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Pharmacy (Basel, Switzerland) Feb 2024Compounding solid oral dosage forms into liquid preparations is a common practice for administering drug therapy to patients with swallowing difficulties. This is...
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.
PubMed: 38392939
DOI: 10.3390/pharmacy12010032 -
The British Journal of General Practice... Feb 2024UK cardiovascular disease (CVD) incidence and mortality have declined in recent decades but socioeconomic inequalities persist.
BACKGROUND
UK cardiovascular disease (CVD) incidence and mortality have declined in recent decades but socioeconomic inequalities persist.
AIM
To present a new CVD model, and project health outcomes and the impact of guideline-recommended statin treatment across quintiles of socioeconomic deprivation in the UK.
DESIGN AND SETTING
A lifetime microsimulation model was developed using 117 896 participants in 16 statin trials, 501 854 UK Biobank (UKB) participants, and quality-of-life data from national health surveys.
METHOD
A CVD microsimulation model was developed using risk equations for myocardial infarction, stroke, coronary revascularisation, cancer, and vascular and non-vascular death, estimated using trial data. The authors calibrated and further developed this model in the UKB cohort, including further characteristics and a diabetes risk equation, and validated the model in UKB and Whitehall II cohorts. The model was used to predict CVD incidence, life expectancy, quality-adjusted life years (QALYs), and the impact of UK guideline-recommended statin treatment across socioeconomic deprivation quintiles.
RESULTS
Age, sex, socioeconomic deprivation, smoking, hypertension, diabetes, and cardiovascular events were key CVD risk determinants. Model-predicted event rates corresponded well to observed rates across participant categories. The model projected strong gradients in remaining life expectancy, with 4-5-year (5-8 QALYs) gaps between the least and most socioeconomically deprived quintiles. Guideline-recommended statin treatment was projected to increase QALYs, with larger gains in quintiles of higher deprivation.
CONCLUSION
The study demonstrated the potential of guideline-recommended statin treatment to reduce socioeconomic inequalities. This CVD model is a novel resource for individualised long-term projections of health outcomes of CVD treatments.
PubMed: 38373851
DOI: 10.3399/BJGP.2023.0198 -
Best Practice & Research. Clinical... Mar 2024Preeclampsia is a relatively common pregnancy complication and constitutes a major cause of morbidity and mortality for mothers and children worldwide. It... (Review)
Review
Preeclampsia is a relatively common pregnancy complication and constitutes a major cause of morbidity and mortality for mothers and children worldwide. It disproportionally affects low-resource countries. Appropriate identification of individuals at increased risk and prevention of the disease and its complications remain healthcare and research priorities, and the investigation of potential interventions to prevent preeclampsia has driven much of the obstetric research in recent decades. In this article, we review the scientific literature on the topic, highlighting established benefits and remaining questions regarding different non-pharmacological and pharmacological strategies, including exercise, the timing of birth, aspirin and calcium use, among others, as well as potential novel therapies under investigation.
Topics: Pregnancy; Female; Child; Humans; Pre-Eclampsia; Aspirin; Pregnancy Complications
PubMed: 38373378
DOI: 10.1016/j.bpobgyn.2024.102481 -
Hypertension (Dallas, Tex. : 1979) Apr 2024Chemerin, an inflammatory adipokine, is upregulated in preeclampsia, and its placental overexpression results in preeclampsia-like symptoms in mice. Statins may lower...
BACKGROUND
Chemerin, an inflammatory adipokine, is upregulated in preeclampsia, and its placental overexpression results in preeclampsia-like symptoms in mice. Statins may lower chemerin.
METHODS
Chemerin was determined in a prospective cohort study in women suspected of preeclampsia and evaluated as a predictor versus the sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio. Chemerin release was studied in perfused placentas and placental explants with or without the statins pravastatin and fluvastatin. We also addressed statin placental passage and the effects of chemerin in chorionic plate arteries.
