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Trials Jun 2023Cognitive impairment is a common medical issue in rat sarcoma (RAS) pathway disorders, so-called RASopathies, like Neurofibromatosis type 1 (NF1) or Noonan syndrome... (Randomized Controlled Trial)
Randomized Controlled Trial
Improvement of synaptic plasticity and cognitive function in RASopathies-a monocentre, randomized, double-blind, parallel-group, placebo-controlled, cross-over clinical trial (SynCoRAS).
BACKGROUND
Cognitive impairment is a common medical issue in rat sarcoma (RAS) pathway disorders, so-called RASopathies, like Neurofibromatosis type 1 (NF1) or Noonan syndrome (NS). It is presumed to be caused by impaired synaptic plasticity. In animal studies, pathway-specific pharmacological interventions with lovastatin (LOV) and lamotrigine (LTG) have been shown to improve synaptic plasticity as well as cognitive function. The aim of this clinical trial is to translate the findings of animal studies to humans and to probe the effect of lovastatin (NS) and lamotrigine (NS and NF1) on synaptic plasticity and cognitive function/alertness in RASopathies.
METHODS
Within this phase IIa, monocentre, randomized, double-blind, parallel-group, placebo-controlled, cross-over clinical trial (syn. SynCoRAS), three approaches (approaches I-III) will be carried out. In patients with NS, the effect of LTG (approach I) and of LOV (approach II) is investigated on synaptic plasticity and alertness. LTG is tested in patients with NF1 (approach III). Trial participants receive a single dose of 300 mg LTG or placebo (I and III) and 200 mg LOV or placebo (II) daily for 4 days with a cross-over after at least 7 days. Synaptic plasticity is investigated using a repetitive high-frequency transcranial magnetic stimulation (TMS) protocol called quadri-pulse theta burst stimulation (qTBS). Attention is examined by using the test of attentional performance (TAP). Twenty-eight patients are randomized in groups NS and NF1 with n = 24 intended to reach the primary endpoint (change in synaptic plasticity). Secondary endpoints are attention (TAP) and differences in short interval cortical inhibition (SICI) between placebo and trial medication (LTG and LOV).
DISCUSSION
The study is targeting impairments in synaptic plasticity and cognitive impairment, one of the main health problems of patients with RASopathies. Recent first results with LOV in patients with NF1 have shown an improvement in synaptic plasticity and cognition. Within this clinical trial, it is investigated if these findings can be transferred to patients with NS. LTG is most likely a more effective and promising substance improving synaptic plasticity and, consecutively, cognitive function. It is expected that both substances are improving synaptic plasticity as well as alertness. Changes in alertness may be a precondition for improvement of cognition.
TRIAL REGISTRATION
The clinical trial is registered in ClinicalTrials.gov (NCT03504501; https://www.
CLINICALTRIALS
gov ; date of registration: 04/11/2018) and in EudraCT (number 2016-005022-10).
Topics: Humans; Lamotrigine; Neuronal Plasticity; Cognition; Double-Blind Method; Anticonvulsants; Lovastatin
PubMed: 37280688
DOI: 10.1186/s13063-023-07392-z -
International Journal of Molecular... Apr 2023Ovarian aging hampers in vitro fertilization in assisted reproductive medicine and has no cure. Lipoprotein metabolism is associated with ovarian aging. It remains...
Ovarian aging hampers in vitro fertilization in assisted reproductive medicine and has no cure. Lipoprotein metabolism is associated with ovarian aging. It remains unclear how to overcome poor follicular development with aging. Upregulation of the low-density lipoprotein receptor (LDLR) enhances oogenesis and follicular development in mouse ovaries. This study investigated whether upregulation of LDLR expression using lovastatin enhances ovarian activity in mice. We performed superovulation using a hormone and used lovastatin to upregulate LDLR. We histologically analyzed the functional activity of lovastatin-treated ovaries and investigated gene and protein expression of follicular development markers, using RT-qPCR and Western blotting. Histological analysis showed that lovastatin significantly increased the numbers of antral follicles and ovulated oocytes per ovary. The in vitro maturation rate was 10% higher for lovastatin-treated ovaries than for control ovaries. Relative LDLR expression was 40% higher in lovastatin-treated ovaries than in control ovaries. Lovastatin significantly increased steroidogenesis in ovaries and promoted the expression of follicular development marker genes such as anti-Mullerian hormone, Oct3/4, Nanog, and Sox2. In conclusion, lovastatin enhanced ovarian activity throughout follicular development. Therefore, we suggest that upregulation of LDLR may help to improve follicular development in clinical settings. Modulation of lipoprotein metabolism can be used with assisted reproductive technologies to overcome ovarian aging.
