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The motor protein prestin, found in the inner ear's outer hair cells (OHCs), is responsible for high sensitivity and sharp frequency selectivity in mammalian hearing. Some studies have suggested that prestin could be a serological biomarker for cochlear damage, as OHCs are highly vulnerable to damage from various sources. However, the reported data are inconsistent and lack appropriate negative controls. To investigate whether prestin can be used as a serological biomarker for cochlear damage or stress, we measured prestin quantities in the bloodstreams of mice using ELISA kits from different companies. Wildtype (WT) mice were exposed to different ototoxic treatments, including noise exposure and ototoxic reagents that rapidly kill OHCs. Prestin-knockout (KO) mice were used as a negative control. Our data show that some ELISA kits were not able to detect prestin specifically. The ELISA kit that could detect the prestin protein from cochlear homogenates failed to detect prestin in the bloodstream, despite there being significant damage to OHCs in the cochleae. Furthermore, the optical densities of the serum samples, which correlate to prestin quantities, were significantly influenced by hemolysis in the samples. In conclusion, Prestin from OHCs is not a sensitive and reliable serological biomarker for detecting cochlear damage in mice using ELISA. [ABSTRACT FROM AUTHOR]

There is a growing interest in the use of natural compounds to tackle inflammatory diseases and cancers. However, most of them face the bioavailability and solubility challenges to reaching cellular compartments and exert their potential biological effects. Polyphenols belong to that class of molecules, and numerous efforts have been made to improve and overcome these problems. Curcumin is widely studied for its antioxidant and anti-inflammatory properties as well as its use as an anticancer agent. However, its poor solubility and bioavailability are often a source of concern with disappointing or unexpected results in cellular models or in vivo, which limits the clinical use of curcumin as such. Beside nanoparticles and liposomes, cyclodextrins are one of the best candidates to improve the solubility of these molecules. We have used lysine and cyclodextrin to form a water-soluble curcumin complex, named NDS27, in which potential anti-inflammatory effects were demonstrated in cellular and in vivo models. Herein, we investigated for the first time its direct free radicals scavenging activity on DPPH/ABTS assays as well as on hydroxyl, superoxide anion, and peroxyl radical species. The ability of NDS27 to quench singlet oxygen, produced by rose bengal photosensitization, was studied, as was the inhibiting effect on the enzyme-catalyzed oxidation of the co-substrate, luminol analog (L012), using horseradish peroxidase (HRP)/hydrogen peroxide (H2O2) system. Finally, docking was performed to study the behavior of NDS27 in the active site of the peroxidase enzyme. [ABSTRACT FROM AUTHOR]

Background and Purpose: Apixaban (AP) is a factor X inhibitor, an orally active drug that inhibits blood coagulation for better prevention of venous thromboembolism. It has poor solubility, dissolution rate and low bioavailability. The aim of this study was to improve the aqueous solubility and dissolution rate of oral AP as a step to enhance its bioavailability by preparing it as an inclusion complex with beta- and hydroxy propyl beta-cyclodextrin. Experimental Approach: A simple, rapid method of analysis of AP was developed using ultraviolet spectrophotometry (UV) and partially validated in terms of linearity, precision and accuracy, recovery, and robustness. AP was prepared as a complex with beta cyclodextrin (βCD) and hydroxy propyl beta cyclodextrin (HPβCD) in weight ratios 1:1, 1:2, and 1:3 by kneading, solvent evaporation and spray drying methods and characterized by Fourier transfer infra-red (FTIR), differential scanning calorimetry (DSC), and percent drug content in each of the prepared complex. Using the computer simulation, the interactions of AP with βCD and HPβCD were investigated. Key Results: The phase solubility study showed that the solubility of AP was greatly enhanced from 54×10-3 mmol /L to 66 mmol/L using HPβCD with acceptable stability constant. Computer docking supports the formation of a stable 1:1 complex between AP and CD’s. The dissolution test results showed that the complex gave a significantly higher percentage of drug release (95%) over one hour compared to the free AP (60%) (p

Propofol is a widely used general anesthetic in clinical practice, but its use is limited by its water-insoluble nature and associated pharmacokinetic and pharmacodynamic limitations. Therefore, researchers have been searching for alternative formulations to lipid emulsion to address the remaining side effects. In this study, novel formulations for propofol and its sodium salt Na-propofolat were designed and tested using the amphiphilic cyclodextrin (CD) derivative hydroxypropyl-β-cyclodextrin (HPβCD). The study found that spectroscopic and calorimetric measurements suggested complex formation between propofol/Na-propofolate and HPβCD, which was confirmed by the absence of an evaporation peak and different glass transition temperatures. Moreover, the formulated compounds showed no cytotoxicity and genotoxicity compared to the reference. The molecular modeling simulations based on molecular docking predicted a higher affinity for propofol/HPβCD than for Na-propofolate/HPβCD, as the former complex was more stable. This finding was further confirmed by high-performance liquid chromatography. In conclusion, the CD-based formulations of propofol and its sodium salt may be a promising option and a plausible alternative to conventional lipid emulsions. [ABSTRACT FROM AUTHOR]

There is a growing interest in the use of natural compounds to tackle inflammatory diseases and cancers. However, most of them face the bioavailability and solubility challenges to reaching cellular compartments and exert their potential biological effects. Polyphenols belong to that class of molecules, and numerous efforts have been made to improve and overcome these problems. Curcumin is widely studied for its antioxidant and anti-inflammatory properties as well as its use as an anticancer agent. However, its poor solubility and bioavailability are often a source of concern with disappointing or unexpected results in cellular models or in vivo, which limits the clinical use of curcumin as such. Beside nanoparticles and liposomes, cyclodextrins are one of the best candidates to improve the solubility of these molecules. We have used lysine and cyclodextrin to form a water-soluble curcumin complex, named NDS27, in which potential anti-inflammatory effects were demonstrated in cellular and in vivo models. Herein, we investigated for the first time its direct free radicals scavenging activity on DPPH/ABTS assays as well as on hydroxyl, superoxide anion, and peroxyl radical species. The ability of NDS27 to quench singlet oxygen, produced by rose bengal photosensitization, was studied, as was the inhibiting effect on the enzyme-catalyzed oxidation of the co-substrate, luminol analog (L012), using horseradish peroxidase (HRP)/hydrogen peroxide (H2O2) system. Finally, docking was performed to study the behavior of NDS27 in the active site of the peroxidase enzyme.

