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BMC Endocrine Disorders Sep 2022Although lithium is considered the gold-standard treatment for bipolar disorder (BD), it is associated with a variety of major endocrine and metabolic side effects,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Although lithium is considered the gold-standard treatment for bipolar disorder (BD), it is associated with a variety of major endocrine and metabolic side effects, including parathyroid hormone (PTH) dependent hypercalcemia. Aside from surgery and medication discontinuation, there are limited treatments for hypercalcemia. This paper will assess data from a randomized controlled trial (RCT).
METHODS
This is a secondary analysis of an RCT that explored the effects of atorvastatin (n = 27) versus placebo (n = 33) on lithium-induced nephrogenic diabetes insipidus (NDI) in patients with BD and major depressive disorder (MDD) using lithium (n = 60), over a 12-week period. This secondary analysis will explore serum calcium levels and thyroid stimulating hormone (TSH) measured at baseline, week 4, and week 12.
RESULTS
At 12-weeks follow-up while adjusting results for baseline, linear regression analyses found that corrected serum calcium levels were significantly lower in the treatment group (mean (M) = 2.30 mmol/L, standard deviation (SD) = 0.07) compared to the placebo group (M = 2.33 mmol/L, SD = 0.07) (β = - 0.03 (95% C.I.; - 0.0662, - 0.0035), p = 0.03) for lithium users. There were no significant changes in TSH.
CONCLUSION
In lithium users with relatively normal calcium levels, receiving atorvastatin was associated with a decrease in serum calcium levels. Although exciting, this is a preliminary finding that needs further investigation with hypercalcemic patients. Future RCTs could examine whether atorvastatin can treat PTH dependent hypercalcemia due to lithium and other causes.
Topics: Atorvastatin; Calcium; Humans; Hypercalcemia; Hyperparathyroidism; Lithium; Parathyroid Hormone; Thyrotropin
PubMed: 36153583
DOI: 10.1186/s12902-022-01145-w -
Medicina (Kaunas, Lithuania) May 2023We have recently reported that stains have calcium channel blocking activity in isolated jejunal preparations. In this study, we examined the effects of atorvastatin...
We have recently reported that stains have calcium channel blocking activity in isolated jejunal preparations. In this study, we examined the effects of atorvastatin and fluvastatin on blood vessels for a possible vasorelaxant effect. We also studied the possible additional vasorelaxant effect of atorvastatin and fluvastatin, in the presence of amlodipine, to quantify its effects on the systolic blood pressure of experimental animals. Atorvastatin and fluvastatin were tested in isolated rabbits' aortic strip preparations using 80mM Potassium Chloride (KCl) induced contractions and 1 micro molar Norepinephrine (NE) induced contractions. A positive relaxing effect on 80 mM KCl induced contractions were further confirmed in the absence and presence of atorvastatin and fluvastatin by constructing calcium concentration response curves (CCRCs) while using verapamil as a standard calcium channel blocker. In another series of experiments, hypertension was induced in Wistar rats and different test concentrations of atorvastatin and fluvastatin were administered in their respective EC values to the test animals. A fall in their systolic blood pressure was noted using amlodipine as a standard vasorelaxant drug. The results show that fluvastatin is more potent than amlodipine as it relaxed NE induced contractions where the amplitude reached 10% of its control in denuded aortae. Atorvastatin relaxed KCL induced contractions with an amplitude reaching 34.4% of control response as compared to the amlodipine response, i.e., 39.1%. A right shift in the EC (Log Ca++ M) of Calcium Concentration Response Curves (CCRCs) implies that statins have calcium channel blocking activity. A right shift in the EC of fluvastatin with relatively less EC value (-2.8 Log Ca++ M) in the presence of test concentration (1.2 × 10 M) of fluvastatin implies that fluvastatin is more potent than atorvastatin. The shift in EC resembles the shift of Verapamil, a standard calcium channel blocker (-1.41 Log Ca++ M). Atorvastatin and fluvastatin relax the aortic strip preparations predominantly through the inhibition of voltage gated calcium channels in high molar KCL induced contractions. These statins also inhibit the effects of NE induced contractions. The study also confirms that atorvastatin and fluvastatin potentiate blood pressure lowering effects in hypertensive rats.
