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Keywords = pitavastatin

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13 pages, 1832 KiB  
Article
Evaluation of Complex Drug Interactions Between Elexacaftor-Tezacaftor-Ivacaftor and Statins Using Physiologically Based Pharmacokinetic Modeling
by Eunjin Hong, Peter S. Chung, Adupa P. Rao and Paul M. Beringer
Pharmaceutics 2025, 17(3), 318; https://doi.org/10.3390/pharmaceutics17030318 - 1 Mar 2025
Viewed by 1107
Abstract
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 [...] Read more.
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
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15 pages, 807 KiB  
Article
The Association of Statin Therapy with Liver and Pancreatic Fat Fraction in Type 2 Diabetes Mellitus
by Mehmet Akif Parlar, Hakan Mutlu, Betül Doğantekin, İsmail Serhat Musaoğlu, Nisa Demirboşnak Albayrakoğlu, Mustafa Lütfi Yavuz, Zehra Buşra Özbolat and Mustafa Kaplan
Diagnostics 2025, 15(4), 426; https://doi.org/10.3390/diagnostics15040426 - 10 Feb 2025
Viewed by 1301
Abstract
Background/Objectives: It has been shown that the use of statins in patients with type 2 diabetes mellitus (T2DM) worsens hyperglycemia and hemoglobin A1c levels but may help in the preservation of pancreatic β-cell function. The potential role of a high pancreatic fat [...] Read more.
Background/Objectives: It has been shown that the use of statins in patients with type 2 diabetes mellitus (T2DM) worsens hyperglycemia and hemoglobin A1c levels but may help in the preservation of pancreatic β-cell function. The potential role of a high pancreatic fat fraction (PFF) in this process has not yet been clarified. This study aimed to investigate whether the liver fat fraction (LFF) and PFF in T2DM patients is affected by statin therapy. Methods: This cross-sectional study involved a total of 140 T2DM patients, including both those who were receiving (n = 70) and those who were not receiving (n = 70) statin therapy. The mapping of the LFF and PFF utilizing the IDEAL-IQ sequence was conducted in magnetic resonance imaging. Results: In T2DM patients who used statins, the median PFF was higher compared to those who did not use statins (8.4 vs. 6.2%, p = 0.021), while the median LFF was found to be similar (8.4 vs. 8.9, p = 0.572). Variations in PFF were associated with the use of various statins (non-statin group: 6.2 vs. atovastatin: 8.7 vs. rosuvastatin: 3.2 vs. pitavastatin: 9.2, p = 0.004). The multivariable regression analysis indicated that insulin usage decreased log(LFF) by a factor of 0.16-fold (ꞵ ± SE = −0.16 ± 0.05, p = 0.010), and rosuvastatin usage reduced log(PFF) by 0.16-fold (ꞵ ± SE = −0.16 ± 0.07, p = 0.025), irrespective of other risk factors. Furthermore, the use of atorvastatin (ꞵ ± SE = 0.17 ± 0.06, p = 0.011) and pitavastatin (ꞵ ± SE = 0.19 ± 0.07, p = 0.008) were independently associated with an increase in log(PFF). Conclusions: In patients with T2DM, statin use did not show a significant effect on the liver fat fraction, but it caused differences in the pancreatic fat fraction. The observation of a lower pancreatic fat fraction in patients taking a rosuvastatin and atorvastatin dose of 40 mg/day suggests that different types and doses of statins may have varying effects on pancreatic fat accumulation. Full article
(This article belongs to the Section Medical Imaging and Theranostics)
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23 pages, 612 KiB  
Systematic Review
Systematic Review on Efficacy, Effectiveness, and Safety of Pitavastatin in Dyslipidemia in Asia
by Nam Xuan Vo, Huong Lai Pham, Tan Trong Bui and Tien Thuy Bui
Healthcare 2025, 13(1), 59; https://doi.org/10.3390/healthcare13010059 - 31 Dec 2024
Cited by 1 | Viewed by 2794
Abstract
Objectives: Dyslipidemia, a significant risk factor for cardiovascular disease (CVD), is marked by abnormal lipid levels, such as the elevated lowering of low-density lipoprotein cholesterol (LDL-C). Statins are the first-line treatment for LDL-C reduction. Pitavastatin (PIT) has shown potential in lowering LDL-C and [...] Read more.
