The Janus kinase (JAK)/signal transducer and activatorof transcription(STAT) signaling pathway is a key therapeutic target for inflammatoryand neoplastic diseases such as rheumatoid arthritis (RA) and certaintypes of cancer. Although several inhibitors have been approved formedical use, their associated adverse effects limit their therapeuticuse. Therefore, it is essential to search for new, safer inhibitors.In this work, we applied computer-aided approaches consisting of consensusmolecular docking and molecular dynamics using the JAK2 structureas a filter of 3330 drugs approved by the Food and Drug Administration(FDA) retrieved from the ZINC20 database. The best predicted virtualhits were evaluated in an ex vivo STAT1,3 phosphorylationfunctional model in human lymphocytes induced by IL-6 stimulation.The docking-based consensus-scoring strategy allowed the selectionof pitavastatin (PIT), eltrombopag (ELT), flavoxate (FLA), and empagliflozin(EMP) as potential JAK2 inhibitors. Their stability was confirmedby running independent molecular dynamics simulations of 200 ns intriplicate, which showed comparable stability with baricitib (BAR)and showed that hydrogen bonding is involved in their binding withkey amino acids of the ATP-binding site. In the ex vivo evaluations, pitavastatin (0.5004 μM), eltrombopag (0.2548μM), flavoxate (0.1536 μM), and empagliflozin (0.2548μM) affected the phosphorylation of downstream STAT1 and STAT3signaling molecules, similarly to tofacitinib citrate (TOF) (1.2 nM). These results encourage further in-depth preclinical experimentsaimed at exploring the additional effects of the JAK2-STAT1/3 signalingpathway.

Triple-negative breast cancer (TNBC) is notorious for its poor prognosis, high metastatic rates, and resistance to chemotherapy. We sought to investigate the anticancer effects of pitavastatin (PITA), a promising candidate for drug repurposing due to its potent inhibition of myeloid cell leukemia 1 (Mcl-1). The impact of PITA on TNBC cells was assessed in vitro by examining cell viability, apoptosis, mitochondrial function, and effects on cancer stem cell (CSC) properties. The interaction between PITA and Mcl-1 was explored using molecular docking simulations and surface plasmon resonance (SPR) assays. In vivo studies using CSC-enriched allografts and a paclitaxel-resistant metastatic model were conducted to understand translational relevance. PITA's direct inhibition of Mcl-1 enabled potent suppression of TNBC cells by selectively enhancing mitochondrial ROS production, reducing mitochondrial membrane potential, and depleting ATP content, triggering caspase-mediated apoptosis. PITA effectively targeted CSC-like subpopulations, marked by high ALDH1 activity and the CD44high/CD24low phenotype. By downregulating p-glycoprotein and Mcl-1/Bcl-2 signaling, PITA was also effective at counteracting paclitaxel resistance, and disrupted AKT/STAT3 survival pathways. PITA significantly inhibited the growth of TNBC patient-derived tumor organoids (PDTOs). Furthermore, its combination with paclitaxel exhibited a synergistic effect on TNBC organoid growth inhibition. In vivo, PITA exhibited potent anti-tumorigenic and anti-metastatic effects, significantly reducing tumor growth and lung metastasis in TNBC allograft models without overt toxicity. PITA's inhibition of Mcl-1 represents a novel mechanism to address treatment-refractory metastatic TNBC. Further assessment of PITA's therapeutic potential is warranted.

Rare-earth-free magnesium (Mg) alloy bioresorbable stent (BRS) exhibits significant potential in vascular intervention due to its exceptional biosafety. However, its susceptibility to corrosion complicates surface functionalization and renders existing coating strategies ineffective for degradation-remodeling kinetics, resulting in delayed re-endothelialization and excessive lumen loss. Herein, a hierarchical MgF2/polyurethane (PU)/pitavastatin (PTV) coating system is constructed on Mg-Zn-Mn BRS using elastomeric PU as an intermediate layer. Studies confirm the PU layer effectively accommodates stent deformation, alleviates stress concentrations, and confines corrosion propagation triggered by deformation-induced MgF2 microcracks. The in situ formed MgF2 layer concurrently decreases substrate reactivity, establishes stable interfaces with PU, and synergistically enhances the corrosion resistance. The surface PTV-loaded poly-L-lactic acid layer maintains sustained drug release through PU-mediated interfacial stability while serving as an initial corrosion barrier. In vivo evaluations demonstrate the MgF2/PU/PTV-functionalized stent significantly suppresses neointimal hyperplasia in rabbit models while achieving synchronized degradation-remodeling kinetics. This hierarchical coating architecture, which synergistically integrates controlled drug elution with degradation modulation, provides a viable solution to clinical challenges of post-implant restenosis and vascular remodeling mismatch.