Topics: Rats; Rabbits; Animals; Calcium Channel Blockers; Atorvastatin; Fluvastatin; Vasodilator Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Amlodipine; Calcium; Blood Pressure; Rats, Wistar; Verapamil; Calcium Channels; Potassium Chloride
PubMed: 37374229
DOI: 10.3390/medicina59061023 -
Diagnostic Pathology Sep 2023Our research was designed to figure out the influence and mechanism of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor on the improvement of elderly... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect and mechanism of HMG-CoA reductase inhibitor on the improvement of elderly essential hypertension-induced vascular endothelial function impairment based on the JAK/STAT pathway.
OBJECTIVE
Our research was designed to figure out the influence and mechanism of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor on the improvement of elderly essential hypertension-induced vascular endothelial function impairment based on the JAK/STAT pathway.
METHODS
Eighty-six elderly patients with essential hypertension were randomized into a control group (oral Amlodipine Besylate Tablets) and an observation group (oral Amlodipine Besylate Tablets + HMG-CoA reductase inhibitor atorvastatin calcium). Patients in both groups were treated with the drug for 12 weeks. Blood pressure, serum levels of inflammatory factors, and vascular endothelial function indicators, and levels of blood lipids were measured. The modeled rats were treated with atorvastatin calcium and a JAK/STAT pathway inhibitor (AG490), and the levels of cardiac function-related indices, left ventricular mass index, lipid levels, serum inflammatory factors and vascular endothelial function-related indices were detected in each group.
RESULTS
HMG-CoA reductase inhibitor improved blood pressure levels, lipid levels, serum inflammatory factor levels and cardiac function in elderly patients with essential hypertension. Both HMG-CoA reductase inhibitor and AG490 improved blood pressure levels, lipid levels, serum inflammatory factor levels and cardiac function in SHR rats. Both HMG-CoA reductase inhibitor and AG490 decreased p-JAK2/JAK2 and p-STAT3/STAT3 expression levels.
CONCLUSION
Our study demonstrates that HMG-CoA reductase inhibitor improves elderly essential hypertension-induced vascular endothelial function impairment by blocking the JAK/STAT pathway.
Topics: Humans; Rats; Animals; Aged; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Janus Kinases; Rats, Inbred SHR; Signal Transduction; STAT Transcription Factors; Essential Hypertension; Amlodipine; Hydroxymethylglutaryl CoA Reductases
PubMed: 37759223
DOI: 10.1186/s13000-023-01393-x -
Medicina (Kaunas, Lithuania) Jun 2023We aimed to evaluate the efficacy of the combination of atorvastatin and N-acetyl cysteine in increasing platelet counts in patients with immune thrombocytopenia who... (Clinical Trial)
Clinical Trial
We aimed to evaluate the efficacy of the combination of atorvastatin and N-acetyl cysteine in increasing platelet counts in patients with immune thrombocytopenia who were resistant to steroid therapy or had a relapse after treatment. : The patients included in this study received oral treatment of atorvastatin at a dose of 40 mg daily and N-acetyl cysteine at a dose of 400 mg every 8 h. The desired treatment duration was 12 months, but we included patients who completed at least 1 month of treatment in the analysis. The platelet counts were measured prior to the administration of the study treatment and in the first, third, sixth, and twelfth months of treatment (if available). A value < 0.05 was considered statistically significant. : We included 15 patients who met our inclusion criteria. For the total treatment duration, the global response was 60% (nine patients); eight patients (53.3%) had a complete response and one patient (6.7%) had a partial response. Six patients (40%) were considered as having undergone treatment failure. Of the responder group, five patients maintained a complete response after treatment (55.5%), three patients maintained a partial response (33.3%), and one patient (11.1%) lost their response to the treatment. All of the patients in the responder group had significant increases in their platelet counts after treatment ( < 0.05). : This study provides evidence of a possible treatment option for patients with primary immune thrombocytopenia. However, further studies are needed.
Topics: Humans; Acetylcysteine; Atorvastatin; Platelet Count; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Treatment Outcome
PubMed: 37374326
DOI: 10.3390/medicina59061122 -
Impact of atorvastatin and mesenchymal stem cells combined with ivermectin on murine trichinellosis.Parasitology Research Dec 2023Trichinellosis is one of the global food-borne parasitic diseases that can cause severe tissue damage. The traditionally used drugs for the treatment of trichinellosis...