Paclitaxel (PTX) is a hydrophobic chemotherapeutic agent cytotoxic against many serious cancers. This study aimed at designing novel PTX nanocrystals (PTX-NCs) coated with the biocompatible and biodegradable hydroxypropyl-beta-cyclodextrin (HPβCD) polymer with specific characteristics through the formation of a non-inclusion complex. Briefly, PTX-NCs were prepared by the anti-solvent method followed by homogenization. Then, the surface of the prepared PTX-NCs was modified using the HPβCD coat (HPβCD-PTX-NCs). The prepared nanocrystals, both coated and uncoated, were characterized in terms of size, polydispersity index, charge, morphology, and stability. Moreover, the nanocrystals were investigated using powder X-ray diffraction (PXRD), differential scanning calorimeter (DSC), and Fourier transform infrared spectroscopy (FTIR). As well, the in vitro release of PTX from the nanocrystals was determined under conditions similar to the IV route of administration. Furthermore, the tendency of the nanocrystals to induce hemolysis was investigated. Results indicated that the size was about 241.4 and 310.5 nm, the polydispersity index was 0.14 and 0.21, and the zeta potential was about − 22.6 and − 16.4 mV for PTX-NCs and HPβCD-PTX-NCs, respectively. Additionally, the PXRD, FTIR, and DSC profiles can be explained by the NCs’ integrity and coat formation. The SEM images showed that both PTX-NCs and HPβCD-PTX-NCs have rod-like structures. Moreover, HPβCD-PTX-NCs had significantly superior in vitro release than both PTX-NCs and PTX. Interestingly, the hemolytic assay showed that HPβCD-PTX-NCs had a more efficient and safer profile than PTX-NCs. This study emphasized that HPβCD could be an interesting candidate for the surface modification of PTX-NCs providing superior properties such as release and safety profiles. [ABSTRACT FROM AUTHOR]

Niemann–Pick disease type C1 (NPC1) is a neurodegenerative disorder characterized by lysosomal storage of free cholesterol. 2-Hydroxypropyl-β-cyclodextrin (HPβCD) is a cyclic oligosaccharide derivative that is being developed to treat NPC1. Recently, metformin was reported to be beneficial in various neurodegenerative diseases, such as Alzheimer’s and Huntington’s diseases. In this study, we examined the effects of combined treatment with HPβCD and metformin on Npc1−/− mice. Unfortunately, body weight and survival rates showed that cotreatment with metformin did not extend survival time and increase the body weight of HPβCD-treated Npc1−/− mice. However, cotreatment with metformin reduced inflammatory response and inhibited the proinflammatory cytokine release in the brain, liver and spleen of HPβCD-treated Npc1−/− mice. Furthermore, metformin did not reduce the free cholesterol levels in Npc1−/− brain tissue or fibroblasts. In conclusion, our results demonstrate that metformin does not show beneficial effects on body weight or survival time but reduced the inflammatory response in a mouse model of NPC1 when combined with HPβCD.

Niemann–Pick disease type C1 (NPC1) is a neurodegenerative disorder characterized by lysosomal storage of free cholesterol. 2-Hydroxypropyl-β-cyclodextrin (HPβCD) is a cyclic oligosaccharide derivative that is being developed to treat NPC1. Recently, metformin was reported to be beneficial in various neurodegenerative diseases, such as Alzheimer's and Huntington's diseases. In this study, we examined the effects of combined treatment with HPβCD and metformin on Npc1 −/− mice. Unfortunately, body weight and survival rates showed that cotreatment with metformin did not extend survival time and increase the body weight of HPβCD-treated Npc1 −/− mice. However, cotreatment with metformin reduced inflammatory response and inhibited the proinflammatory cytokine release in the brain, liver and spleen of HPβCD-treated Npc1 −/− mice. Furthermore, metformin did not reduce the free cholesterol levels in Npc1 −/− brain tissue or fibroblasts. In conclusion, our results demonstrate that metformin does not show beneficial effects on body weight or survival time but reduced the inflammatory response in a mouse model of NPC1 when combined with HPβCD. [ABSTRACT FROM AUTHOR]

Formulation development of KO-947-K mesylate injectable drug products was described. Solution formulations were initially attempted, and key parameters such as drug concentration, buffer, pH, complexing agent, and tonicity modifying agent were carefully evaluated in the lab setting, mainly focusing on solubility and chemical stability. A lead solution formulation was advanced to a scaleup campaign. An unexpected stability issue was encountered, and the root cause was attributed to the heterogeneous liquid freezing process of the formulated solution at −20°C, which had not been captured in the lab setting. A lyophilized product was then designed to overcome the issue and supplied to the phase I clinical trial. [ABSTRACT FROM AUTHOR]

Abstract Niemann-Pick Type C1 (NPC1) disease is a fatal neurovisceral disorder caused by dysfunction of NPC1 protein, which plays a role in intracellular cholesterol trafficking. The cholesterol-chelating agent, 2-hydroxypropyl-β-cyclodextrin (HPβCD), is currently undergoing clinical trials for treatment of this disease. Though promising in alleviating neurological symptoms, HPβCD causes irreversible hearing loss in NPC1 patients and outer hair cell (OHC) death in animal models. We recently found that HPβCD-induced OHC death can be significantly alleviated in a mouse model lacking prestin, an OHC-specific motor protein required for the high sensitivity and sharp frequency selectivity of mammalian hearing. Since cholesterol status is known to influence prestin’s electromotility, we examined how prestin contributes to HPβCD-induced OHC death in the disease context using the NPC1 knockout (KO) mouse model (NPC1-KO). We found normal expression and localization of prestin in NPC1-KO OHCs. Whole-cell patch-clamp recordings revealed a significant depolarization of the voltage-operating point of prestin in NPC1-KO mice, suggesting reduced levels of cholesterol in the lateral membrane of OHCs that lack NPC1. OHC loss and elevated thresholds were found for high frequency regions in NPC1-KO mice, whose OHCs retained their sensitivity to HPβCD. To investigate whether prestin’s electromotile function contributes to HPβCD-induced OHC death, the prestin inhibitor salicylate was co-administered with HPβCD to WT and NPC1-KO mice. Neither oral nor intraperitoneal administration of salicylate mitigated HPβCD-induced OHC loss. To further determine the contribution of prestin’s electromotile function, a mouse model expressing a virtually nonelectromotile prestin protein (499-prestin) was subjected to HPβCD treatment. 499-prestin knockin mice showed no resistance to HPβCD-induced OHC loss. As 499-prestin maintains its ability to bind cholesterol, our data imply that HPβCD-induced OHC death is ascribed to the structural role of prestin in maintaining the OHC’s lateral membrane, rather than its motor function.