Objectives: Dyslipidemia, a significant risk factor for cardiovascular disease (CVD), is marked by abnormal lipid levels, such as the elevated lowering of low-density lipoprotein cholesterol (LDL-C). Statins are the first-line treatment for LDL-C reduction. Pitavastatin (PIT) has shown potential in lowering LDL-C and improving high-density lipoprotein cholesterol (HDL-C). This review assesses pitavastatin’s efficacy, effectiveness, and safety in dyslipidemia management in Asia. Methods: A systematic review was conducted using PubMed, Cochrane, and Embase databases up to November 2024, adhering to Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Seventeen studies (12 RCTs and 5 non-RCTs) were analyzed, focusing on LDL-C reduction, safety profiles, and adverse events. The quality of the studies was assessed using checklists to ensure the selection of the best studies and to limit bias. Results: Pitavastatin doses (1–4 mg) reduced LDL-C by 28–47%, comparable to atorvastatin, rosuvastatin, and simvastatin. The 2 mg dose matched atorvastatin’s 10 mg dose in efficacy for both short-term (35–42%) and long-term (28–36%) use. LDL-C target achievement rates were 75–95%. Adverse events, including mild myalgia and elevated liver enzymes, were rare, and discontinuation rates were low. Conclusions: Pitavastatin is an effective and safe alternative to traditional statins for dyslipidemia management in Asia. Further research on long-term outcomes and high-risk groups is warranted. Full article
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17 pages, 5171 KiB  
Article
Ivermectin Strengthens Paclitaxel Effectiveness in High-Grade Serous Carcinoma in 3D Cell Cultures
by Mariana Nunes and Sara Ricardo
Pharmaceuticals 2025, 18(1), 14; https://doi.org/10.3390/ph18010014 - 25 Dec 2024
Cited by 1 | Viewed by 3798
Abstract
Background: Chemoresistance is a major obstacle in high-grade serous carcinoma (HGSC) treatment. Although many patients initially respond to chemotherapy, the majority of them relapse due to Carboplatin and Paclitaxel resistance. Drug repurposing has surfaced as a potentially effective strategy that works synergically with [...] Read more.
Background: Chemoresistance is a major obstacle in high-grade serous carcinoma (HGSC) treatment. Although many patients initially respond to chemotherapy, the majority of them relapse due to Carboplatin and Paclitaxel resistance. Drug repurposing has surfaced as a potentially effective strategy that works synergically with standard chemotherapy to bypass chemoresistance. In a prior study, using 2D cultures and two HGSC chemoresistant cell lines, it was demonstrated that combining Carboplatin or Paclitaxel with Pitavastatin or Ivermectin resulted in the most notable synergy. Acknowledging that 2D culture systems are limited in reflecting the tumor architecture, 3D cultures were generated to provide insights on treatment efficacy tests in more complex models. Objectives: We aimed to investigate whether combining Carboplatin or Paclitaxel with Pitavastatin or Ivermectin offers therapeutic benefits in a Cultrex-based 3D model. Methods: Here, the cytotoxicity of Carboplatin and Paclitaxel, both alone and in combination with Pitavastatin or Ivermectin, were analyzed on two chemoresistant tumor cell lines, OVCAR8 and OVCAR8 PTX R C, in 3D cultures. Cellular viability was assessed using CellTiter-Glo® Luminescent assays. Also, it explored synergistic interactions using zero interaction potency, Loewe, Bliss independence, and High-single agent reference models. Results: Our research indicates combining chemotherapeutic drugs with Pitavastatin or Ivermectin yields significantly more cytotoxic effects than chemotherapy alone. For all the combinations tested, at least one model indicated an additive effect; however, only the combination of Paclitaxel and Ivermectin consistently demonstrated an additive effect across all chemoresistant cell lines cultured in 3D models, as well as in all four synergy reference models used to assess drug interactions. Conclusions: Combining Paclitaxel with Ivermectin has the highest cytotoxic and the strongest additive effect for both chemoresistant cell lines compared to Paclitaxel alone. Full article
(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy and Diagnosis)
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21 pages, 3774 KiB  
Article
NIR-Guided Coating Optimization of Omega-3 Fatty Acid Mini Soft Capsules with Pitavastatin and Ezetimibe
by Hye-Ri Han, Ji Hoon Choi, Je Hwa Yoo, Jin-Hyuk Jeong, Sang-Beom Na, Ji-Hyun Kang, Dong-Wook Kim and Chun-Woong Park
Pharmaceutics 2024, 16(11), 1374; https://doi.org/10.3390/pharmaceutics16111374 - 26 Oct 2024
Viewed by 1721
Abstract
Background: This study aimed to optimize the coating process of Omega-3 fatty acid (OM3-FA) mini soft capsules containing the active pharmaceutical ingredients (APIs) pitavastatin and ezetimibe using near-infrared (NIR) spectroscopy for in-process monitoring. Cardiovascular disease treatments benefit from combining OM3-FA with lipid-lowering agents, [...] Read more.