Trichinellosis is one of the global food-borne parasitic diseases that can cause severe tissue damage. The traditionally used drugs for the treatment of trichinellosis have limited efficacy against the encysted larvae in the muscular phase of the disease. Therefore, this study aimed to evaluate the role of atorvastatin and mesenchymal stem cells combined with ivermectin against different phases of Trichinella in experimentally infected mice. A total of 120 male Swiss albino mice were divided into two major groups (n = 60 of each), intestinal and muscular phases. Then, each group was subdivided into 10 subgroups (n = 6); non-infected control, infected non-treated control, infected ivermectin treated, infected atorvastatin treated, infected mesenchymal stem cells treated, infected combined ivermectin and atorvastatin treated, infected combined mesenchymal stem cells and ivermectin treated, infected combined mesenchymal stem cells and atorvastatin treated, infected combined mesenchymal stem cells and a full dose of (ivermectin and atorvastatin) treated, and infected combined mesenchymal stem cells and half dose of (ivermectin and atorvastatin) treated. Mice were sacrificed at days 5 and 35 post-infection for the intestinal and muscular phases, respectively. The assessment was performed through many parameters, including counting the adult intestinal worms and muscular encysted larvae, besides histopathological examination of the underlying tissues. Moreover, a biochemical assay for the inflammatory and oxidative stress marker levels was conducted. In addition, levels of immunohistochemical CD31 and VEGF gene expression as markers of angiogenesis during the muscular phase were investigated. The combined mesenchymal stem cells and atorvastatin added to ivermectin showed the highest significant reduction in adult worms and encysted larvae counts, the most noticeable improvement of the histopathological changes, the most potent anti-inflammatory (lowest level of IL-17) and anti-angiogenic (lowest expression of CD31 and VEGF) activities, and also revealed the highly effective one to relieve the oxidative stress (lowest level of SOD, GSH, and lipid peroxidase enzymes). These observed outcomes indicate that adding mesenchymal stem cells and atorvastatin to ivermectin synergistically potentiates its therapeutic efficacy and provides a promising candidate against trichinellosis.
Topics: Mice; Male; Animals; Trichinellosis; Ivermectin; Atorvastatin; Trichinella spiralis; Vascular Endothelial Growth Factor A; Larva
PubMed: 38105357
DOI: 10.1007/s00436-023-08077-x -
Journal of Medicine and Life May 2023Evolocumab, a PCSK-9 inhibitor, is known for its ability to reduce low-density lipoprotein cholesterol (LDL-C). This study aimed to investigate the effects of...
Evolocumab, a PCSK-9 inhibitor, is known for its ability to reduce low-density lipoprotein cholesterol (LDL-C). This study aimed to investigate the effects of evolocumab, alone or in combination with atorvastatin, on the progression of atherosclerosis. Fifty male domestic rabbits were randomly assigned to five groups: control, high cholesterol diet, evolocumab vehicle (dimethyl sulfoxide, DMSO), evolocumab alone, and evolocumab plus atorvastatin. Serum levels of interleukin 10 (IL-10), IL-17, IL-1β, intracellular adhesion molecule (ICAM), and vascular adhesion molecule (VCAM) were measured. Toll-like receptor (TLR) expression on monocytes was evaluated using flow cytometry. Histopathological examination and measurement of intimal thickness (IT) were also conducted. The results revealed that the evolocumab produced a statistically significant (p<0.05) reduction in lipid profile at 5 weeks, with the peak effect occurring at 10 weeks. Furthermore, the inhibitor reduced TLRs at 10 weeks to 10.83±1.8 and intimal thickness to 160.66±9.45. IL-17, IL-1β, ICAM, and VCAM were significantly reduced by evolocumab treatment, with the improvement of the histopathological changes in the aortic wall. The combination of evolocumab and atorvastatin caused a more statistically significant reduction in TLRs at 10 weeks to 5.08±1.2 and intimal thickness to 121.79±5.3. IL-17, IL-1β, ICAM, and VCAM were significantly (p<0.05) reduced by the combination, and the histopathological changes in the aortic wall were significantly improved. In conclusion, evolocumab delays the progression of atherosclerosis by modulating inflammatory pathways.