Abstract Background Tay-Sachs disease (TSD) is a rare neurodegenerative disorder caused by autosomal recessive mutations in the HEXA gene on chromosome 15 that encodes β-hexosaminidase. Deficiency in HEXA results in accumulation of GM2 ganglioside, a glycosphingolipid, in lysosomes. Currently, there is no effective treatment for TSD. Results We generated induced pluripotent stem cells (iPSCs) from two TSD patient dermal fibroblast lines and further differentiated them into neural stem cells (NSCs). The TSD neural stem cells exhibited a disease phenotype of lysosomal lipid accumulation. The Tay-Sachs disease NSCs were then used to evaluate the therapeutic effects of enzyme replacement therapy (ERT) with recombinant human Hex A protein and two small molecular compounds: hydroxypropyl-β-cyclodextrin (HPβCD) and δ-tocopherol. Using this disease model, we observed reduction of lipid accumulation by employing enzyme replacement therapy as well as by the use of HPβCD and δ-tocopherol. Conclusion Our results demonstrate that the Tay-Sachs disease NSCs possess the characteristic phenotype to serve as a cell-based disease model for study of the disease pathogenesis and evaluation of drug efficacy. The enzyme replacement therapy with recombinant Hex A protein and two small molecules (cyclodextrin and tocopherol) significantly ameliorated lipid accumulation in the Tay-Sachs disease cell model.

Ashwaq Shakir AL-Abboodi,1,2 Abdullah Rasedee,3 Ahmad Bustamam Abdul,1,4 Yun Hin Taufiq-Yap,5 Wafaa Abd Alwahed Alkaby,6 Mostafa Saddam Ghaji,7 Peter M Waziri,1,8 Mothanna Sadiq Al-Qubaisi1 1MAKNA-UPM, Cancer Research Laboratory, Institute of Bioscience, University Putra Malaysia, Serdang, Malaysia; 2Basic Science Branch, Faculty of Dentistry, University of Al-Qadisiyah, Al Diwaniyah, Iraq; 3Department of Veterinary Laboratory Diagnosis, Faculty of Veterinary Medicine, University Putra Malaysia, Serdang, Malaysia; 4Department of Biomedical Science, Faculty of Medicine and Health Science, University Putra Malaysia, Serdang, Malaysia; 5Department of Chemistry, Faculty of Science, University Putra Malaysia, Serdang, Malaysia; 6Department of Biomedical, Faculty of Biotechnology, University of AL-Qadisiyah, Al Diwaniyah, Iraq; 7Department of Anatomy and Histology, Faculty of Veterinary Medicine, University of Basrah, Basrah, Iraq; 8Department of Biochemistry, Kaduna State University, Main Campus, Kaduna, Nigeria Introduction: Dentatin (DEN) (5-methoxy-2, 2-dimethyl-10-(1, 1-dimethyl-2propenyl) dipyran-2-one), a natural compound present in the roots of Clausena excavata Burm f, possesses pro-apoptotic and antiproliferative effects in various cancer cells. Because of its hydrophobicity, it is believed that its complexation with hydroxy-β-cyclodextrin (HPβCD) will make it a potent inhibitor of cancer cell growth. In the current work, the molecular mechanisms of apoptosis induced by DEN and DEN-HPβCD complex were demonstrated in human colon HT-29 cancer cells.Materials and methods: After the human colon HT-29 cancer cells were treated with DEN and DEN-HPβCD complex, their effects on the expression of apoptotic-regulated gene markers in mitochondria-mediated apoptotic and death receptor pathways were detected by Western blot analysis and reverse transcription polymerase chain reaction. These markers included caspases-9, 3, and 8, cytochrome c, poly (ADP-ribose) polymerase, p53, p21, cyclin A as well as the Bcl-2 family of proteins.Results: At 3, 6, 12, and 24 µg/mL exposure, DEN and DEN-HPβCD complex significantly affected apoptosis in HT-29 cells through the down-regulation of Bcl-2 and cyclin A in turn, and up-regulation of Bax, p53, p21, cytochrome c at both protein and mRNA levels. DEN and DEN-HPβCD complex also decreased cleaved poly (ADP-ribose) polymerase and induced caspases-3, -8, and -9.Conclusion: Results of this study indicate that the apoptotic pathway caused by DEN and DEN-HPβCD complex are mediated by the regulation of caspases and Bcl-2 families in human colon HT-29 cancer cells. The results also suggest that DEN-HPβCD complex may have chemotherapeutic benefits for colon cancer patients. Keywords: natural products, HPβCD, apoptosis, pro-apoptotic proteins, anti-apoptotic proteins

The great potential of hydroxypropyl beta-cyclodextrin (HPßCD), as a dried-protein stabilizer, has been attributed to various mechanisms namely water-replacement, vitrification and surfactant-like effects. Highlighting the best result in our previous study (weight ratio IgG: HPßCD of 1:0.4), herein we designed to evaluate the efficacy of upper (1:2) and lower (1:0.05) ratios of HPßCD in stabilization and aerosol properties of spray freeze-dried IgG. The protective effect of HPβCD, as measured by size exclusion chromatography (SEC-HPLC) was most pronounced at C3′ and C3″, IgG:trehalose:HPβCD ratios of 1:2:0.25 and 1:2:0.05 with aggregation rate constants of 0.46 ± 0.02 and 0.58 ± 0.01 (1/month), respectively. The secondary conformations were analyzed through Fourier transform infrared spectroscopy (FTIR) and all powders well-preserved with the lack of any visible fragments qualified through sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PPAGE). Scanning electron microscopy (SEM) and twin stage impinger (TSI) were employed to characterize the suitability of particles for further inhalation therapy of antibodies and the highest values of fine particle fraction (FPF) were achieved by C3′ and C3″, 56.43 and 48.12%. The powders produced at the current ratio 1:2:0.25 and 1:2:0.05 are superior to our previous examination with regards to manifesting lower aggregation and comparable FPF values. [ABSTRACT FROM AUTHOR]

Synthetic glucocorticoids such as budesonide (BUD) are potent anti-inflammatory drugs commonly used to treat patients suffering from chronic inflammatory diseases. A previous animal study reported a higher anti-inflammatory activity with a 2-hydroxypropyl-β-cyclodextrin (HPβCD)-based formulation of BUD (BUD:HPβCD). This study investigated, on cellular models (A549 and A-THP-1), the effect of BUD:HPβD in comparison with BUD and HPβCD on the effects induced by oxidative and inflammatory stress as well as the role of cholesterol. We demonstrated the protective effect afforded by BUD:HPβCD against cytotoxicity and ROS generation induced by oxidative and inflammatory stress. The effect observed for BUD:HPβCD was comparable to that observed with HPβCD with no major effect of cholesterol content. We also demonstrated (i) the involvement of the canonical molecular pathway including ROS generation, a decrease in PI3K/Akt activation, and decrease in phosphorylated/unphosphorylated HDAC2 in the effect induced by BUD:HPβCD, (ii) the maintenance of IL-8 decrease with BUD:HPβCD, and (iii) the absence of improvement in glucocorticoid insensitivity with BUD:HPβCD in comparison with BUD, in conditions where HDAC2 was inhibited. Resulting from HPβCD antioxidant and anticytotoxic potential and protective capacity against ROS-induced PI3K/Akt signaling and HDAC2 inhibition, BUD:HPβCD might be more beneficial than BUD alone in a context of concomitant oxidative and inflammatory stress.