Background: This study aimed to optimize the coating process of Omega-3 fatty acid (OM3-FA) mini soft capsules containing the active pharmaceutical ingredients (APIs) pitavastatin and ezetimibe using near-infrared (NIR) spectroscopy for in-process monitoring. Cardiovascular disease treatments benefit from combining OM3-FA with lipid-lowering agents, but formulating such combinations in mini soft capsules presents challenges in maintaining stability and mechanical integrity. Methods: The coating process was developed using a pan coater and real-time NIR monitoring to ensure uniformity and quality. NIR spectroscopy enabled precise control of coating thickness, ensuring consistent drug distribution across the capsule surface. Results: The optimized process minimized OM3-FA oxidation and preserved the mechanical integrity of the capsules, as confirmed by texture analysis and in-vitro dissolution testing. This integration of NIR spectroscopy as a process analytical technology (PAT) significantly improved coating quality control, resulting in a stable and effective combination therapy for pitavastatin and ezetimibe in a mini soft capsule form. Conclusion: This approach offers an efficient solution for enhancing patient adherence in cardiovascular disease management. The application of NIR spectroscopy for real-time monitoring highlights its broader significance in pharmaceutical manufacturing, where it can serve as a versatile tool for ensuring product quality and optimizing production efficiency in diverse formulation processes. By incorporating NIR-based PAT, manufacturers can not only achieve product-specific improvements but also establish a foundation for continuous manufacturing and automated quality assurance systems, ultimately contributing to a more streamlined and robust production environment. Full article
(This article belongs to the Special Issue Pharmaceutical Solids: Advanced Manufacturing and Characterization)
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22 pages, 2884 KiB  
Article
Molecular Mechanisms Underlying the Anticancer Properties of Pitavastatin against Cervical Cancer Cells
by Ya-Hui Chen, Jyun-Xue Wu, Shun-Fa Yang, Yun-Chia Wu and Yi-Hsuan Hsiao
Int. J. Mol. Sci. 2024, 25(14), 7915; https://doi.org/10.3390/ijms25147915 - 19 Jul 2024
Cited by 1 | Viewed by 2372
Abstract
Cervical cancer ranks as the fourth most prevalent form of cancer and is a significant contributor to female mortality on a global scale. Pitavastatin is an anti-hyperlipidemic medication and has been demonstrated to exert anticancer and anti-inflammatory effects. Thus, the purpose of this [...] Read more.
Cervical cancer ranks as the fourth most prevalent form of cancer and is a significant contributor to female mortality on a global scale. Pitavastatin is an anti-hyperlipidemic medication and has been demonstrated to exert anticancer and anti-inflammatory effects. Thus, the purpose of this study was to evaluate the anticancer effect of pitavastatin on cervical cancer and the underlying molecular mechanisms involved. The results showed that pitavastatin significantly inhibited cell viability by targeting cell-cycle arrest and apoptosis in Ca Ski, HeLa and C-33 A cells. Pitavastatin caused sub-G1- and G0/G1-phase arrest in Ca Ski and HeLa cells and sub-G1- and G2/M-phase arrest in C-33 A cells. Moreover, pitavastatin induced apoptosis via the activation of poly-ADP-ribose polymerase (PARP), Bax and cleaved caspase 3; inactivated the expression of Bcl-2; and increased mitochondrial membrane depolarization. Furthermore, pitavastatin induced apoptosis and slowed the migration of all three cervical cell lines, mediated by the PI3K/AKT and MAPK (JNK, p38 and ERK1/2) pathways. Pitavastatin markedly inhibited tumor growth in vivo in a cancer cell-originated xenograft mouse model. Overall, our results identified pitavastatin as an anticancer agent for cervical cancer, which might be expanded to clinical use in the future. Full article
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16 pages, 3339 KiB  
Article
Pharmacophore Modeling and Binding Affinity of Secondary Metabolites from Angelica keiskei to HMG Co-A Reductase
by Diah Lia Aulifa, Siti Rafa Amirah, Driyanti Rahayu, Sandra Megantara and Muchtaridi Muchtaridi
Molecules 2024, 29(13), 2983; https://doi.org/10.3390/molecules29132983 - 23 Jun 2024
Cited by 3 | Viewed by 2241
Abstract
Statins are cholesterol-lowering drugs with a mechanism of inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase, but long-term use can cause side effects. An example of a plant capable of reducing cholesterol levels is Angelica keiskei (ashitaba). Therefore, this study aimed to obtain suitable compounds with inhibitory activity [...] Read more.
