2.24), and rosuvastatin (1.83). Conclusions: Based on these findings, rosuvastatin appears to exhibit a weak interaction with ETI, whereas other statins exhibited a moderate interaction, potentially requiring appropriate dose reductions. These data indicate potential clinically significant DDIs between ETI and certain statins, which warrants a clinical study to validate these findings. Full article

Background: Cisplatin, a widely used chemotherapeutic agent, is associated with significant ototoxicity, leading to progressive and irreversible sensorineural hearing loss in up to 93% of patients. Cisplatin generates reactive oxygen species (ROS) in the cochlea, activating apoptotic and necroptotic pathways that result in hair cell death. Inflammatory processes and nitrative stress also contribute to cochlear damage. Methods: This literature review was conducted to explore the mechanisms underlying cisplatin-induced ototoxicity and evaluate protective strategies, including both current and emerging approaches. A structured search was performed in multiple scientific databases, including PubMed and ScienceDirect, for articles published up to November 2024. Results: Current otoprotective strategies include systemic interventions such as antioxidants, anti-inflammatory agents, and apoptosis inhibitors, as well as localized delivery methods like intratympanic injection and nanoparticle-based systems. However, these approaches have limitations, including potential interference with cisplatin’s antitumor efficacy and systemic side effects. Emerging strategies focus on genetic and biomarker-based risk stratification, novel otoprotective agents targeting alternative pathways, and combination therapies. Repurposed drugs like pravastatin also show promise in reducing cisplatin-induced ototoxicity. Conclusions: Despite these advancements, significant research gaps remain in translating preclinical findings to clinical applications and developing selective otoprotective agents that do not compromise cisplatin’s efficacy. This review examines the mechanisms of cisplatin-induced ototoxicity, current otoprotective strategies, and emerging approaches to mitigate this adverse effect. Full article

Background and Aims: Elevated lipoprotein(a) [Lp(a)] and familial hypercholesterolemia (FH) are both inherited dyslipidemias that are independently associated with cardiovascular disease. Surrogate markers to assess signs of atherosclerosis, such as arterial stiffness, might be useful to evaluate the cardiovascular risk in young patients. The aim of this study is to evaluate the contribution of Lp(a) to arterial stiffness, as measured by carotid pulse wave velocity (cPWV) in young adults with FH. Methods: For this cross-sectional study, 214 children with FH who participated in a randomized controlled trial between 1997 and 1999 on the efficacy and safety of pravastatin were eligible. After 20 years, these patients were invited for a hospital visit, including cPWV assessment (by 4D flow MRI) and Lp(a) measurement. Linear mixed-effects models were used to evaluate the association between Lp(a) and cPWV. Results: We included 143 patients (mean [standard deviation] age: 31.8 [3.2] years) from 108 families. Median (interquartile range) cPWV was 1.62 (1.31–2.06) m/s. Both the unadjusted (ß = −0.0014 m/s per 1 mg/dL increase in Lp(a), 95% CI: −0.0052 to 0.0023, p = 0.455) and adjusted model (ß = −0.0005 m/s per 1 mg/dL increase in Lp(a), 95% CI: −0.0042 to 0.0032, p = 0.785) showed no significant association between Lp(a) and cPWV. Conclusions: Our findings indicate that Lp(a) levels are not associated with carotid arterial stiffness in young adults with FH. Possibly, High Lp(a) might cause atherosclerosis by mechanisms beyond arterial stiffness in young adults. Other surrogate markers of early signs of atherosclerosis may be more suitable to evaluate the Lp(a)-mediated contribution to atherosclerosis in young FH patients. Full article