RESULTS
Serum chemerin was elevated in women with preeclampsia, and its addition to a predictive model yielded significant effects on top of the sFlt-1/PlGF ratio to predict preeclampsia and its fetal complications. Perfused placentas and explants of preeclamptic women released more chemerin and sFlt-1 and less PlGF than those of healthy pregnant women. Statins reversed this. Both statins entered the fetal compartment, and the fetal/maternal concentration ratio of pravastatin was twice that of fluvastatin. Chemerin constricted plate arteries, and this was blocked by a chemerin receptor antagonist and pravastatin. Chemerin did not potentiate endothelin-1 in chorionic plate arteries. In explants, statins upregulated low-density lipoprotein receptor expression, which relies on the same transcription factor as chemerin, and NO release.
CONCLUSIONS
Chemerin is a biomarker for preeclampsia, and statins both prevent its placental upregulation and effects, in an NO and low-density lipoprotein receptor-dependent manner. Combined with their capacity to improve the sFlt-1/PlGF ratio, this offers an attractive mechanism by which statins may prevent or treat preeclampsia.
Topics: Humans; Pregnancy; Female; Animals; Mice; Placenta; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Placenta Growth Factor; Pravastatin; Up-Regulation; Prospective Studies; Pre-Eclampsia; Fluvastatin; Vascular Endothelial Growth Factor Receptor-1; Lipoproteins, LDL; Biomarkers; Chemokines; Intercellular Signaling Peptides and Proteins
PubMed: 38361240
DOI: 10.1161/HYPERTENSIONAHA.123.22457 -
BMC Pregnancy and Childbirth Jan 2024Preeclampsia is a life-threatening disease of pregnancy that lacks effective pharmaceuticals which can target its pathogenesis. Since preeclampsia involves complex...
BACKGROUND
Preeclampsia is a life-threatening disease of pregnancy that lacks effective pharmaceuticals which can target its pathogenesis. Since preeclampsia involves complex pathological processes, including autophagy, this study aims to explore autophagy-related mechanisms of preeclampsia and to screen potential drugs.
METHODS
Firstly, the datasets GSE75010, GSE24129, GSE66273, and autophagic genes lists were downloaded from public databases. Then, a weighted gene co-expression network analysis (WGCNA) was applied to filter autophagic-related hub genes of preeclampsia. The differential expression levels of the hub genes were validated with datasets GSE24129 and GSE66273. Next, the GO and KEGG enrichment, protein-protein interacting (PPI) network, as well as the downstream pathways was analyzed via the starBase, STRING and Cytoscape to determine the functions and regulatory network of the hub genes. Additionally, the immune microenvironment of preeclampsia was investigated by the CIBERSORTX database. Finally, three herb ingredients, berberine, baicalein, and luteolin were screened by molecular docking in comparison to pravastatin, metformin, and aspirin, to predict potential drugs for treating preeclampsia.
RESULTS
A total of 54 autophagy-related genes were filtered by WGCNA. After filtering with |GS| > 0.5 and |MM| > 0.8, three hub genes, namely PKM, LEP, and HK2, were identified and validated. Among these genes, PKM and LEP were overexpressed in women older than 35 years old ( p<0.05; p<0.05); the expression of PKM, LEP, and HK2 differed remarkably in women with different BMI (all p<0.05); PKM overexpressed in women with hypertension (p<0.05). The regulatory network of hub genes demonstrated that they were mainly enriched in metabolic pathways, including the AMPK signaling pathway, glucagon signaling pathway, adipocytokine signaling pathway, and central carbon metabolism. Then, immune microenvironment analysis turned out that M2 macrophages were reduced in preeclampsia women (p<0.0001) and were negatively correlated with the expression of PKM (r=-0.2, p<0.05), LEP (r=-0.4, p<0.0001), and HK2 (r=-0.3, p<0.001). Lastly, molecular docking showed baicalein and luteolin could bind intimately to hub genes.
CONCLUSION
PKM, LEP, and HK2 could be promising biomarkers for preeclampsia, which might regulate the pathogenesis of preeclampsia via metabolism pathways and immune microenvironment. Baicalein and luteolin could be potential therapeutics for preeclampsia.