Statins are cholesterol-lowering drugs with a mechanism of inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase, but long-term use can cause side effects. An example of a plant capable of reducing cholesterol levels is Angelica keiskei (ashitaba). Therefore, this study aimed to obtain suitable compounds with inhibitory activity against the HMG-CoA reductase enzyme from ashitaba through in silico tests. The experiment began with screening and pharmacophore modeling, followed by molecular docking on ashitaba’s compounds, statins groups, and the native ligand was (3R,5R)-7-[4-(benzyl carbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-imidazole-1-yl]-3,5-dihydroxyheptanoic acid (4HI). Based on the results of the molecular docking simulations, 15 hit compounds had a small binding energy (ΔG). Pitavastatin, as the comparator drug (ΔG = −8.24 kcal/mol; Ki = 2.11 µM), had a lower ΔG and inhibition constant (Ki) than the native ligand 4HI (ΔG = −7.84 kcal/mol; Ki = 7.96µM). From ashitaba’s compounds, it was found that 4′-O-geranylnaringenin, luteolin, isobavachalcone, dorsmannin A, and 3′-carboxymethyl-4,2′-dihydroxy-4′-methoxychalcone have low ΔG of below −6 kcal/mol. The lowest ΔG value was found in 3′-carboxymethyl-4,2′-dihydroxy-4′-methoxy chalcone with a ΔG of −6.67 kcal/mol and Ki value of 16.66 µM, which was lower than the ΔG value of the other comparator drugs, atorvastatin (ΔG = −5.49 kcal/mol; Ki = 1148.17 µM) and simvastatin (ΔG = −6.50 kcal/mol; Ki = 22.34 µM). This compound also binds to the important amino acid residues, including ASN755D, ASP690C, GLU559D, LYS735D, LYS691C, and SER684C, through hydrogen bonds. Based on the results, the compound effectively binds to six important amino acids with good binding affinity and only requires a small concentration to reduce half of the enzyme activity. Full article
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28 pages, 7717 KiB  
Article
Pitavastatin Calcium Confers Fungicidal Properties to Fluconazole by Inhibiting Ubiquinone Biosynthesis and Generating Reactive Oxygen Species
by Wanqian Li, Yanru Feng, Zhe Feng, Li Wang, Malcolm Whiteway, Hui Lu and Yuanying Jiang
Antioxidants 2024, 13(6), 667; https://doi.org/10.3390/antiox13060667 - 29 May 2024
Cited by 6 | Viewed by 1739
Abstract
Fluconazole (FLC) is extensively employed for the prophylaxis and treatment of invasive fungal infections (IFIs). However, the fungistatic nature of FLC renders pathogenic fungi capable of developing tolerance towards it. Consequently, converting FLC into a fungicidal agent using adjuvants assumes significance to circumvent [...] Read more.
Fluconazole (FLC) is extensively employed for the prophylaxis and treatment of invasive fungal infections (IFIs). However, the fungistatic nature of FLC renders pathogenic fungi capable of developing tolerance towards it. Consequently, converting FLC into a fungicidal agent using adjuvants assumes significance to circumvent FLC resistance and the perpetuation of fungal infections. This drug repurposing study has successfully identified pitavastatin calcium (PIT) as a promising adjuvant for enhancing the fungicidal activity of FLC from a comprehensive library of 2372 FDA-approved drugs. PIT could render FLC fungicidal even at concentrations as low as 1 μM. The median lethal dose (LD50) of PIT was determined to be 103.6 mg/kg. We have discovered that PIT achieves its synergistic effect by inhibiting the activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, thereby impeding ubiquinone biosynthesis, inducing reactive oxygen species (ROS) generation, triggering apoptosis, and disrupting Golgi function. We employed a Candida albicans strain that demonstrated a notable tolerance to FLC to infect mice and found that PIT effectively augmented the antifungal efficacy of FLC against IFIs. This study is an illustrative example of how FDA-approved drugs can effectively eliminate fungal tolerance to FLC. Full article
(This article belongs to the Section ROS, RNS and RSS)
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10 pages, 4094 KiB  
Case Report
Histological, Clinical Assessment, and Treatment of a Permanent Filler Complication in the Upper Lip: A Case Report with 16-Year Follow-Up
by Samuel Fiuza, Tiago Marques, Irving Padin, Maria Teresa Carvalho, Nelio Veiga, Juliana Campos Hasse Fernandes, Gustavo Vicentis Oliveira Fernandes and Patrícia Couto
Cosmetics 2024, 11(2), 50; https://doi.org/10.3390/cosmetics11020050 - 1 Apr 2024
Cited by 3 | Viewed by 3652
Abstract
There is a considerable increase in the use of substances and medical procedures aimed at changing the esthetics of the face, particularly the appearance of the lips. Permanent fillers such as polydimethylsiloxane, also called liquid silicone, are widely used, but their application for [...] Read more.