ProposeSailuotong (SLT), a standardized Chinese herbal preparation for vascular dementia (VaD), is frequently co-administered with pitavastatin (PIV). Potential herb-drug interactions (HDIs) between these agents remain uncharacterized. Given the high likelihood of using this combination to treat VaD, this study aims to systematically evaluate the effects of SLT on PIV’s pharmacokinetics and elucidate underlying mechanisms.MethodsRats received single or repeated doses of SLT followed by oral or intravenous PIV. Plasma and hepatic PIV concentrations were quantified via LC-MS/MS. Biliary excretion and enterohepatic circulation interruption models assessed elimination pathways. The expression of hepatic and intestinal transporters was analyzed by RT-PCR and Western blot. Transporter functionality was validated using MDR1 substrates (digoxin and betrixaban).ResultsSingle-dose SLT increased PIV’s Cmax and AUC0-9h by approximately 23.30% and 15.70%, respectively. Repeated SLT administration significantly decreased PIV’s AUC by 32.90%, and reduced its hepatic accumulation by 68.96%. Intravenous studies revealed that SLT primarily affected the later exposure phases. Multiple doses of SLT decreased PIV’s total biliary excretion by 33.10%. Mechanistically, SLT significantly induced the expression of MDR1 mRNA and proteins in the intestine and liver, and MRP2 in the liver. Additionally, SLT significantly decreased the exposure levels of digoxin and betrixaban, with betrixaban’s Cmax and AUC remarkably reduced by 86.44% and 79.74%, respectively.ConclusionCombining SLT and PIV can lead to HDIs, with multiple doses of SLT significantly reducing the plasma and hepatic exposure of PIV in rats. The primary mechanism appears to be the induction of the intestinal efflux transporter MDR1, resulting in decreased bioavailability of PIV.

Diabetic cardiomyopathy (DCM) is a serious outcome of type II diabetes mellitus (T2DM) and a key contributor to high morbidity and death in diabetic individuals. The current research is intended to elucidate and compare the therapeutic benefits of rosuvastatin (RVS) and pitavastatin (PTS) in mitigating DMC-induced in rats and exploring the possible underlying molecular signaling pathways. DCM was prompted by feeding rats a high-fat/fructose (F/Fr) diet for eight weeks with a sub-diabetogenic dose of streptozotocin (35 mg/kg; i.p) injection at week seven. All rats were allocated into four groups: a normal control group, a DCM-induced positive control group, the RVS group of DCM-induced rats that were treated once daily with 10 mg/kg of RVS, and the PTS group of DCM rats that were treated with 0.8 mg/kg of PTS. Rats were given the treatments orally for four consecutive weeks. The outcome of the existing work discovered that RVS and PTS significantly improved T2DM-associated DCM, as evidenced by the amelioration of glucose, lipids, cardiac markers, ECG parameters, and redox status. Considering the relationship between oxidative stress and inflammation, this attenuation was evidenced by the downregulation of redox, inflammatory, and cellular fibrotic cascades, namely RISK, NF-κB/NLRP3 inflammasome, and TLR4/NF-κB signaling pathways. Additionally, the histopathological examinations confirmed these structural alterations in the myocardium. Besides, RVS and PTS diminished the expression of caspase-1 assessed by immunochemical staining. In summary, the present study demonstrated that RVS and PTS mitigated the metabolic abnormalities associated with T2DM-induced DCM.