Topics: Adult; Female; Humans; Pregnancy; Autophagy; Biomarkers; Luteolin; Molecular Docking Simulation; Pre-Eclampsia
PubMed: 38166707
DOI: 10.1186/s12884-023-06211-2 -
Contemporary Clinical Trials Feb 2024Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development and continued growth of multiple cysts in the kidneys leading to ultimate loss... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development and continued growth of multiple cysts in the kidneys leading to ultimate loss of kidney function in most patients. Currently, tolvaptan is the only agency approved therapy to slow kidney disease advancement in patients with faster progressing disease underscoring the need for additional ADPKD therapies suitable for all patients. We previously showed that pravastatin slowed kidney disease progression in children and young adults with ADPKD. However, the intervention has not been tested in an adult cohort.
AIMS
The aim of the study is to conduct a single center, randomized, placebo-controlled double-blinded clinical trial to determine the efficacy of pravastatin on slowing kidney disease progression in adult patients with early stage ADPKD.
METHODS
One hundred and fifty adult patients with ADPKD and eGFR ≥60 ml/min/1.73m will be enrolled in the study and randomized to receive 40 mg/day pravastatin or placebo for a period of 2-years.
OUTCOMES
The primary outcome of the trial is change in total kidney volume assessed by magnetic resonance imaging (MRI). Secondary outcomes include change in kidney function by iothalamate GFR and renal blood flow and markers of inflammation and oxidative stress.
CONCLUSION
This study will assess the kidney therapeutic benefits of pravastatin in adult patients with ADPKD. The recruitment goal of 150 subjects was attained and the study is ongoing.
REGISTRATION
This study is registered on Clinicaltrials.gov # NCT03273413.
Topics: Young Adult; Child; Humans; Adult; Polycystic Kidney, Autosomal Dominant; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pravastatin; Double-Blind Method; Disease Progression; Glomerular Filtration Rate
PubMed: 38151173
DOI: 10.1016/j.cct.2023.107423 -
Biomolecules Nov 2023Despite the development of modern drugs, drug resistance in oncology remains the main factor limiting the curability of patients. This paper shows the use of a group of...
Despite the development of modern drugs, drug resistance in oncology remains the main factor limiting the curability of patients. This paper shows the use of a group of hydrophobic statins to inhibit drug resistance (Pgp protein). In a chemoresistance melanoma cell model, viability, necroptosis with DNA damage, the absorption of the applied pharmaceuticals, and the functional activity of the ABCB1 drug transporter after administration of docetaxel or docetaxel with a selected hydrophobic statin were studied. Taxol-resistant human melanoma cells from three stages of development were used as a model: both A375P and WM239A metastatic lines and radial growth phase WM35 cells. An animal model ( SCID) was developed for the A375P cell line. The results show that hydrophobic statins administered with docetaxel increase the accumulation of the drug in the tumor cell a.o. by blocking the ABCB1 channel. They reduce taxol-induced drug resistance. The tumor size reduction was observed after the drug combination was administrated. It was shown that the structural similarity of statins is of secondary importance, e.g., pravastatin and simvastatin. Using cytostatics in the presence of hydrophobic statins increases their effectiveness while reducing their overall toxicity.
Topics: Animals; Mice; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Docetaxel; Melanoma; Drug Resistance, Neoplasm; Paclitaxel; Cell Line, Tumor
PubMed: 38136555
DOI: 10.3390/biom13121682 -
Journal of Diabetes Jun 2024Pravastatin is an oral lipid-lowering drug, commonly used by patients with diabetes that is positively correlated with the occurrence of vascular calcification (VC), but...
BACKGROUND
Pravastatin is an oral lipid-lowering drug, commonly used by patients with diabetes that is positively correlated with the occurrence of vascular calcification (VC), but the mechanism is unclear.
METHODS
In this study, 16S rRNA sequencing and qRT-PCR wereused to detect the differential gut bacteria. Metabolomics and ELISA were used to analyze the differential metabolites. qRT-PCR and western blotting (WB) were used to detect genes expression. Flow cytometry was used to analyze macrophage phenotype. Immunohistochemistry was used to analyze aortic calcification.