The combined effect of hydroxypropyl-β-cyclodextrin (HPβCD) and polyvinylpyrrolidone (PVP) or sodium carboxymethylcellulose (CMC) on the solubility of pyrimethamine (PYR) was studied. Equimolar PYR-HPβCD solid systems, in the presence or the absence of 0.25% (w/v) PVP or 0.10% (w/v) CMC were prepared by coevaporation or freeze-drying, and characterized by differential scanning calorimetry, X-ray diffraction analysis and dissolution profile. Phase-solubility analysis was used to investigate the interactions in aqueous solution between PYR and HPβCD, in the absence or presence of polymers, which showed a linear increase of PYR solubility depending on the concentration of HPβCD. The presence of polymer did not alter the stoichiometry of the complexes. DSC results were indicative of complexation, due to the loss of the characteristic endothermic peak of PYR. X-ray diffraction analysis confirmed the DSC results. Binary and ternary complexes showed higher dissolution rate when compared with the pure drug.

Cardiovascular diseases, like atherosclerosis, and neurodegenerative diseases affecting the central nervous system (CNS) are closely linked to alterations of cholesterol metabolism. Therefore, innovative pharmacological approaches aiming at counteracting cholesterol imbalance display promising therapeutic potential. However, these approaches need to take into account the existence of biological barriers such as intestinal and blood-brain barriers which participate in the organ homeostasis and are major defense systems against xenobiotics. Interest in cyclodextrins (CDs) as medicinal agents has increased continuously based on their ability to actively extract lipids from cell membranes and to provide suitable carrier system for drug delivery. Many novel CD derivatives are constantly generated with the objective to improve CD bioavailability, biocompatibility and therapeutic outcomes. Newly designed drug formulation complexes incorporating CDs as drug carriers have demonstrated better efficiency in treating cardiovascular and neurodegenerative diseases. CD-based therapies as cholesterol-sequestrating agent have recently demonstrated promising advances with KLEPTOSE® CRYSMEB in atherosclerosis as well as with the 2-hydroxypropyl-β-cyclodextrin (HPβCD) in clinical trials for Niemann-Pick type C disease. Based on this success, many investigations evaluating the therapeutical beneficial of CDs in Alzheimer's, Parkinson's and Huntington's diseases are currently on-going. [ABSTRACT FROM AUTHOR]

The solid inclusion complex of gemifloxacin (GFX) and hydroxyl propyl β-cyclodextrin (HPβ-CD) was prepared and examined by UV–visible, FTIR, NMR, electrospray ionization mass spectrometry (ESI-MS) and fluorescence spectroscopy. The formation of inclusion complex has been confirmed on the basis of changes of spectroscopic properties. Further the interaction between GFX and HPβ-CD was studied using molecular modeling approaches. The results showed that HPβCD reacted with GFX to form a 1:1 host–guest inclusion complex. Based on the enhancement of the fluorescence intensity of GFX produced through complex formation, a simple, accurate, rapid and highly sensitive spectrofluorometric method for the determination of GFX in pharmaceutical formulation was developed. The linear relationships between the intensity and GFX concentration was obtained in the concentration range of 20–140 ng/mL with good correlation coefficients (0.9997). The limit of detection (LOD) was found to be 4 ng/mL. The proposed method was successfully applied to the analysis of GFX in pharmaceutical preparation. [ABSTRACT FROM AUTHOR]

Background: The lysosomal storage disorder, Niemann Pick type C1 (NPC1), presents a variable phenotype including neurovisceral and neurological symptoms. 2-Hydroxypropyl-ß-cyclodextrin (HPßCD)-based therapies are presently the most promising route of intervention. While severe cerebellar dysfunction remains the main disabling feature of NPC1, sensory functions including auditory and olfactory ones are also affected. Morphological and functional anomalies of Npc1 (-/-) mouse retina have also been observed, although the functional integrity of the visual pathway from retina to visual cortex is still unsettled. We have addressed this issue by characterizing the visual evoked potential (VEP) response of Npc1 (-/-) mice and determining if/how HPßCD administration influences the VEPs of both Npc1 (-/-) and Npc1 (+/+) mice.Methods: VEP elicited by a brief visual stimulus were recorded from the scalp overlying the visual cortex of adult (PN, postnatal days 60, 75, 85 and 100) Npc1 (+/+) and Npc1 (-/-) mice that had received repeated injections of either HPßCD or plain vehicle. The first injection was given at PN4 and was followed by a second one at PN7 and thereafter by weekly injections up to PN49. Cholesterol accumulation and myelin loss were finally assessed by filipin staining and myelin basic protein immunohistochemistry, respectively.Results and Discussion: We have found that the transmission of visual signals from retina to visual cortex is negatively influenced by the loss of Npc1 function. In fact, the VEP response of Npc1 (-/-) mice displayed a highly significant increase in the latency compared to that of Npc1 (+/+) mice. HPßCD administration fully rescued this defect and counteracted the cholesterol accumulation in retinal ganglion cells and dorsal lateral geniculate nucleus neurons, as well as the myelin loss in optic nerve fibers and axons projecting to the visual cortex observed in of Npc1 (-/-) mice. By contrast, HPßCD administration had no effect on the VEP response of Npc1 (+/+) mice, further strengthening the treatment efficacy.Conclusions: This study pinpoints the analysis of VEP response as a potentially accurate and non-invasive approach to assess neural activity and visual information processing in NPC1 patients, as well as for monitoring the progression of the disease and assessing the efficacy of potential therapies. [ABSTRACT FROM AUTHOR]

The study aimed to develop novel ITZ-loaded deformable liposomes (DL) in presence of hydroxypropyl-β-cyclodextrin (HPβCD) (DL-CD) to enhance antifungal activity. These formulations have been reported as conceivable vesicles to deliver drug molecules to the skin layers. The efficiency of the prepared systems was compared with conventional liposomes (CL) and ITZ solution. The developed liposomes were characterized for particle size, entrapment efficiency (EE %), deformability, stability, and morphology of the vesicles. In addition, ex vivo penetration and antifungal activity were evaluated. It was found that the presence of HPβCD played a significant role in reducing the vesicle size to nano range. The deformability study and TEM images revealed that membrane deformability of DL and DL–CD was much higher than that of CL. Moreover, DL–CD enhanced the amount of ITZ in SC and deeper skin layers compared to DL and CL. The antifungal activity of ITZ-loaded deformable liposomes remained intact compared to ITZ solution. It can be concluded that deformable liposomes in the presence of HPβCD may be a promising carrier for effective cutaneous delivery of ITZ. [ABSTRACT FROM AUTHOR]

The article presents a study on the fabrication and evaluation of clotrimazole-loaded nanofiber mats for oropharyngeal candidiasis (OPC). The researchers have investigated the properties of the electrospun nanofiber and the drug release antifungal characteristics in the CZ-loaded electrospun nanofiber mats. They find that electrospinning can be a viable solution for the production of nanofibers because of its easy control on the morphology of ultrafine fibers.