There is a considerable increase in the use of substances and medical procedures aimed at changing the esthetics of the face, particularly the appearance of the lips. Permanent fillers such as polydimethylsiloxane, also called liquid silicone, are widely used, but their application for facial esthetics is currently obsolete. Silicone belongs to this polymer family; its viscosity is determined by its degree of polymerization. Liquid injectable silicone is odorless, colorless, non-volatile, and oily to the touch. The substance is not altered by storage at room temperature and is not carcinogenic or teratogenic. However, the long-term complications remain a reality, as they can occur decades after the application. Thus, the goal of this case report was to present a complication after 16 years of treatment using liquid silicone. This case report involved a 52-year-old male with a complication of bilateral permanent filler in the upper lip performed 16 years ago, its surgical removal, and histological analysis. The patient had the first appointment at the University Dental Clinic—Universidade Católica Portuguesa (Viseu, Portugal) in April 2022, dissatisfied with his upper lip’s esthetic appearance and shape. He was not a smoker or diabetic but had hypertension and hypercholesterolemia and was medicated with Losartan, Hydrochlorothiazide, and Pitavastatin. No relevant findings were observed in the extraoral examination; he had bruxism and a good periodontal condition. The patient had an asymptomatic bilateral mass, hard to palpation, located on the upper lip due to permanent lip filling performed to increase its volume in 2006 associated with non-related generalized granules of Fordyce. The treatment options presented just observation or complete material removal in two surgical steps, which was the patient’s choice. Then, the first surgical procedure was performed under local anesthesia on the right side of the lip, one carpule of Lidocaine 2% with adrenaline 1:100,000, with a chalazion clamp, a diode laser for hemorrhagic control, and a simple suture. In this procedure, three fragments were biopsied: a cuboid measuring 1 × 1 × 0.8 cm and an irregular one consisting of two fragments that at one end of the piece were in continuity with each other, one measuring 1.6 × 0.5 × 0.4 cm and the other 2.5 × 0.6 × 0.5 cm. A similar macroscopic appearance in all the material, white in color, irregular surface, elastic, white section surface, or slightly fasciculate. The patient was medicated with Tylenol 500 mg thrice a day for two days. With 20-day intervals, the sutures from the first surgery were removed, as well as the foreign body from the upper lip on the left side, following the same surgical technique and medication. Histologically, it was possible to identify a chronic inflammatory, lymphoplasmacytic, and granulomatous reaction, with foreign body giant cells’ reaction, in relation to non-polarizable exogenous material due to the reaction to silicone. The most common complications are granulomas’ appearance and material displacement. The case report shows these granulomas are characterized as chronic low-caliber inflammation around the silicone. They have an unknown etiology but are probably multifactorial, from continuous trauma, friction or irritation, iatrogenic factors, infection, immunological mechanisms, and genetic and molecular variations, and can be highly related to the impurity of the injected material. This case brings the opportunity for health professionals to increase awareness of the long-term adverse effects of the silicone material used to fill the lip in order to make its application more predictable and conscious. Full article
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7 pages, 580 KiB  
Proceeding Paper
Precision Meets Affordability: A Highly Sensitive HPLC-FLD Technique for Accurate Pitavastatin Quantification in Human Plasma
by João Basso, Ana Fortuna, Rui Vitorino and Carla Vitorino
Eng. Proc. 2023, 48(1), 46; https://doi.org/10.3390/CSAC2023-14931 - 12 Oct 2023
Viewed by 1498
Abstract
High-Performance Liquid Chromatography (HPLC) combined with ultraviolet/visible (UV/Vis) or diode array detection (DAD) is routinely used for drug quantification in R&D around the world. However, it may lack the sensitivity required for bioanalytical studies. On the other hand, HPLC with fluorescence detection (FLD) [...] Read more.