Background/Objectives: Rhabdomyolysis, a dangerous breakdown of skeletal muscle, has been reported as an adverse event in those prescribed a statin therapy for the treatment of hypercholesterolemia. Statin drugs are some of the most prescribed treatments for elevated cholesterol levels. The purpose of this comparative study was to determine the association between the statin drugs used and the risk of rhabdomyolysis using the FDA Adverse Event Reporting System (FAERS) and transcriptomic data. Methods: A disproportionality analysis was performed to compare the risk of rhabdomyolysis between the reference statin drug (simvastatin) and the treatment group, with patient age assessed as a possible confounder. In addition, association rule mining was utilized to both identify other adverse events that frequently presented with rhabdomyolysis and identify possible drug-drug interactions (DDIs). Finally, public transcriptomic data were explored to identify the possible genetic underpinnings highlighting these differences in rhabdomyolysis risk across statins. Results: Rhabdomyolysis is a commonly reported adverse event for patients treated with statins, particularly those prescribed simvastatin. Simvastatin was associated with a more than 2-fold increased likelihood of rhabdomyolysis compared to other statins. Men were twice as likely to report rhabdomyolysis than women regardless of statin treatment, with the highest risk observed for pravastatin (ROR = 2.30, p < 0.001) and atorvastatin (ROR = 2.03, p < 0.0001). Several possible DDIs were identified, including furosemide/Lasix, allopurinol clopidogrel/Plavix, and pantoprazole, which may elevate rhabdomyolysis risk through impaired muscle function and delayed statin metabolism. Finally, nine myopathic genes were identified as possible regulators of statin-induced rhabdomyolysis, including DYSF, DES, PLEC, CAPN3, SCN4A, TNNT1, SDHA, MYH7, and PYGM in primary human muscle cells. Conclusions: Simvastatin was associated with the highest risk of rhabdomyolysis. The risk of rhabdomyolysis was more pronounced in men than women. Several possible DDIs were identified including furosemide/Lasix, allopurinol clopidogrel/Plavix, and pantoprazole. Full article

Background/Objectives: Thickened waters are commonly used for dysphagic patients to ensure hydration, facilitate safer swallowing, and administer oral therapies, yet their impact on drug dissolution remains unclear. This study aims to investigate how thickening agents, viscosity, and solid oral dosage form (SODF) formulations influence drug release in gelled vehicles. Methods: Twelve commercially available thickened waters, including both ready-to-use products and powders for extemporaneous preparation, were used to disperse crushed sodium pravastatin tablets. The resulting preparations were evaluated for their rheological properties and dissolution performance. Results: Thickened water products vary in consistency, with starch-based thickeners providing more consistent results than gum-based ones. Pravastatin release profiles closely matched the original tablets with starch thickeners, while gum-based thickeners showed greater variability, primarily influenced by viscosity. Conclusions: These findings emphasize the importance of selecting the appropriate thickening agent for controlling drug release in thickened water products, highlighting the need to balance patient compliance with the potential impact on drug release during product development. Full article

Background/Objectives: Bempedoic acid (BA) is a novel cholesterol-lowering agent with proven positive effects on cardiovascular endpoints. Because it is an inhibitor of the hepatic transporters OATP1B1 and OATP1B3, two uptake transporters regulating the intrahepatic availability of statins, it increases the systemic exposure of co-administered statins. This interaction could raise the risk of myopathy. We hypothesized that the drug interaction between BA and statins could be mitigated by staggered administration. Methods: This was a single-centre, open-label, randomized, two-arm, cross-over, phase I drug interaction trial in healthy volunteers (EudraCT-No: 2022-001096-13). The primary objective was to evaluate the OATP1B1 inhibitory effect of BA on exposure to pravastatin after simultaneous administration versus different schedules of staggered administration. A secondary objective was to evaluate the impact of SLCO1B1 genotypes (*1, *5, *15, *37) on pravastatin exposure. Pravastatin was administered in single oral doses of 40 mg at six visits. After a baseline visit with pravastatin alone, BA was dosed to steady state at the approved oral dose of 180 mg. Outcome measures were the area under the plasma concentration–time curve, extrapolated to infinity (AUC_∞) and C_max of pravastatin, 3α-hydroxy-pravastatin (pravastatin 3-iso), and pravastatin lactone, and their geometric mean ratios (GMRs) of different schedules of administration. Log-transformed AUC_∞ and C_max were compared with one-way ANOVA with a 90% confidence interval (CI). Results: Fourteen participants completed all visits. At BA steady state, the GMRs of pravastatin AUC_∞ and C_max were 1.80 (90% CI 1.31–2.46) and 1.95 (90% CI 1.40–2.72), respectively, compared to baseline. There was no significant difference in pravastatin exposure between simultaneous vs. staggered administration. There was no statistically significant difference in pravastatin 3-iso or pravastatin lactone between different administration modes. For the AUC_∞ of pravastatin and pravastatin 3-iso, haplotype was a significant source of variation (63% and 20%, respectively), while the type of administration (simultaneous vs. staggered) had no significant impact. Conclusions: The increase in pravastatin exposure with concomitant intake of BA was larger than expected. There was no significant difference between simultaneous vs. staggered administration of pravastatin and BA, possibly due to a population that was heterogenous in SLCO1B1 haplotypes. Full article