Topics: Female; Animals; Mice; Ovary; Lovastatin; Ovarian Follicle; Oocytes; Lipoproteins, LDL; Lipoproteins
PubMed: 37108426
DOI: 10.3390/ijms24087263 -
CMAJ : Canadian Medical Association... Feb 1993
Topics: Adult; Cholestasis; Humans; Lovastatin; Male
PubMed: 8439902
DOI: No ID Found -
Scientific Reports Apr 2016Statins are used widely to lower serum cholesterol and the incidence of cardiovascular diseases. Growing evidence shows that statins also exhibit beneficial effects...
Statins are used widely to lower serum cholesterol and the incidence of cardiovascular diseases. Growing evidence shows that statins also exhibit beneficial effects against cancers. In this study, we investigated the molecular mechanisms involved in lovastatin-induced cell death in Fadu hypopharyngeal carcinoma cells. Lovastatin caused cell cycle arrest and apoptosis in FaDu cells. Lovastatin increased p21(cip/Waf1) level while the survivin level was decreased in the presence of lovastatin. Survivin siRNA reduced cell viability and induced cell apoptosis in FaDu cells. Lovastatin induced phosphorylation of AMP-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (MAPK) and transcription factor p63. Lovastatin also caused p63 acetylation and increased p63 binding to survivin promoter region in FaDu cells. AMPK-p38MAPK signaling blockade abrogated lovastatin-induced p63 phosphorylation. Lovastatin's enhancing effect on p63 acetylation was reduced in HDAC3- or HDAC4- transfected cells. Moreover, transfection of cells with AMPK dominant negative mutant (AMPK-DN), HDAC3, HDAC4 or p63 siRNA significantly reduced lovastatin's effects on p21(cip/Waf1) and survivin. Furthermore, lovastatin inhibited subcutaneous FaDu xenografts growth in vivo. Taken together, lovastatin may activate AMPK-p38MAPK-p63-survivin cascade to cause FaDu cell death. This study establishes, at least in part, the signaling cascade by which lovastatin induces hypopharyngeal carcinoma cell death.
Topics: AMP-Activated Protein Kinases; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Epithelial Cells; Humans; Inhibitor of Apoptosis Proteins; Lovastatin; Signal Transduction; Survivin; Transcription Factors; Tumor Suppressor Proteins
PubMed: 27122225
DOI: 10.1038/srep25082 -
The Journal of Pharmacology and... Apr 2011Exposure of the human malignant peripheral nerve sheath tumor cell lines STS-26T, ST88-14, and NF90-8 to nanomolar concentrations of both lovastatin and farnesyl... (Comparative Study)
Comparative Study
Exposure of the human malignant peripheral nerve sheath tumor cell lines STS-26T, ST88-14, and NF90-8 to nanomolar concentrations of both lovastatin and farnesyl transferase inhibitor (FTI)-1 but not to either drug alone induced cell death. ST88-14 and NF90-8 cells underwent apoptosis, yet dying STS-26T cells did not. FTI-1 cotreatment induced a strong and sustained autophagic response as indicated by analyses of microtubule-associated protein-1 light chain 3 (LC3)-II accumulation in STS-26T cultures. Extensive colocalization of LC3-positive punctate spots was observed with both lysosome-associated membrane protein (LAMP)-1 and LAMP-2 (markers of late endosomes/lysosomes) in solvent or FTI-1 or lovastatin-treated STS-26T cultures but very little colocalization in lovastatin/FTI-1-cotreated cultures. The absence of colocalization in the cotreatment protocol correlated with loss of LAMP-2 expression. Autophagic flux studies indicated that lovastatin/FTI-1 cotreatment inhibited the completion of the autophagic program. In contrast, rapamycin induced an autophagic response that was associated with cytostasis but maintenance of viability. These studies indicate that cotreatment of STS-26T cells with lovastatin and FTI-1 induces an abortive autophagic program and nonapoptotic cell death.
Topics: Animals; Apoptosis; Autophagy; Cell Death; Cell Line; Cell Line, Tumor; Cells, Cultured; Drug Combinations; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Lovastatin; Mice; Rats
PubMed: 21228063
DOI: 10.1124/jpet.110.174573 -
The Western Journal of Medicine Feb 1991
Topics: Drug Therapy, Combination; Humans; Lovastatin; Myositis
PubMed: 2006584
DOI: No ID Found -
International Journal of Molecular... Oct 2021Previously published, off-target effects of statins on skeletal smooth muscle function have linked structural characteristics within this drug class to myopathic...
Off-Target Effect of Lovastatin Disrupts Dietary Lipid Uptake and Dissemination through Pro-Drug Inhibition of the Mesenteric Lymphatic Smooth Muscle Cell Contractile Apparatus.