High-Performance Liquid Chromatography (HPLC) combined with ultraviolet/visible (UV/Vis) or diode array detection (DAD) is routinely used for drug quantification in R&D around the world. However, it may lack the sensitivity required for bioanalytical studies. On the other hand, HPLC with fluorescence detection (FLD) is a cost-effective alternative that significantly increases drug signals, enabling the detection of compounds at very low concentrations. Pitavastatin is a lipid-lowering drug that contains the structure of quinoline, a highly fluorescent molecule. Recently, it has gained interest due to its pleiotropic effects on different conditions. Bearing this in mind, an HPLC-FLD method was developed and validated for the quantification of pitavastatin in human plasma. Overall, a signal gain of 54–70 times compared to that of UV detection was achieved when using fluorescence. Sample preparation included one-step protein precipitation with acetonitrile, followed by centrifugation and filtration prior to injection. Pitavastatin was separated from endogenous matrix interferents using a C18 column and by applying gradient elution. Atorvastatin was used as an internal standard. Accordingly, the method was shown to be selective, specific, and sensitive, with a lower limit of quantification of 3 ng/mL and complete absolute and relative recoveries higher than 94%. The method was linear over the wide concentration range of 3–900 ng/mL (R2 = 0.998), accurate (bias < 7.15%), and precise (RSD < 9.63%). This method allows for the therapeutic monitoring of patients treated with pitavastatin but can also support novel clinical studies of this drug in human plasma. Full article
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12 pages, 2198 KiB  
Article
Pitavastatin and Lovastatin Exhibit Calcium Channel Blocking Activity Which Potentiate Vasorelaxant Effects of Amlodipine: A New Futuristic Dimension in Statin’s Pleiotropy
by Wajid Ali, Niaz Ali, Abid Ullah, Shafiq Ur Rahman and Shujaat Ahmad
Medicina 2023, 59(10), 1805; https://doi.org/10.3390/medicina59101805 - 10 Oct 2023
Cited by 4 | Viewed by 2463
Abstract
Background and Objectives: We have recently reported that Fluvastatin, Atorvastatin, Simvastatin and Rosuvastatin have calcium channel antagonistic activities using rabbits’ intestinal preparations. The current study is focused on the effects of Pitavastatin and Lovastatin for possible inhibition of vascular L-Type calcium channels, [...] Read more.
Background and Objectives: We have recently reported that Fluvastatin, Atorvastatin, Simvastatin and Rosuvastatin have calcium channel antagonistic activities using rabbits’ intestinal preparations. The current study is focused on the effects of Pitavastatin and Lovastatin for possible inhibition of vascular L-Type calcium channels, which may have vasorelaxant effect(s). Combined effects of Pitavastatin and Lovastatin in the presence of Amlodipine were also tested for vasorelaxation. Materials and Methods: Possible relaxing effects of Pitavastatin and Lovastatin on 80 mM Potassium chloride (KCL)-induced contractions and on 1 µM norepinephrine (N.E)-induced contractions were studied in isolated rabbit’s aortic strips preparations. Relaxing effects on 80 mM KCL-induced vascular contractions were further verified by constructing Calcium Concentration Response Curves (CCRCs), in the absence and presence of three different concentrations of Pitavastatin and Lovastatin using CCRCs as negative control. Verapamil was used as a standard drug that has L-Type calcium channel binding activity. In other series of experiments, we studied drug interaction(s) among Pitavastatin, Lovastatin, and amlodipine. Results: The results of this study imply that Lovastatin is more potent than Pitavastatin for having comparatively lower EC50 (7.44 × 10−5 ± 0.16 M) in intact and (4.55 × 10−5 ± 0.10 M) in denuded aortae for KCL-induced contractions. Lovastatin amplitudes in intact and denuded aortae for KCL-induced contractions were, respectively, 24% and 35.5%; whereas amplitudes for Pitavastatin in intact and denuded aortae for KCL-induced contractions were 34% and 40%, respectively. A left shift in the EC50 values for the statins was seen when we added amlodipine in EC50 (Log Ca++ M). Right shift for CCRCs state that Pitavastatin and Lovastatin have calcium channel antagonistic effects. Lovastatin in test concentration (6.74 × 10−7 M) produced a right shift in relatively lower EC50 (−2.5 ± 0.10) Log Ca++ M as compared to Pitavastatin, which further confirms that lovastatin is relatively more potent. The right shift in EC50 resembles the right shift of Verapamil. Additive effect of Pitavastatin and Lovastatin was noted in presence of amlodipine (p < 0.05). Conclusions: KCL (80 mM)-induced vascular contractions were relaxed by Pitavastatin and Lovastatin via inhibitory effects on L-Type voltage-gated calcium channels. Lovastatin and Pitavastatin also relaxed Norepinephrine (1 µM)-induced contractions giving an insight for involvement of dual mode of action of Pitavastatin and Lovastatin. Full article
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14 pages, 3303 KiB  
Article
Development of an In Vitro Methodology to Assess the Bioequivalence of Orally Disintegrating Tablets Taken without Water
by Toshihide Takagi, Takato Masada, Keiko Minami, Makoto Kataoka and Shinji Yamashita
Pharmaceutics 2023, 15(9), 2192; https://doi.org/10.3390/pharmaceutics15092192 - 24 Aug 2023
Cited by 4 | Viewed by 2423
Abstract
To assess the probability of bioequivalence (BE) between orally disintegrating tablets (ODTs) taken without water and conventional tablets (CTs) taken with water, an in vitro biorelevant methodology was developed using the BE Checker, which reproduces fluid shifts in the gastrointestinal tract and drug [...] Read more.