Diabetic cardiomyopathy (DCM) is a serious outcome of type II diabetes mellitus (T2DM) and a key contributor to high morbidity and death in diabetic individuals. The current research is intended to elucidate and compare the therapeutic benefits of rosuvastatin (RVS) and pitavastatin (PTS) in mitigating DMC-induced in rats and exploring the possible underlying molecular signaling pathways. DCM was prompted by feeding rats a high-fat/fructose (F/Fr) diet for eight weeks with a sub-diabetogenic dose of streptozotocin (35 mg/kg; i.p) injection at week seven. All rats were allocated into four groups: a normal control group, a DCM-induced positive control group, the RVS group of DCM-induced rats that were treated once daily with 10 mg/kg of RVS, and the PTS group of DCM rats that were treated with 0.8 mg/kg of PTS. Rats were given the treatments orally for four consecutive weeks. The outcome of the existing work discovered that RVS and PTS significantly improved T2DM-associated DCM, as evidenced by the amelioration of glucose, lipids, cardiac markers, ECG parameters, and redox status. Considering the relationship between oxidative stress and inflammation, this attenuation was evidenced by the downregulation of redox, inflammatory, and cellular fibrotic cascades, namely RISK, NF-κB/NLRP3 inflammasome, and TLR4/NF-κB signaling pathways. Additionally, the histopathological examinations confirmed these structural alterations in the myocardium. Besides, RVS and PTS diminished the expression of caspase-1 assessed by immunochemical staining. In summary, the present study demonstrated that RVS and PTS mitigated the metabolic abnormalities associated with T2DM-induced DCM.

Aspergillus species are a significant cause of aspergillosis, with invasive pulmonary aspergillosis (IPA) being particularly severe and often fatal. The increasing resistance to azole antifungals and limited treatment options highlight the need for new therapeutic strategies. This study explores the synergistic effects of pitavastatin (PIT), a statin, combined with itraconazole (ITZ) against various Aspergillus species. In vitro assessments included plate inoculation, liquid medium incubation, and microscopic observation of spore germination, alongside ergosterol content analysis, intracellular itraconazole retention, and rhodamine 6G (Rh6G) uptake and efflux assays. The PIT and ITZ combination exhibited significant synergistic antifungal activity against Aspergillus flavus, Aspergillus niger, Aspergillus terreus, and Aspergillus fumigatus. The synergistic mechanism was attributed to decreased ergosterol levels, increased intracellular itraconazole retention, reduced spore germination, and abnormal hyphal formation in fungal cells. An in vivo Galleria mellonella infectious model demonstrated reduced mortality in larvae treated with the drug combination compared to those treated with ITZ alone. These findings suggest that the PIT and ITZ combination enhances antifungal effects against Aspergillus species, potentially offering a novel therapeutic strategy for IPA treatment. Further clinical trials are warranted to explore the potential of this drug combination in treating aspergillosis.

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.

Pitavastatin Potentiates Mitochondrial Dysfunction and Venetoclax Cytotoxicity in Acute Myeloid Leukemia Cells

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 (collectively, OATP1B) transporters encoded by the solute carrier organic anion transporter (SLCO) genes mediate uptake of multiple pharmaceutical compounds. Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease (NAFLD), decreases OATP1B abundance. This research characterized the pathologic and pharmacokinetics effects of three diet- and one chemical-induced NAFLD model in male and female humanized OATP1B mice, which comprises knock-out of rodent Oatp orthologs and insertion of human SLCO1B1 and SLCO1B3. Histopathology scoring demonstrated elevated steatosis and inflammation scores for all NAFLD-treatment groups. Female mice had minor changes in SLCO1B1 expression in two of the four NAFLD treatment groups, and pitavastatin (PIT) area under the concentration-time curve (AUC) increased in female mice in only one of the diet-induced models. OATP1B3 expression decreased in male and female mice in the chemical-induced NAFLD model, with a coinciding increase in PIT AUC, indicating the chemical-induced model may better replicate changes in OATP1B3 expression and OATP substrate disposition observed in NASH patients. This research also tested a reported multifactorial pharmacokinetic interaction between NAFLD and silymarin, an extract from milk thistle seeds with notable OATP-inhibitory effects. Males showed no change in PIT AUC, whereas female PIT AUC increased 1.55-fold from the diet alone and the 1.88-fold from the combination of diet with silymarin, suggesting that female mice are more sensitive to pharmacokinetic changes than male mice. Overall, the humanized OATP1B model should be used with caution for modeling NAFLD and multifactorial pharmacokinetic interactions. SIGNIFICANCE STATEMENT: Advanced stages of NAFLD cause decreased hepatic OATP1B abundance and increase systemic exposure to OATP substrates in human patients. The humanized OATP1B mouse strain may provide a clinically relevant model to recapitulate these observations and predict pharmacokinetic interactions in NAFLD. This research characterized three diet-induced and one drug-induced NAFLD model in a humanized OATP1B mouse model. Additionally, a multifactorial pharmacokinetic interaction was observed between silymarin and NAFLD.