RESULTS
We found that gut Bacteroides fragilis (BF) increased significantly in patients who took pravastatin or type 2 diabetes (T2D) mice treated with pravastatin. In vitro experiments showed that pravastatin had little effect on BF but significantly promoted BF proliferation in vivo. Further analysis showed that ArsR was an important gene for pravastatin to regulate the activation of BF, and overexpression of ArsR significantly promoted the secretion of 3,4,5-trimethoxycinnamic acid (TMCA). Importantly, pravastatin significantly promoted BF secretion of TMCA and significantly increased TMCA secretion in T2D patients or T2D mice. TMCA had little effect on vascular smooth muscle cell calcification but significantly promoted macrophage M1 polarization, which we had demonstrated that M1 macrophages promoted T2D VC. In vivo studies found that pravastatin significantly upregulated TMCA levels in the feces and serum of T2D mice transplanted with BF and promoted the macrophage M1 polarization in bone marrow and the osteoblastic differentiation of aortic cells. Similar results were obtained in T2D mice after intravenous infusion of TMCA.
CONCLUSIONS
Promoting intestinal BF to secrete TMCA, which leads to macrophage M1 polarization, is an important mechanism by which pravastatin promotes calcification, and the result will be used for the optimization of clinical medication strategies of pravastatin supplying a theoretical basis and experimental basis.
Topics: Pravastatin; Animals; Vascular Calcification; Mice; Macrophages; Humans; Diabetes Mellitus, Type 2; Bacteroides fragilis; Male; Gastrointestinal Microbiome; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice, Inbred C57BL; Female
PubMed: 38112268
DOI: 10.1111/1753-0407.13514 -
Journal of Ovarian Research Nov 2023High-grade serous carcinoma (HGSC) is the most common and aggressive subtype of epithelial ovarian cancer, characterized by gain-of-function TP53 mutations originating...
High-grade serous carcinoma (HGSC) is the most common and aggressive subtype of epithelial ovarian cancer, characterized by gain-of-function TP53 mutations originating in the fallopian tube epithelium. Therapeutic intervention occurs at advanced metastatic disease, due to challenges in early-stage diagnosis, with common disease recurrence and therapy resistance despite initial therapy success. The mevalonate pathway is exploited by many cancers and is potently inhibited by statin drugs. Statins have shown anti-cancer activity in many, but not all cancers. Here, we investigated the role of p53 status in relation to mevalonate pathway signaling in murine oviductal epithelial (OVE) cells and identified OVE cell sensitivity to statin inhibition. We found that p53 mutant and Trp53 knockout OVE cells have increased mevalonate pathway signaling compared to p53 wild-type OVE cells. Through orthotopic implantation to replicate the fallopian tube origin of HGSC, p53 mutant cells upregulated the mevalonate pathway to drive progression to advanced-stage ovarian cancer, and simvastatin treatment abrogated this effect. Additionally, simvastatin was more efficacious at inhibiting cell metabolic activity in OVE cells than atorvastatin, rosuvastatin and pravastatin. In vitro, simvastatin demonstrated potent effects on cell proliferation, apoptosis, invasion and migration in OVE cells regardless of p53 status. In vivo, simvastatin induced ovarian cancer disease regression through decreased primary ovarian tumor weight and increased apoptosis. Simvastatin also significantly increased cytoplasmic localization of HMG-CoA reductase in ovarian tumors. Downstream of the mevalonate pathway, simvastatin had no effect on YAP or small GTPase activity. This study suggests that simvastatin can induce anti-tumor effects and could be an important inhibitor of ovarian cancer progression.
Topics: Female; Mice; Animals; Humans; Fallopian Tubes; Simvastatin; Tumor Suppressor Protein p53; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mevalonic Acid; Epithelial Cells; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial
PubMed: 37986175
DOI: 10.1186/s13048-023-01307-x