To assess the probability of bioequivalence (BE) between orally disintegrating tablets (ODTs) taken without water and conventional tablets (CTs) taken with water, an in vitro biorelevant methodology was developed using the BE Checker, which reproduces fluid shifts in the gastrointestinal tract and drug permeation. In addition to the fluid shift from the stomach to the small intestine, the process of ODT disintegration in a small amount of fluid in the oral cavity and the difference in gastric emptying caused by differences in water intake were incorporated into the evaluation protocol. Assuming a longer time to maximum plasma concentration after oral administration of ODTs taken without water than for CTs taken with water due to a delay in gastric emptying, the fluid shift in the donor chamber of the BE Checker without water was set longer than that taken with water. In the case of naftopidil ODTs and CTs, the values of the f2 function, representing the similarity of the permeation profiles, were 50 or higher when the fluid shift in ODTs taken without water was set at 1.5 or 2 times longer than that of the CTs taken with water. The values of the f2 function in permeation profiles of pitavastatin and memantine ODTs were both 62 when the optimized experimental settings for naftopidil formulations were applied. This methodology can be useful in formulation studies for estimating the BE probability between ODTs and CTs. Full article
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18 pages, 4782 KiB  
Article
Repurposing Pitavastatin and L-Glutamine: Replenishing β-Cells in Hyperlipidemic Type 2 Diabetes Mouse Model
by Sayantani Pramanik Palit, Roma Patel, Nishant Parmar, Nirali Rathwa, Nilay Dalvi, A. V. Ramachandran and Rasheedunnisa Begum
Life 2023, 13(4), 929; https://doi.org/10.3390/life13040929 - 1 Apr 2023
Viewed by 2482
Abstract
Type 2 diabetes (T2D) is associated with obesity and declining β-cells. L-glutamine has been implicated in the amelioration of T2D by virtue of its incretin secretagogue property while, there are mixed reports on pitavastatin’s adiponectin potentiating ability. We aimed to investigate the effect [...] Read more.
Type 2 diabetes (T2D) is associated with obesity and declining β-cells. L-glutamine has been implicated in the amelioration of T2D by virtue of its incretin secretagogue property while, there are mixed reports on pitavastatin’s adiponectin potentiating ability. We aimed to investigate the effect of pitavastatin (P), L-glutamine (LG), and combination (P + LG) on glycemic control and β-cell regeneration in a high-fat diet (HFD) + streptozotocin (STZ)-induced T2D mouse model. C57BL6/J mice treated with HFD + STZ were divided into four groups: diabetes control (HFD + STZ), P, LG, and P + LG, while the control group (NCD) was fed with the normal-chow diet. Significant amelioration was observed in the combination therapy as compared to monotherapies in respect of (i) insulin resistance, glucose intolerance, lipid profile, adiponectin levels, and mitochondrial complexes I, II, and III activities, (ii) reduced phosphoenolpyruvate carboxykinase, glucose 6-phophatase, glycogen phosphorylase, and GLUT2 transcript levels with increased glycogen content in the liver, (iii) restoration of insulin receptor 1β, pAkt/Akt, and AdipoR1 protein levels in skeletal muscle, and (iv) significant increase in islet number due to β-cell regeneration and reduced β-cell death. L-glutamine and pitavastatin in combination can ameliorate T2D by inducing β-cell regeneration and regulating glucose homeostasis. Full article
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17 pages, 1682 KiB  
Article
Effects of Statin Dose, Class, and Use Intensity on All-Cause Mortality in Patients with Type 2 Diabetes Mellitus
by Jung-Min Yu, Wan-Ming Chen, Mingchih Chen, Ben-Chang Shia and Szu-Yuan Wu
Pharmaceuticals 2023, 16(4), 507; https://doi.org/10.3390/ph16040507 - 29 Mar 2023
Cited by 4 | Viewed by 4661
Abstract
Purpose: to examine the impact of statins on reducing all-cause mortality among individuals diagnosed with type 2 diabetes. This investigation explored the potential correlations between dosage, drug classification, and usage intensity with the observed outcomes. Methods: The research sample consisted of individuals aged [...] Read more.