Previously published, off-target effects of statins on skeletal smooth muscle function have linked structural characteristics within this drug class to myopathic effects. However, the effect of these drugs on lymphatic vascular smooth muscle cell function, and by proxy dietary cholesterol uptake, by the intestinal lymphatic network has not been investigated. Several of the most widely prescribed statins (Atorvastatin, Pravastatin, Lovastatin, and Simvastatin) were tested for their in-situ effects on smooth muscle contractility in rat mesenteric collecting lymphatic vessels. Lovastatin and Simvastatin had a concentration-dependent effect of initially increasing vessel contraction frequency before flatlining the vessel, a phenomenon which was found to be a lactone-ring dependent phenomenon and could be ameliorated through use of Lovastatin- or Simvastatin-hydroxyacid (HA). Simvastatin treatment further resulted in mitochondrial depolymerization within primary-isolated rat lymphatic smooth muscle cells (LMCs) while Lovastatin was found to be acting in a mitochondrial-independent manner, increasing the function of RhoKinase. Lovastatin's effect on RhoKinase was investigated through pharmacological testing and in vitro analysis of increased MLC and MYPT1 phosphorylation within primary isolated LMCs. Finally, acute in vivo treatment of rats with Lovastatin, but not Lovastatin-HA, resulted in a significantly decreased dietary lipid absorption in vivo through induced disfunction of mesenteric lymph uptake and trafficking.
Topics: Animals; Cholesterol, Dietary; Lovastatin; Lymphatic Vessels; Male; Mesentery; Muscle Contraction; Muscle, Smooth; Prodrugs; Rats; Rats, Sprague-Dawley
PubMed: 34769187
DOI: 10.3390/ijms222111756 -
The Cochrane Database of Systematic... Nov 2016Elevated levels of total cholesterol and low-density lipoprotein play an important role in the development of atheromas and, therefore, in cardiovascular diseases.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Elevated levels of total cholesterol and low-density lipoprotein play an important role in the development of atheromas and, therefore, in cardiovascular diseases. Cholesterol biosynthesis follows a circadian rhythm and is principally produced at night (between 12:00 am and 6:00 am). The adjustment of hypolipaemic therapy to biologic rhythms is known as chronotherapy. Chronotherapy is based on the idea that medication can have different effects depending on the hour at which it is taken. Statins are one of the most widely used drugs for the prevention of cardiovascular events. In usual clinical practice, statins are administered once per day without specifying the time when they should be taken. It is unknown whether the timing of statin administration is important for clinical outcomes.
OBJECTIVES
To critically evaluate and analyse the evidence available from randomised controlled trials regarding the effects of chronotherapy on the effectiveness and safety of treating hyperlipidaemia with statins.
SEARCH METHODS
We searched the CENTRAL, MEDLINE, Embase, LILACS, ProQuest Health & Medical Complete, OpenSIGLE, Web of Science Conference Proceedings, and various other resources including clinical trials registers up to November 2015. We also searched the reference lists of relevant reviews for eligible studies.
SELECTION CRITERIA
We included randomised controlled trials (RCTs), enrolling people with primary or secondary hyperlipidaemia. To be included, trials must have compared any chronotherapeutic lipid-lowering regimen with statins and any other statin lipid-lowering regimen not based on chronotherapy. We considered any type and dosage of statin as eligible, as long as the control and experimental arms differed only in the timing of the administration of the same statin. Quasi-randomised studies were excluded.
DATA COLLECTION AND ANALYSIS
We used the standard methodological procedures expected by Cochrane. We extracted the key data from studies in relation to participants, interventions, and outcomes for safety and efficacy. We calculated odds ratios (OR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI). Using the GRADE approach, we assessed the quality of the evidence and we used the GRADEpro Guideline Development Tool to import data from Review Manager to create 'Summary of findings' tables.
MAIN RESULTS
This review includes eight RCTs (767 participants analysed in morning and evening arms). The trials used different lipid-lowering regimens with statins (lovastatin: two trials; simvastatin: three trials; fluvastatin: two trials; pravastatin: one trial). All trials compared the effects between morning and evening statin administration. Trial length ranged from four to 14 weeks. We found a high risk of bias in the domain of selective reporting in three trials and in the domain of incomplete outcome data in one trial of the eight trials included. None of the studies included were judged to be at low risk of bias.None of the included RCTs reported data on cardiovascular mortality, cardiovascular morbidity, incidence of cardiovascular events, or deaths from any cause. Pooled results showed no evidence of a difference in total cholesterol (MD 4.33, 95% CI -1.36 to 10.01), 514 participants, five trials, mean follow-up 9 weeks, low-quality evidence), low-density lipoprotein cholesterol (LDL-C) levels (MD 4.85 mg/dL, 95% CI -0.87 to 10.57, 473 participants, five trials, mean follow-up 9 weeks, low-quality evidence), high-density lipoprotein cholesterol (HDL-C) (MD 0.54, 95% CI -1.08 to 2.17, 514 participants, five trials, mean follow-up 9 weeks, low-quality evidence) or triglycerides (MD -8.91, 95% CI -22 to 4.17, 510 participants, five trials, mean follow-up 9 weeks, low-quality evidence) between morning and evening statin administration.With regard to safety outcomes, five trials (556 participants) reported adverse events. Pooled analysis found no differences in statins adverse events between morning and evening intake (OR 0.71, 95% CI 0.44 to 1.15, 556 participants, five trials, mean follow-up 9 weeks, low-quality evidence).