The objective of the present study was to formulate inclusion complex of saquinavir mesylate to improve the aqueous solubility and dissolution rate. Saquinavir mesylate is a BCS class II drug having low aqueous solubility and therefore low oral bioavailability. In the present study, inclusion complex of saquinavir mesylate with hydroxypropyl-β-cyclodextrin were prepared by kneading method. Inclusion complex were characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), H NMR studies, and Fourier transform infrared spectroscopy and evaluated for in vitro dissolution, and phase solubility studies. DSC and XRD study demonstrated that there was a significant decrease in crystallinity of pure drug present in inclusion complex, which resulted in an increased dissolution rate of saquinavir mesylate and H NMR studies strongly, confirmed that the inclusion complex has formed. Inclusion complexation results in improvement in solubility and dissolution rate. The inclusion complexation would be suitable method for dissolution and bioavailability enhancement of saquinavir mesylate. [ABSTRACT FROM AUTHOR]

The underprivileged pharmacodynamic action of curcumin, which arose from its low water solubility and rapid metabolism, restricts its therapeutic performance. In this study, (2-Hydroxy isopropyl)-β-cyclodextrin (HPβCD) as a macrocycle host molecule was employed to enhance the availability and control release of curcumin by forming a host-guest inclusion complex within an in-situ forming alginate hydrogel. The formation of the inclusion complexes of curcumin with a single host molecule was characterized by FTIR, XRD, TGA, SEM, and DLS analyses. The inclusion complex of curcumin and HPβCD (HPβCD-Cur) showed a high encapsulation efficiency of 88.2 %. According to DLS results, aqueous dispersion of HPβCD-Cur exhibited a unimodal histogram after 2 and 7 days with average particles size of 207.5 and 230.6 nm, respectively. This observation could be because of the formation of an inclusion complex that effectively distributed in solution and prevented curcumin agglomeration. The prepared alginate hydrogel containing HPβCD-Cur demonstrated >87 % reduction in colonies of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, which significantly is higher than that for Alg/Cur (<69 %). The Alg/HPβCD-Cur hydrogel exhibited a high water uptake of 470 % after 2 h, and a curcumin cumulative release of 80 % over 72 h, with proper cytocompatibility. Consequently, it was shown that the HPβCD carrier could act as an apt host molecule that can properly encapsulate curcumin and enhance its release from the Alg/HPβCD-Cur hydrogel., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: To gain mechanistic insights into drug loading and lyophilization of polymeric micelles. Methods: PEGylated poly-4-(vinylpyridine) micelles were loaded with dexamethasone. Three different methods were applied and compared: O/W emulsion, direct dialysis, cosolvent evaporation. Micellar dispersions with the highest drug load were lyophilized with varying lyoprotectors: sucrose, trehalose, maltose, a polyvinylpyrrolidine derivative, and β-cyclodextrin derivatives. For comparison, other PEGylated block copolymer micelles (PEGylated polylactic acid, polylactic acid-co-glycolic acid, polycaprolactone) were freeze-dried. Results: Drug loading via direct dialysis from acetone was a less effective loading method which led to dexamethasone loads <2% w/w. O/W emulsion technique from dichlormethane increased drug load up to ~13% w/w; optimized cosolvent evaporation increased load up to ~19% w/w. An important step for cosolvent evaporation was solubility screen of the drug prior to preparation. Loading was maintained upon lyophilization with β-cyclodextrins which proved to be versatile stabilizers for other block copolymer micelles. Conclusion: Careful solvent selection prior to cosolvent evaporation was a beneficial approach to load hydrophobic drugs into polymeric micelles. Moreover, β-cyclodextrins could be used as versatile lyoprotectors for these micelles. [ABSTRACT FROM AUTHOR]

Glyburide, a sulfonylurea derivative, widely used as hypoglycaemic agent. In the present study, an attempt has been made to investigate the most effective third component which can be used with hydroxylpropyl-β-cyclodextrin (HPβCd) to form a ternary complex with glyburide in order to enhance its dissolution rate, as well as reduce the amount of HPβCd used for formulating the binary complex with glyburide. Moreover, the objective of this study was also to develop a discriminatory dissolution media in order to discriminate the effect of the different solubilizing agents used for formulating the ternary complex system. Sodium lauryl sulphate, Poloxamer-188, Polyvinylpyrrolidone K-30, lactose and l-arginine were used to formulate ternary system along with HPβCd and glyburide. The ternary system formulated with glyburide:HPβCd: l-arginine in a proportion of 1:1:0.5 has shown the fastest dissolution rate when compared to other solubilizing agents. Unbuffered aqueous media with stirring speed 50 rpm has produced the most discriminatory dissolution profiles. The DSC thermograms and the powder X-ray analysis revealed the decrease in crystallinity of the drug. This was an indication of amorphous solid dispersion or molecular encapsulation of the drug into the cyclodextrin cavity. [ABSTRACT FROM AUTHOR]

Purpose: An efficient method was developed for treating polychlorinated biphenyl (PCB)-contaminated soil by soil washing and subsequent TiO photocatalytic degradation, and the photocatalytic degradation mechanism of PCBs was explored. Materials and methods: Hydroxypropyl-β-cyclodextrin (HPΒCD) and polyoxyethylene lauryl ether (Brij35) were used to extract PCBs from contaminated soil at first, and then the degradation of PCBs in the soil extracts was performed by TiO photocatalysis under UV irradiation. Results and discussion: Washing conditions including washing time, the concentration of HPΒCD/Brij35, and the ratio of soil mass to solution volume for extracting 2,4,4′-trichlorobiphenyl (PCB28) from a PCB28-spiked soil were investigated at first. The results indicated that both HPΒCD and Brij35 exhibited good performance. The intermediates of photocatalytic degradation of PCB28 were from its dechlorination and hydroxylation in the HPCD and aqueous solutions, respectively. A field PCB-contaminated soil from e-waste recycling sites was treated by this method. The results showed that the extracting percentage was significantly affected by the chlorination degree of PCBs, and HPΒCD slowed down the photocatalytic degradation efficiency of overall PCBs. Conclusions: Soil washing and subsequent TiO photocatalytic degradation was successfully applied for treating PCB-contaminated soil, and HPΒCD strongly altered the pathways of the photocatalytic degradation of PCBs. [ABSTRACT FROM AUTHOR]