Purpose: to examine the impact of statins on reducing all-cause mortality among individuals diagnosed with type 2 diabetes. This investigation explored the potential correlations between dosage, drug classification, and usage intensity with the observed outcomes. Methods: The research sample consisted of individuals aged 40 years or older diagnosed with type 2 diabetes. Statin usage was determined as a frequent usage over a minimum of one month subsequent to type 2 diabetes diagnosis, where the average statin dose was ≥28 cumulative defined daily doses per year (cDDD-year). The analysis employed an inverse probability of treatment-weighted Cox hazard model, utilizing statin usage status as a time-varying variable, to evaluate the impact of statin use on all-cause mortality. Results: The incidence of mortality was comparatively lower among the cohort of statin users (n = 50,804 (12.03%)), in contrast to nonusers (n = 118,765 (27.79%)). After adjustments, the hazard ratio (aHR; 95% confidence interval (CI)) for all-cause mortality was estimated to be 0.32 (0.31–0.33). Compared with nonusers, pitavastatin, rosuvastatin, pravastatin, simvastatin, atorvastatin, fluvastatin, and lovastatin users demonstrated significant reductions in all-cause mortality (aHRs (95% CIs) = 0.06 (0.04–0.09), 0.28 (0.27–0.29), 0.29 (0.28–0.31), 0.31 (0.30–0.32), 0.31 (0.30–0.32), 0.36 (0.35–0.38), and 0.48 (0.47–0.50), respectively). In Q1, Q2, Q3, and Q4 of cDDD-year, our multivariate analysis demonstrated significant reductions in all-cause mortality (aHRs (95% CIs) = 0.51 (0.5–0.52), 0.36 (0.35–0.37), 0.24 (0.23–0.25), and 0.13 (0.13–0.14), respectively; p for trend <0.0001). Because it had the lowest aHR (0.32), 0.86 DDD of statin was considered optimal. Conclusions: In patients diagnosed with type 2 diabetes, consistent utilization of statins (≥28 cumulative defined daily doses per year) was shown to have a beneficial effect on all-cause mortality. Moreover, the risk of all-cause mortality decreased as the cumulative defined daily dose per year of statin increased. Full article
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16 pages, 2797 KiB  
Article
One-Step Microwell Plate-Based Spectrofluorimetric Assay for Direct Determination of Statins in Bulk Forms and Pharmaceutical Formulations: A Green Eco-Friendly and High-Throughput Analytical Approach
by Ibrahim A. Darwish, Hany W. Darwish, Nourah Z. Alzoman and Awadh M. Ali
Molecules 2023, 28(6), 2808; https://doi.org/10.3390/molecules28062808 - 20 Mar 2023
Cited by 3 | Viewed by 2165
Abstract
This study describes the development of a one-step microwell spectrofluorimetric assay (MW-SFA) with high sensitivity and throughput for the determination of four statins in their pharmaceutical and formulations (tablets). These statins were pitavastatin (PIT), fluvastatin (FLU), rosuvastatin (ROS) and atorvastatin (ATO). The MW-SFA [...] Read more.
This study describes the development of a one-step microwell spectrofluorimetric assay (MW-SFA) with high sensitivity and throughput for the determination of four statins in their pharmaceutical and formulations (tablets). These statins were pitavastatin (PIT), fluvastatin (FLU), rosuvastatin (ROS) and atorvastatin (ATO). The MW-SFA involves the measurement of the native fluorescence of the statin aqueous solutions. The assay was conducted in white opaque 96-microwell plates, and the fluorescence intensities of the solutions were measured by using a fluorescence microplate reader. The optimum conditions of the assay were established; under which, linear relationships with good correlation coefficients (0.9991–0.9996) were found between the fluorescence intensity and the concentration of the statin drug in a range of 0.2–200 µg mL–1 with limits of detection in a range of 0.1–4.1 µg mL–1. The proposed MW-SFA showed high precision, as the values of the relative standard deviations did not exceed 2.5%. The accuracy of the assay was proven by recovery studies, as the recovery values were 99.5–101.4% (±1.4–2.1%). The assay was applied to the determination of the investigated statins in their tablets. The results were statistically compared with those obtained by a reference method and the results proved to have comparable accuracy and precision of both methods, as evidenced by the t- and F-tests, respectively. The green and eco-friendly feature of the proposed assay was assessed by four different metric tools, and all the results proved that the assay meets the requirements of green and eco-friendly analytical approaches. In addition, ever-increasing miniaturization as handling of large numbers of micro-volume samples simultaneously in the proposed assay gave it a high-throughput feature. Therefore, the assay is a valuable tool for the rapid routine application in the pharmaceutical quality control units for the determination of statins. Full article
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