AUTHORS' CONCLUSIONS
Limited and low-quality evidence suggested that there were no differences between chronomodulated treatment with statins in people with hyperlipidaemia as compared to conventional treatment with statins, in terms of clinically relevant outcomes. Studies were short term and therefore did not report on our primary outcomes, cardiovascular clinical events or death. The review did not find differences in adverse events associated with statins between both regimens. Taking statins in the evening does not have an effect on the improvement of lipid levels with respect to morning administration. Further high-quality trials with longer-term follow-up are needed to confirm the results of this review.
Topics: Anticholesteremic Agents; Drug Chronotherapy; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hyperlipidemias; Indoles; Lovastatin; Pravastatin; Randomized Controlled Trials as Topic; Simvastatin
PubMed: 27888640
DOI: 10.1002/14651858.CD009462.pub2 -
Bioengineered Jan 2018Fungi produce a variety of secondary metabolites (SMs), low-molecular weight compounds associated with many potentially useful biologic activities. The examples of... (Review)
Review
Fungi produce a variety of secondary metabolites (SMs), low-molecular weight compounds associated with many potentially useful biologic activities. The examples of biotechnologically relevant fungal metabolites include penicillin, a β-lactam antibiotic, and lovastatin, a cholesterol-lowering drug. The discovery of pharmaceutical lead compounds within the microbial metabolic pools relies on the selection and biochemical characterization of promising strains. Not all SMs are produced under standard cultivation conditions, hence the uncovering of chemical potential of investigated strains often requires the use of induction strategies to awake the associated biosynthetic genes. Triggering the secondary metabolic pathways can be achieved through the variation of cultivation conditions and growth media composition. The alternative strategy is to use genetic engineering to activate the respective genomic segments, e.g. by the manipulation of regulators or chromatin-modifying enzymes. Recently, whole-genome sequencing of several fungi isolated from the Chernobyl accident area was reported by Singh et al. (Genome Announc 2017; 5:e01602-16). These strains were selected for exposure to microgravity at the International Space Station. Biochemical characterization of fungi cultivated under extreme conditions is likely to provide valuable insights into the adaptation mechanism associated with metabolism and, possibly, a catalog of novel molecules of potential pharmaceutical importance.
Topics: Anti-Bacterial Agents; Anticholesteremic Agents; Biological Products; Chernobyl Nuclear Accident; Fungi; Gene Expression Regulation, Fungal; Genetic Engineering; Genome, Fungal; Lovastatin; Penicillins; Secondary Metabolism; Space Flight; Weightlessness
PubMed: 28632991
DOI: 10.1080/21655979.2017.1341022 -
Asian Pacific Journal of Cancer... 2016Cervical cancer is the second most common malignancy in women worldwide and thus one of the leading causes of mortality in women. Lovastatin, a non polar,...
Cervical cancer is the second most common malignancy in women worldwide and thus one of the leading causes of mortality in women. Lovastatin, a non polar, anticholesterol drug has previously been reported to exert antitumour activity in vitro. In the present study, lovastatin from Aspergillus terreus (KM017963) was purified by adsorption chromatography and evaluated for its anticancer and anti-oxidant properties with a human cervical cancer cell line (HeLa). Growth inhibitory and proapoptotic effects of purified lovastatin on HeLa cells were investigated by determining its influence on cell numbers, mitochondrial membrane potential (MMP), DNA fragmentation and antioxidant properties in terms of hydroxy radical scavenging effects as well as levels of total reduced glutathione. Cell cycle analysis by ow cytometry (propidium iodide staining) confirmed induction of apoptotic cell death and revealed cell cycle arrest in the G0/G1 phase. The results of the study give leads for the anticancer effects of lovastatin and its potential usefulness in the chemotherapy of cervical cancer.
Topics: Antineoplastic Agents; Antioxidants; Aspergillus; Biological Factors; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA Fragmentation; Female; G1 Phase; HeLa Cells; Humans; Lovastatin; Membrane Potential, Mitochondrial; Resting Phase, Cell Cycle
PubMed: 27644619
DOI: No ID Found