Pitavastatin (PTV) is a potent lipid lowering drug that acts on hepatocytes by blocking the 3-hydroxy-3- methylglutaryl-CoA reductase enzyme. As a Biopharmaceutical Classification System (BCS) Class II drug, PTV possesses very low water solubility; hence, poor bioavailability leads to poor drug delivery to the target organ. The study aims to develop various PTV solid dispersion (SD) formulations and to investigate the release profile of PTV SD systems. Different PTV physical mixing and SD formulations were prepared using polyvinylpyrrolidone (Kollidon®90F) and Kollicoat®IR hydrophilic polymers by fusion and solvent evaporation approaches. The efficacy of the formulations was evaluated by in vitro PTV release studies. Subsequently, the characterization of SD formulations was performed using thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). The in vitro release studies confirmed that all the developed formulations showed a comparatively better release percentage (75.31–98.45%) than the pure PTV (61.76%) after 60 min. Additionally, the outcomes showed that raising the concentration of both polymers improved PTV's ability to dissolve. In comparison to physical mixing formulations, SD formulations made using fusion and solvent evaporation processes performed better during dissolution. The TGA, DSC, and FTIR studies confirmed that the tested SD formulations (1:2, 1:3 ratios) were stable at high temperatures with a reduction in crystallinity and no notable interaction between the drug and polymers. The SEM analysis showed that the PTV was evenly spread out in the carriers and that the crystal-like structure of the PTV had changed into an amorphous form. Bangladesh Pharmaceutical Journal 27(1): 37-50, 2024 (January)

Abstract Although experiments have long provided empirical evidence that statins can suppress various oxidation pathways, theoretical attempts to quantify the antioxidant activity of statins (read, atorvastatin ATV, the only one studied so far) are not published until last year. Extensive results reported here for pitavastatin (PVT) and derivatives include the thermodynamic antioxidant descriptors (bond dissociation enthalpy [BDE], adiabatic ionization potential [IP], proton dissociation enthalpy [PDE], proton affinity [PA], and electron transfer enthalpy [ETE]) related to the three antioxidant mechanisms (hydrogen atom transfer [HAT], stepwise electron transfer proton transfer [SETPT], sequential proton loss electron transfer [SPLET]). The particular emphasis is on the PVT's hydroxylated derivatives wherein a hydroxy group replaces a hydrogen atom either on the quinoline core (Q‐hydroxylated metabolites) or on the fluorophenyl ring (F‐hydroxylated metabolites). The calculations indicate that both the Q‐ and F‐hydroxylated derivatives possess antioxidant properties superior to the parent PVT molecule. Given the fact that, to the best of the knowledge, no experimental data for the antioxidant potency of PVT and its hydroxylated derivatives exist, this is a theoretical prediction for the validation of which it is aimed hereby to stimulate companion experimental in vivo and in vitro investigations and inspire pharmacologists in further drug developments.