To improve poor water solubility of cyclosporine A (CsA), hydroxypropyl-beta-cyclodextrin (HPβCD) was incorporated into the nanoparticle formulation. Solid complexes of CsA with HPβCD in different ratios were prepared by the kneading method. CsA containing alone or in combination with HPβCD in poly-lactide-co-glycolide (P-CsA or P-CsA-HPβCD) nanoparticles were prepared by the emulsification solvent evaporation method. The mean size of CsA-loaded NPs was found to be approximately 220 nm. The solubility of CsA was significantly improved and the phase solubility diagram of CsA-HPβCD systems showed an AL type phase. Nanoparticles showed high CsA encapsulation efficiency (88%) and production yield (89%). Release rate was increased by the presence of HPβCD and total cumulative release ranged from 75% to 96% in 24 h. In vitro cytotoxicity study assay resulted in a low toxicity for all types of nanoparticles. After 6 h incubation period, the cellular uptake was found at 33% and 32% for P-CsA and P-HPβCD-CsA nanoparticles, respectively. [ABSTRACT FROM AUTHOR]

Abstract: Recently it has been shown that aggregation of drug/cyclodextrin inclusion complexes is strongly influenced by the drug molecule in addition to self-assembling tendencies of the cyclodextrin itself in aqueous media. Whereas the mechanistic basis of cyclodextrin self-assembly is known, the driving forces for complex aggregation are still unknown. In the present study, the influence of temperature on hydrocortisone/2-hydroxypropyl-β-cyclodextrin complex aggregation is investigated as are influences associated with the addition of ethanol or water soluble polymers to the aqueous systems. Furthermore the effect of stirring on the aggregation is assessed. Size exclusion permeability studies were conducted to estimate complex aggregation tendencies. The results indicate that self-assembled complex aggregates are metastable and notably become smaller with increasing temperature and the addition of ethanol. Water soluble polymers also reduce the size of the complex aggregates. Specifically, hexadimethrine bromide had the greatest impact, since addition of this compound eliminated aggregates from the systems or reduced their size below the molecular weight cut-off of the sizing membrane (8kDa). Similar observations are made when aqueous solutions of hydrocortisone and 2-hydroxypropyl-β-cyclodextrin are equilibrated by stirred. [Copyright &y& Elsevier]

Abstract: Aggregation is arguably the biggest challenge for the development of stable formulations and robust manufacturing processes of therapeutic proteins. In search of novel excipients inhibiting protein aggregation, cyclodextrins and their derivatives have been under examination for use in parenteral protein products since more than 20years and significant research work has been accomplished highlighting the great potential of cyclodextrins as stabilizers of therapeutic proteins. Oftentimes, the potential of cyclodextrins to inhibit protein aggregation has been attributed to their capability to incorporate hydrophobic residues on aggregation-prone proteins or on their partially unfolded intermediates into the hydrophobic cavity. In addition, also other mechanisms besides or even instead of complex formation play a role in the stabilization mechanism, e.g. non-ionic surfactant-like effects. In this review a comprehensive overview of the available research work on the beneficial use of cyclodextrins and their derivatives in protein formulations, liquid as well as dried, is provided. The mechanisms of stabilization against different kinds of stress conditions, such as thermal or surface-induced, are discussed in detail. [Copyright &y& Elsevier]

Abstract: We recently reported a novel curcuminoid 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] or CLEFMA as a potent anti-proliferative agent, and showed that it induces autophagic cell death in lung cancer cells. We are now reporting a drug-in-CD-in-liposome approach to formulate CLEFMA liposomes that could be labeled with Tc-99m radionuclide for non-invasive imaging of their biodistribution. CLEFMA encapsulation was enabled by hydroxypropyl-β-cyclodextrin. In vitro studies showed that CLEFMA possessed more potent anti-proliferative activity in lung adenocarcinoma H441 cells than naturally occurring curcumin. At the same time, it had no effect on the proliferative capacity of normal lung fibroblasts. CLEFMA liposomes retained the antiproliferative potency of free CLEFMA, while maintaining its non-toxic nature in normal lung fibroblasts. In nude rats bearing xenograft H441 tumors, the tumor volume significantly reduced after i.v. treatment with CLEFMA liposomes (p <0.05); the tumor inhibition was determined to be 94%. The anti-tumor activity of CLEFMA liposomes was confirmed by the observation that F-18-fluorodeoxyglucose uptake in tumors of treated rats was reduced as compared to those of control rats. Tc-99m-labeled CLEFMA liposomes accumulated in liver (33.7%); spleen showed the largest accumulation on per gram tissue basis (6.2%/g). Upon histopathological examination of liver, lung and kidney, we found no apparent toxicity from multiple CLEFMA liposome administrations. The results demonstrate the utility of liposomes to serve as a carrier for CLEFMA. This study is the first to demonstrate the efficacy of novel curcuminoid CLEFMA in a preclinical model. [Copyright &y& Elsevier]

Abstract: The principle action by which cyclodextrins solubilize compounds is via inclusion complex formation. However, data suggest that cyclodextrins and their complexes also aggregate in solution and this aggregation contributes to their ability to solubilize poorly water-soluble materials. The current effort aims at better understanding the role of guest molecule nature (i.e. its structural and functional peculiarities) in cyclodextrin complex aggregation as well as in the aggregate stability assessed using a cellophane membrane permeability assay. A test set of 11 acidic, basic and neutral drugs and antibacterial agents (i.e. guests) were examined with regard to their interaction with hydroxypropyl-β-cyclodextrin (HPβCD) and the resulting ability of the formed aggregates to move through a semi-permeable membrane of various molecular weight cut-off values. The data suggested that the interaction of HPβCD with certain guests resulted in the formation of structure large enough to poorly penetrate semi-permeable membrane. The aggregates appeared to be highly dynamic in that there were no qualitative differences between systems that were diluted immediately prior to permeation experiments and those allowed to equilibrate. Pharmaceutical polymers which have been shown to enhance solubilizing efficiency of cyclodextrins had little or no effect on the stability of the aggregates using the permeability paradigm as an endpoint with the exception of carboxymethylcellulose. [Copyright &y& Elsevier]