Preeclampsia, a hypertensive disorder during pregnancy, frequently correlates with adverse neurological outcomes in offspring, including cognitive impairments, autism spectrum disorder, depressive disorder, attention deficit hyperactivity disorder, and cerebral palsy. Despite these known consequences, the understanding of neuronal damage in the offspring of preeclamptic mothers remains insufficient. Here, we review the neuronal abnormalities resulting from maternal preeclampsia exposure, which include disrupted neurogenesis, loss of neuronal cell integrity, accumulation of cellular debris, decreased synaptogenesis and myelination, and increased neurite growth stimulated by maternal preeclampsia serum. The underlying mechanisms potentially driving these effects involve microglial activation, inflammatory responses, and reduced angiogenesis. Intervention strategies aimed at improving fetal neuronal outcomes are also discussed, encompassing pharmacological treatments such as pravastatin, tadalafil, and melatonin, as well as non-pharmacological approaches like dietary modifications, maternal exercise, and standard care for children. These interventions hold promise for clinical application, offering avenues to address early neuronal abnormalities and prevent the onset of long-term neurological disorders. Full article

Pravastatin is a popular statin agent with applications in the treatment of cardiovascular diseases for patients with an abnormal lipid panel. The starting form of pravastatin is amorphous and following recrystallization, it becomes a crystalline solid with tert-butylamine salt molecules embedded within the lattice. Its molecular and crystal structure were elucidated based on single-crystal X-ray diffraction and characterized by ss-NMR. Full article

There are no effective therapies to prevent preeclampsia (PE). Pravastatin shows promise by attenuating processes associated with PE such as decreased cytotrophoblast (CTB) migration, aberrant angiogenesis, and increased oxidative stress. This study assesses the effects of pravastatin on hyperglycemia-induced CTB dysfunction. Methods: Human CTB cells were treated with 100, 150, 200, 300, or 400 mg/dL glucose for 48 h. Some cells were pretreated with pravastatin (1 µg/mL), while others were cotreated with pravastatin and glucose. The expression of urokinase plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1) mRNA, vascular endothelial growth factor (VEGF), placenta growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble endoglin (sEng) were measured. CTB migration was assayed using a CytoSelect migration assay kit. Statistical comparisons were performed using an analysis of variance with Duncan’s post hoc test. Results: The hyperglycemia-induced downregulation of uPA was attenuated in CTB cells pretreated with pravastatin at glucose levels > 200 mg/dL and cotreated at glucose levels > 300 mg/dL (p < 0.05). Hyperglycemia-induced decreases in VEGF and PlGF and increases in sEng and sFlt-1 were attenuated in both the pretreatment and cotreatment samples regardless of glucose dose (p < 0.05). Pravastatin attenuated hyperglycemia-induced dysfunction of CTB migration. Conclusions: Pravastatin mitigates stress signaling responses in hyperglycemic conditions, weakening processes leading to abnormal CTB migration and invasion associated with PE in pregnancy. Full article