Tissue drug concentrations determine the efficacy and toxicity of drugs. When a drug is the substrate of transporters that are present at the blood:tissue barrier, the steady-state unbound tissue drug concentrations cannot be predicted from their corresponding plasma concentrations. To accurately predict transporter-modulated tissue drug concentrations, all clearances (CLs) mediating the drug's entry and exit (including metabolism) from the tissue must be accurately predicted. Because primary cells of most tissues are not available, we have proposed an alternative approach to predict such CLs, that is the use of transporter-expressing cells/vesicles (TECs/TEVs) and relative expression factor (REF). The REF represents the abundance of the relevant transporters in the tissue vs. in the TECs/TEVs. Here, we determined the transporter-based intrinsic CL of glyburide (GLB) and pitavastatin (PTV) in OATP1B1, OATP1B3, OATP2B1, and NTCP-expressing cells and MRP3-, BCRP-, P-gp-, and MRP2-expressing vesicles and scaled these CLs to in vivo using REF. These predictions fell within a priori set twofold range of the hepatobiliary CLs of GLB and PTV, estimated from their hepatic positron emission tomography imaging data: 272.3 and 607.8 mL/min for in vivo hepatic sinusoidal uptake CL, 47.8 and 17.4 mL/min for sinusoidal efflux CL, and 0 and 4.20 mL/min for biliary efflux CL, respectively. Moreover, their predicted hepatic concentrations (area under the hepatic concentration-time curve (AUC) and maximum plasma concentration (Cmax )), fell within twofold of their mean observed data. These data, together with our previous findings, confirm that the REF approach can successfully predict transporter-based drug CLs and tissue concentrations to enhance success in drug development.

Pitavastatin (PITA) is a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor to treat hypercholesterolemia and in recent studies is focused that its potential anti-cancer effect. This study was aimed to elucidate the effect of PITA alone and in combination with cisplatin on cervical cancer cells (HeLa) in vitro. Cytotoxicity of PITA (5-200 μM) was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and neutral red uptake (NRU) assays for 24, 48, and 72 h. Cell apoptosis and cell cycle analyses were performed in flow cytometry (0.1-100 μM). The evaluation of genotoxic effects and oxidative DNA damage of PITA (2-200 μM) were performed with standard comet assay, formamidopyrimidine glycosylase (fpg)-modified comet assay, and reactive oxygen species (ROS) activation in HeLa cells. PITA alone reduced cell viability in a dose-dependent manner (20-200, 20-200, and 5-200 μM for 24, 48, and 72 h, respectively, in MTT). The combined treatment of PITA with cisplatin resulted in significantly greater inhibition of cell viability. ROS and DNA damage increased significantly at 100 μM for 4 h and 20 μM for 24 h, respectively. PITA-induced apoptosis, an increased proportion of sub G1 cells, was monitored, and also, it increased the expression of active caspase-9 and caspase-3 and upregulated cleaved poly adenosine diphosphate ribose polymerase (PARP) by western blotting and caspase 3/8/9 multiple assay kit. We conclude that PITA can be used to efficiently cervical cancer studies, and promising findings have been obtained for further studies.

A Phase 1 Study of Adding Pitavastatin to Venetoclax-Based Therapy in AML and CLL/SLL

Azole resistance in Aspergillus fumigatus is a worldwide concern and new antifungal drugs are required to overcome this problem. Statin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, has been reported to suppress the growth of A. fumigatus, but little is known about its in vivo antifungal effect against A. fumigatus. In this study, we evaluated the in vivo efficacy of pitavastatin (PIT) combined with itraconazole (ITC) against azole-susceptible and azole-resistant strains with silkworm models. Prolongation of survival was confirmed in the combination-therapy (PIT and ITC) group compared to the no-treatment group in both azole-susceptible and azole-resistant strain models. Furthermore, when the azole-susceptible strain was used, the combination-therapy resulted in a higher survival rate than with ITC alone. Histopathological analysis of the silkworms revealed a reduction of the hyphal amount in both azole-susceptible and azole-resistant strain models. Quantitative evaluation of fungal DNA by qPCR in azole-susceptible strain models clarified the reduction of fungal burden in the combination-therapy group compared with the no-treatment group and ITC-alone group. These results indicate that the efficacy of PIT was enhanced when combined with ITC in vivo. As opposed to most statins, PIT has little drug-drug interaction with azoles in humans and can be used safely with ITC. This combination therapy may be a promising option as an effective treatment in clinical settings in the future. IMPORTANCE Azole resistance among A. fumigatus isolates has recently been increasingly recognized as a cause of treatment failure, and alternative antifungal therapies are required to overcome this problem. Our study shows the in vivo efficacy of PIT combined with ITC against A. fumigatus using silkworm models by several methods including evaluation of survival rates, histopathological analysis, and assessment of fungal burden. Contrary to most statins, PIT can be safely administered with azoles because of less drug-drug interactions, so this study should help us to verify how to make use of the drug in clinical settings in the future.