Abstract: The purpose of this work is to study the molecular association that occurs between 2-hydroxypropyl-β-cyclodextrin (HPβCD) and 6-chloro-5-(1-naphthyloxy)-2-(trifluoromethyl)-1H-benzimidazole (RCB20), an antiparasitic compound recently found by our research group, with poor aqueous solubility. The complex stability constant and stoichiometric ratio determined by phase-solubility diagram and Job’s plot provided evidence that HPβCD enhanced water solubility of RCB20 through inclusion complex formation. Two-dimensional 1H NMR spectroscopy is used to study the molecular arrangement of inclusion complex in solution. These results are further supported using molecular modeling studies. In the solid state, the complexation is confirmed by differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy. Finally, RCB20/HPβCD complex has better activity than RCB20 against the adult and muscle larvae phase of Trichinella spiralis. [ABSTRACT FROM AUTHOR]

This study was conducted to assess the safety and tolerability of the alternative formulation vehicles polysorbate 80 (PS80), propylene glycol (PG), and hydroxypropyl-beta-cyclodextrin (HPβCD) in general toxicology studies in the mouse, rat, dog, and monkey. Twenty (20) mg/kg of hydroxypropyl methylcellulose (MC, control), 10 mg/kg PS80, 1000 mg/kg PG, 500 mg/kg HPβCD, or 1000 mg/kg HPβCD were administered by oral gavage to mice, rats, dogs, and cynomolgus monkeys for approximately 90 days. The effects of these formulations on clinical observations, body weight and food consumption parameters, clinical pathology, and histopathology were evaluated across all species. The suitability of formulations containing up to 20 mg/kg MC, 10 mg/kg PS80, and 1000 mg/kg PG for use in preclinical safety studies was confirmed by a lack of effects on all parameters examined. However, formulations containing HPβCD produced elevated transaminase (aspartate and alanine aminotransferase) levels in rats and mice and fecal changes (loose and soft stool) in large animals. Although the etiology and toxicological significance of the transaminase elevations in rats and mice is uncertain, this finding could represent a significant liability for a preclinical formulation because of the critical importance of these biomarkers in the risk assessment of novel therapeutic agents. Based on these data, PS80 and PG are considered to be practical alternatives to MC in preclinical toxicology studies. However, formulations containing HPβCD should be used with caution because of the elevations in rodent transaminase levels. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to determine whether inclusion complexes between 2-hydroxypropyl-β-cyclodextrin (HPβCD) and finasteride (FIN) are formed, and to characterize these. Equimolar FIN/HPβCD solid systems in the presence or absence of 0.1% (w/v) of polyvinylpyrrolidone K30 (PVP K30) or 0.3% of chitosan were prepared by coevaporation and freeze-drying methods. The systems were characterized by phase solubility, NMR, DSC, and XRD analysis. The results suggest that true binary and ternary inclusion complexes were formed. [Copyright &y& Elsevier]

The effect of polyvinyl pyrrolidone (PVP) K30 and/or l-arginine on etoricoxib-HPβCD complex was investigated. The phase solubility profiles were classified as AL-type, both in absence or presence of auxiliary substances used. The apparent stability constant (Kc) of binary complex obtained at room temperature, 371.80 ± 2.61 M-1, was decreased with the addition of PVP and arginine indicating no benefit of addition of auxiliary substances to promote higher complexation efficiency. Therefore, solid etoricoxib-HPβCD binary systems were prepared and characterized by proton nuclear magnetic resonance spectroscopy (1HNMR), X-ray powder diffractometry, Fourier transformation-infrared spectroscopy, and dissolution studies. Among all binary systems, a lyophilized product showed superior performance in enhancing dissolution of etoricoxib. [ABSTRACT FROM AUTHOR]

Dihydroartemisinin (DHA) is a major metabolite of artemisinin and its derivatives, including arteether, artemether, and artesunate. To improve the solubility and stability of poorly soluble DHA, we prepared inclusion complexes with hydroxypropyl-β-cyclodextrin (HPβCD) and recrystalized DHA to study its thermal stability. The complexes were characterized by differential scanning calorimetery (DSC), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction patterns (XRD), thermal stability, phase, and equilibrium solubility studies. Pure DHA was crystalline and remained crystalline after recrystallization, but its unit cell dimensions changed as exhibited by XRD. DHA-HPβCD complexes showed a phase transitions towards amorphous in DSC thermograms, FTIR spectra, and XRD patterns. The phase solubility profiles of complexes prepared in water, acetate buffer, and phosphate buffers were classified as AL-type, indicating the formation of a 1:1 stoichiometric inclusion complex. The equilibrium solubility of DHA was enhanced as a function of HPβCD concentration. DHA-HPβCD complexes showed an 89-fold increase in solubility compared to DHA. Solubilities of complexes containing 275.1 mM HPβCD in water, acetate buffer (pH 3.0), and phosphate buffer (pH 3.0 and 7.4) were 10.04, 7.96, 6.30, and 11.61 mg/ml, respectively. Hydrogen bonding was found between DHA and HPβCD, and it was stronger in complexes prepared in water than in buffers. However, the ÄH values were higher in buffer than water. DHA-HPβCD complexes prepared using commercial (untreated) or recrystallized DHA (no detectable impurity) showed a 40% increase in thermal stability (50°C) and a 29-fold decrease in hydrolysis rates compared with DHA. The rank order of stability constants (Ks) was: water, acetate buffer (pH 3.0), phosphate buffer (pH 3.0), and phosphate buffer (pH 7.4). Thus, HPβCD complexation with recrystalized DHA increases DHA solubility and stability. [ABSTRACT FROM AUTHOR]

For CD-based formulations, it is important to directly monitor the complexation status of the drug present in final dosage form pharmaceuticals. In this work, Raman spectroscopy was explored for the detection and identification of the Nimodipine/hydroxypropyl-β-cyclodextrin (NMD/HPβCD) complexation present in the tablet. The evident, consistent Raman spectral changes in the shift, height ratio and area ratio for the characteristic bands of NMD molecule were featured in the NMD/HPβCD complex, and employed to distinguish between complexed and uncomplexed NMD in tablets. A number of practical issues for the Raman measurements performed on the tablets were considered and addressed. The Raman approach and dissolution test were applied to different tablets prepared experimentally at variable granulations. The results demonstrated that the Raman approach can serve as a promising methodology for tablet identification on the complexation. Wet granulation facilitated the process-induced transformations in the complexation. The adequate ethanol in the granulating fluid appeared optimized for the complexation of the two components. The spectral characteristics for dissociation in the tablets were in full accordance with the observations of their diminished initial dissolution parameters. It implied the possibility that the tablet dissolution can be predicted from the Raman interpretation. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:2702–2719, 2008 [ABSTRACT FROM AUTHOR]