The primary intervention for pre-eclampsia (PE) remains iatrogenic delivery, which can be very preterm and not optimal for the fetus. Although many efforts have been made to prevent and manage PE, there is still a dearth of drugs to treat its pathophysiological progression. Pravastatin (PRA), a hydrophilic statin, has gained interest for the prevention and treatment of PE. The aim of the present study was to evaluate the ability of PRA to modulate factors involved in placentation, such as Epidermal Growth Factor-Like Domain 7 (EGFL7), in human chorionic villous culture from healthy controls and women with PE. A total of 18 women were enrolled: 10 controls and 8 cases. Chorionic villous explants were maintained in culture for 24 h with or without 10 μM Pravastatin, and the expression of EGFL7 and NOTCH1 pathway members was evaluated by qRT-PCR and Western blot analysis. The rationale of the present study was to establish an ex vivo model to identify potential different responses to PRA treatment of chorionic villous explants in order to clarify the molecular mechanism of PRA in the prevention and treatment of PE and to predict whether there are specific clinical conditions that modulate the response to the drug treatment. Within PE patients, two different groups were identified: the high responders, whose villous cultures exhibit significantly increased expressions of the EGFL7 and Notch pathways after PRA incubation; and the low responders, who are high-risk PE patients in which prophylaxis failed to prevent PE and PRA was not able to modulate EGFL7 expression. In conclusion, we identified EGFL7 as a new factor regulated by PRA, placing interest in early discrimination between low- and high- risk women, in which the well-known pharmacological prophylaxis seems to be ineffective, and to explore new potential prevention strategies. Full article

Aims: The aim of this study was to explore the suspected adverse drug reaction (ADR) data of five licensed statins in the UK: atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin. A secondary aim was to determine if there are any associations between the polypharmacological properties of the statins and their associated muscle-related side effects. Methods: The chemical database of bioactive molecules with drug-like properties, European Molecular Biology Laboratory (ChEMBL), was used to obtain data on the pharmacological interactions of statins with human proteins. The Medicines and Healthcare Products Regulatory Agency’s (MHRA) Yellow Card scheme was used to obtain reports of suspected ADRs from 2018 to 2022. The OpenPrescribing database was used to obtain the prescribing rates for statistical interpretation. Results: The study found no significant difference between the statins association with suspected ADRs across all organ classes (X², p > 0.05). Fluvastatin was found to have a higher incidence of ADRs/100,000 R_x across multiple system organ classes. Conclusions: No significant difference was found between the suspected ADR incidence of the statins across all system organ classes. Full article

The HMG-CoA reductase inhibitors, statins, are drugs used globally for lowering the level of cholesterol in the blood. Different clinical studies of statins in cancer patients have indicated a decrease in cancer mortality, particularly in patients using lipophilic statins compared to those on hydrophilic statins. In this paper, we selected two structurally different statins (simvastatin and pravastatin) with different lipophilicities and investigated their effects on the proliferation and apoptosis of hepatocellular carcinoma cells. Lipophilic simvastatin highly influences cancer cell growth and survival in a time- and concentration-dependent manner, while pravastatin, due to its hydrophilic structure and limited cellular uptake, showed minimal cytotoxic effects. Full article

Background: Compounding solid oral dosage forms into liquid preparations is a common practice for administering drug therapy to patients with swallowing difficulties. This is particularly relevant for those on enteral nutrition, where factors such as the administration procedure and co-administration of enteral nutrition play crucial roles in effective drug delivery. Due to the limited studies focused on this practice, the impact of co-administered nutrition remains unclear. Methods: Pravastatin tablets were compounded into two liquid formulations and administered through three independent tubes for ten cycles. The drug amount was quantified upstream and downstream of the tubes both with and without different (fiber content) nutritional boluses. Results: The compounding procedure did not lower the drug amount with respect to the original tablets. However, when the liquid formulation was pumped through the tubes, a statistically significant reduction in the pravastatin administered (between 4.6% and 11.3%) was observed. The co-administration of different nutritional boluses or the compounding procedure did not affect the general results. Conclusions: Pravastatin loss appears unavoidable when administered via the enteral tube. Although, in this case, the loss was of limited clinical relevance, it is important not to underestimate this phenomenon, especially with drugs having a narrow therapeutic index. Full article