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.

The interaction between alpha casein (α-CN) and two drugs, fluvastatin (FLU) and pitavastatin (PIT) was investigated using fluorescence, UV absorption and FTIR. In addition, the binding site was established by applying molecular modeling technique. Fluorescence data suggested that FLU and PIT quench the intrinsic fluorescence of α-CN. The binding constants for the interaction of FLU and PIT with α-CN were found to be (8.18±0.08)×104 M-1 and (9.04±0.07)×104 M-1, respectively, indicating that the binding affinity of PIT to α-CN was higher than that for FLU. The number of binding site FLU and PIT per α-CN were 1.06 and 1.04 respectively. Docking calculation showed the probable binding sites of FLU and PIT are located in the hydrophobic core of α-CN where the FLU and PIT are lined by hydrophobic residues and make three and four hydrogen bonds with FLU and PIT respectively. Simulation, molecular docking and experimental data reciprocally supported each other. Therefore, it can be concluded that α-CN can act as a carrier of FLU and PIT drugs.

Oral squamous cell carcinoma (OSCC) is the most common epithelial tumor of the oral cavity. Gingival tumors, a unique type of OSCC, account for 10% of these malignant tumors. The antineoplastic properties of statins, including pitavastatin (PV), and the essential oil of the Pinus densiflora leaf (Pd oil) have been adequately reported. The goal of this investigation was to develop nanostructured lipid carriers (NLCs) containing PV combined with Pd oil and to determine their cytotoxicity against the cell line of human gingival fibroblasts (HGF-1). A central composite quadratic design was adopted to optimize the nanocarriers. The particle size and stability index of the nano-formulations were measured to evaluate various characteristics. TEM analysis, the entrapment efficiency, dissolution efficiency, and the cytotoxic efficiency of the optimized PV-loaded nanostructured lipid carrier drug delivery system (PV-Pd-NLCs) were evaluated. Then, the optimal PV-Pd-NLCs was incorporated into a Carbopol 940® gel base and tested for its rheological features and its properties of release and cell viability. The optimized NLCs had a particle size of 98 nm and a stability index of 89%. The gel containing optimum PV-Pd-NLCs had reasonable dissolution efficiency and acceptable rheological behavior and acquired the best cytotoxic activity against HGF-1 cell line among all the formulations developed for the study. The in vitro cell viability studies revealed a synergistic effect between PV and Pd oil in the treatment of gingival cancer. These findings illustrated that the gel containing PV-Pd-NLCs could be beneficial in the local treatment of gingival cancer.

Albeit its established efficacy as an anti-hyperlipidemic agent, pitavastatin (PIT) has been shown to have other various therapeutic effects. One of these effects is the anti-cancer activity against hepatocellular carcinoma (HCC). This effect has been evaluated in this study for the first time via its oral delivery loaded in bilosomes both in vitro in hepatocellular carcinoma (HCC) cell line; HepG2 and in vivo in an Ehrlich ascites carcinoma (EAC) model. Moreover, the impact of surface modification of bilosomes with lactoferrin (LF) as an active targeting ligand for HCC was investigated. Bilosomes were prepared by thin-film hydration and different molar phospholipid to bile salt ratios were used to optimize the bilosomal formulation. The molar phospholipid to bile salt ratio was adjusted to 4:1 at pH 7.4. LF-coated bilosomes possessed a particle size, PDI, entrapment efficiency, and zeta potential of 112.28 nm ± 6.35, 0.229 ± 0.06, 90.56% ± 3.22, and −7.86 mV ± 1.13, respectively. LF-coated bilosomes also increased permeation of PIT when tested on Caco-2 cells by 3.1-folds (compared to uncoated ones or free PIT solution). It also improved the cytotoxicity of HepG2 spheroids 44-folds more than PIT-free solution. RT-PCR analysis showed that LF-coated PIT-loaded bilosomes caused an improvement (2-fold increase) in the apoptotic potential of PIT mediated by caspase-3. In conclusion, the optimized LF-coated PIT-loaded bilosomes were cytotoxic to HCC with improved hepatocytes permeation and cellular uptake. Thus, the proposed formula could be a promising treatment for HCC.