The objective of this study was to improve the dissolution and solubility of dexibuprofen (DEX) using hydroxypropyl beta cyclodextrin (HPβCD) inclusion complexes and also to evaluate the effect of presence of hydrophilic polymers on solubilization efficiency of HPβCD. Three different methods (physical trituration, kneading and solvent evaporation) were used to prepare binary inclusion complexes at various drug-to-cyclodextrin weight ratios. An increase in solubility and drug release was observed with the kneading (KN) method at a DEX/HPβCD (1:4) weight ratio. The addition of hydrophilic polymers poloxamer-188 (PXM-188) and poloxamer-407 (PXM-407) at 2.5, 5.0, 10.0 and 20% w/w enhanced the complexation efficiency and solubility of DEX/HPβCD significantly. Fourier-transform infrared (FTIR) analysis revealed that DEX was successfully incorporated into the cyclodextrin cavity. Differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) revealed less crystallinity of the drug and its entrapment in the cyclodextrin molecular cage. The addition of PXM-188 or PXM-407 reduced the strength of the DEX endothermic peak. With the addition of hydrophilic polymers, sharp and intense peaks of DEX disappeared. Finally, it was concluded that PXM-188 at a weight ratio of 10.0% w/w was the best candidate for improving solubility, stability and release rate of DEX. [ABSTRACT FROM AUTHOR]

• An integrated approach of nanobubbles and HP β CD was developed to enhance ozonation. • The mass transfer coefficient of O 3 was 4.7 times higher than conventional approach. • Small amount of HP β CD addition prolonged 18 times longer lifespan of dissolved O 3. • Mechanisms of inclusion were studied by direct detection and molecular simulation. • This innovative method led to 7 times higher removal of the model micropollutant. Ozone (O 3) has been widely used for the elimination of recalcitrant micropollutants in aqueous environments, due to its strong oxidation ability. However, the utilization efficiency of O 3 is constrained by its low solubility and short half-life during the treatment process. Herein, an integrated approach, using nanobubble technology and micro-environmental chemistry within cyclodextrin inclusion cavities, was studied in order to enhance the reactivity of ozonisation. Compared with traditional macrobubble aeration with O 3 in water, nanobubble aeration achieved 1.7 times higher solubility of O 3, and increased the mass transfer coefficient 4.7 times. Moreover, the addition of hydroxypropyl- β -cyclodextrin (HP β CD) further increased the stability of O 3 through formation of an inclusion complex in its molecule-specific cavity. At a HPβCD:O 3 molar ratio of 10:1, the lifespan of O 3 reached 18 times longer than in a HP β CD-free O 3 solution. Such approach accelerated the removal efficiency of the model micropollutant, 4-chlorophenol by 6.9 times, compared with conventional macrobubble ozonation. Examination of the HP β CD inclusion complex by UV–visible spectroscopy and Nuclear Magnetic Resonance analyses revealed that both O 3 and 4-chlorophenol entered the HP β CD cavity, and Benesi-Hildebrand plots indicated a 1:1 stoichiometry of the host and guest compounds. Additionally, molecular docking simulations were conducted in order to confirm the formation of a ternary complex of HP β CD:4-chlorophenol:O 3 and to determine the optimal inclusion mode. With these results, our study highlights the viability of the proposed integrated approach to enhance the ozonation of organic micropollutants. [Display omitted] [ABSTRACT FROM AUTHOR]

Synthetic glucocorticoids such as budesonide (BUD) are potent anti-inflammatory drugs commonly used to treat patients suffering from chronic inflammatory diseases. A previous animal study reported a higher anti-inflammatory activity with a 2-hydroxypropyl-β-cyclodextrin (HPβCD)-based formulation of BUD (BUD:HPβCD). This study investigated, on cellular models (A549 and A-THP-1), the effect of BUD:HPβD in comparison with BUD and HPβCD on the effects induced by oxidative and inflammatory stress as well as the role of cholesterol. We demonstrated the protective effect afforded by BUD:HPβCD against cytotoxicity and ROS generation induced by oxidative and inflammatory stress. The effect observed for BUD:HPβCD was comparable to that observed with HPβCD with no major effect of cholesterol content. We also demonstrated (i) the involvement of the canonical molecular pathway including ROS generation, a decrease in PI3K/Akt activation, and decrease in phosphorylated/unphosphorylated HDAC2 in the effect induced by BUD:HPβCD, (ii) the maintenance of IL-8 decrease with BUD:HPβCD, and (iii) the absence of improvement in glucocorticoid insensitivity with BUD:HPβCD in comparison with BUD, in conditions where HDAC2 was inhibited. Resulting from HPβCD antioxidant and anticytotoxic potential and protective capacity against ROS-induced PI3K/Akt signaling and HDAC2 inhibition, BUD:HPβCD might be more beneficial than BUD alone in a context of concomitant oxidative and inflammatory stress. [ABSTRACT FROM AUTHOR]

Background: Acute Kidney Injury (AKI), a common disease of the urinary system, can be induced by high doses of gentamicin (GM). The renin-angiotensin system exerts a key role in the progression of the AKI since elevated intrarenal levels of Ang II, and ACE activity is found in this condition. However, it is unknown whether oral administration of angiotensin (Ang)-(1-7), a heptapeptide that evokes opposite effects of Ang II, may attenuate the renal injuries induced by gentamicin., Objectives: To evaluate the effects of Ang-(1-7) on GM-induced renal dysfunction in rats., Methods: AKI was induced by subcutaneous administration of GM (80 mg/Kg) for 5 days. Simultaneously, Ang-(1-7) included in hydroxypropyl β-cyclodextrin (HPβCD) was administered by gavage [46 μg/kg HPβCD + 30 μg/kg Ang-(1-7)]. At the end of the treatment period (sixth day), the rats were housed in metabolic cages for renal function evaluation. Thereafter, blood and kidney samples were collected., Results: Ang-(1-7) attenuated the increase of the plasmatic creatinine and proteinuria caused by GM but did not change the glomerular filtration rate nor tubular necrosis. Ang-(1-7) attenuated the increased urinary flow and the fractional excretion of H2O and potassium observed in GM rats but intensified the elevated excretion of sodium in these animals. Morphological analysis showed that Ang-(1-7) also reduced the tubular vacuolization in kidneys from GM rats., Conclusion: Ang-(1-7) promotes selective beneficial effects in renal injuries induced by GM., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)