Topics: Animals; Male; Rabbits; Atorvastatin; Interleukin-17; Atherosclerosis; Cholesterol, LDL; Treatment Outcome
PubMed: 37520489
DOI: 10.25122/jml-2021-0210 -
Aging Jan 2022Intracerebral hemorrhage (ICH) is a common neurological condition that causes severe disability and even death. Even though the mechanism is not clear, increasing...
Intracerebral hemorrhage (ICH) is a common neurological condition that causes severe disability and even death. Even though the mechanism is not clear, increasing evidence shows the efficacy of atorvastatin on treating ICH. In this study, we examined the impact of atorvastatin on the NOD-like receptor protein 3 (NLRP3) inflammasome and inflammatory pathways following ICH. Mouse models of ICH were established by collagenase injection in adult C57BL/6 mice. IHC mice received atorvastatin treatment 2 h after hematoma establishment. First, the changes of glial cells and neurons in the brains of ICH patients and mice were detected by immunohistochemistry and western blotting. Second, the molecular mechanisms underlying the microglial activation and neuronal loss were evaluated after the application of atorvastatin. Finally, the behavioral deficits of ICH mice without or with the treatment of atorvastatin were determined by neurological defect scores. The results demonstrated that atorvastatin significantly deactivated glial cells by reducing the expression of glial fibrillary acidic protein (GFAP), Ionized calcium binding adapter molecule 1 (Iba1), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 in ICH model mice. For inflammasomes, atorvastatin also showed its efficacy by decreasing the expression of NLRP3, cleaved caspase-1, and IL-1β in ICH mice. Moreover, atorvastatin markedly inhibited the upregulation of toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88), which indicated deactivation of NLRP3 inflammasomes. By inhibiting the activities of inflammasomes in glial cells, neuronal loss was partially prevented by suppressing the apoptosis in the brains of ICH mice, protecting them from neurological defects.
Topics: Animals; Atorvastatin; Cerebral Hemorrhage; Cytokines; Gene Expression Regulation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Mice; Mice, Inbred C57BL; Myeloid Differentiation Factor 88; NLR Family, Pyrin Domain-Containing 3 Protein; Neurons; Signal Transduction; Toll-Like Receptor 4
PubMed: 35017318
DOI: 10.18632/aging.203824 -
PloS One 2023Acid sphingomyelinase (ASM) promotes atherogenesis and acute cardiovascular events. We previously demonstrated ASM inhibitor desipramine attenuated oxidized-LDL-induced...
Acid sphingomyelinase (ASM) promotes atherogenesis and acute cardiovascular events. We previously demonstrated ASM inhibitor desipramine attenuated oxidized-LDL-induced macrophage apoptosis in vitro. Here, we aim to determine whether ASM-mediated apoptosis in plaque improves stability in vivo. In this study, rabbits with abdominal aorta balloon injury and a 12-week high-cholesterol diet (HCD) were used to simulate an atherosclerotic plaque model. Atherosclerotic rabbits received oral administration of saline (Control group), atorvastatin (Ator group), or desipramine (DES group). ASM activity and ceramide level were measured by ultra-performance liquid chromatography (UPLC). Plaque morphology was assessed by histochemistry and immunohistochemistry. Apoptosis was evaluated by SPECT/CT imaging of 99mTc-duramycin uptake and TUNEL. We found that increasing ASM activity and ceramide level in atherosclerotic rabbits was abated by additional atorvastatin and desipramine treatment. Meanwhile, the DES and Ator groups were similar in plaque stability, with smaller plaque size, areas of macrophages, higher smooth muscle cell content, and decreased apoptosis and matrix metalloproteinase (MMP) activities relative to the Control group. 99mTc-duramycin uptake of rabbit aorta was significantly higher in Control than in the Normal group, while it was reduced by desipramine and atorvastatin administration. Moreover, the uptake of 99mTc-duramycin positively correlated with apoptotic cell number, macrophage infiltration, and plaque instability. The present study demonstrated that desipramine exerted plaque-stabilizing effects partially by suppressing apoptosis and MMP activity in a rabbit model. And 99mTc-duramycin SPECT/CT imaging allowed noninvasively monitoring of atherosclerotic disease and evaluation of anti-atherosclerotic therapy.
Topics: Animals; Rabbits; Plaque, Atherosclerotic; Atorvastatin; Desipramine; Atherosclerosis; Molecular Imaging
PubMed: 36996033
DOI: 10.1371/journal.pone.0283612 -
International Journal of Molecular... Apr 2023HMG-CoA reductase inhibitors (statins) are widely used in the therapy of atherosclerosis and have a number of pleiotropic effects, including DNA repair regulation. We...
HMG-CoA reductase inhibitors (statins) are widely used in the therapy of atherosclerosis and have a number of pleiotropic effects, including DNA repair regulation. We studied the cytogenetic damage and the expression of DNA repair genes (, , and ) in human coronary artery (HCAEC) and internal thoracic artery endothelial cells (HITAEC) in vitro exposed to mitomycin C (MMC) (positive control), MMC and atorvastatin (MMC+Atv), MMC followed by atorvastatin treatment (MMC/Atv) and 0.9% NaCl (negative control). MMC/Atv treated HCAEC were characterized by significantly decreased micronuclei (MN) frequency compared to the MMC+Atv group and increased nucleoplasmic bridges (NPBs) frequency compared to both MMC+Atv treated cells and positive control; , , and genes were upregulated in MMC+Atv and MMC/Atv treated HCAEC in comparison with the positive control. MMC+Atv treated HITAEC were characterized by reduced MN frequency compared to positive control and decreased NPBs frequency in comparison with both the positive control and MMC/Atv group. Nuclear buds (NBUDs) frequency was significantly lower in MMC/Atv treated cells than in the positive control. The gene was downregulated in the MMC+Atv group compared to the positive control, and the gene was upregulated in MMC/Atv group compared to both the positive control and MMC+Atv group. We propose that atorvastatin can modulate the DNA damage repair response in primary human endothelial cells exposed to MMC in a cell line- and incubation scheme-dependent manner that can be extremely important for understanding the fundamental aspects of pleoitropic action of atorvastatin and can also be used to correct the therapy of patients with atherosclerosis characterized by a high genotoxic load.
Topics: Humans; Atorvastatin; Mitomycin; Endothelial Cells; DNA Repair; Hydroxymethylglutaryl-CoA Reductase Inhibitors; DNA Damage; Atherosclerosis
PubMed: 37047754
DOI: 10.3390/ijms24076783 -
European Journal of Medical Research Sep 2023Atorvastatin is regarded as the most frequently prescribed statin worldwide for dyslipidemia. However, clinical response and risk of adverse effects to statin therapy... (Review)
Review
INTRODUCTION
Atorvastatin is regarded as the most frequently prescribed statin worldwide for dyslipidemia. However, clinical response and risk of adverse effects to statin therapy are associated with genetic variations. Numerous research linked statins pharmacokinetics (PK) variations to genetic polymorphisms in cytochromes P450 (CYPs) metabolic enzymes.
OBJECTIVE
This article reviews the association between CYP3A4/5 genetic variations and response to atorvastatin therapy globally, which includes atorvastatin PK, and the risk for adverse reactions, with a hint to the Egyptians.
METHODS
Up to March 30, 2022, electronic medical databases like PubMed, Web of Science, MEDLINE, and Egyptian Knowledge Bank (EKB) were searched. All articles that highlighted the relationship between CYP3A4/5 genetic polymorphisms and atorvastatin efficacy/safety profile were included in this review.
RESULTS
Initially, 492 articles were retrieved after an exhaustive search. There were 24 articles included according to the inclusion criteria. Findings of association studies of CYP3A4/5 genetic polymorphisms with response to atorvastatin varied among different ethnicities. CYP3A4*1B was associated with better therapeutic outcomes after atorvastatin therapy in Chileans and vice versa in Americans. Caucasians with myalgia while using atorvastatin were at significant risk of suffering severe muscle damage if they were carriers of CYP3A5*3/*3. As far as we can report for the Egyptian population, the impact of CYP3A4/5 genetic variations on the response to atorvastatin therapy was understudied.
CONCLUSION
More pharmacogenetic studies amongst diverse populations worldwide, like the Egyptian population, are necessary to detect further atorvastatin-gene interactions.
Topics: Humans; Atorvastatin; Cytochrome P-450 CYP3A; Egypt; Genotype; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Polymorphism, Genetic; Treatment Outcome
PubMed: 37759317
DOI: 10.1186/s40001-023-01038-1