Sugammadex and oral contraceptives.

PURPOSE OF REVIEW: This review article explores the evidence regarding sugammadex (MSD Australia) and its potential interaction with hormonal contraceptives. The impact of recent clinical trials and review articles is examined. RECENT FINDINGS: Recent clinical data suggest that the interaction between sugammadex and estrogen and progesterone concentrations may not be clinically significant and may confer some protection against ovulation. There are no clinical trials reporting interactions between sugammadex and the exogenous hormonal compounds found in oral contraceptive pills. The method of contraception is an important consideration, as sugammadex theoretically affects oral and nonoral, and combined versus single agent methods differently. Two large retrospective database studies have reported two cases of pregnancy postoperatively in patients on hormonal contraceptives whose anesthetic included sugammadex. SUMMARY: Strong clinical evidence to support or refute claims of a significant impact of sugammadex on contraceptive efficacy in women on contraception is lacking. The existing evidence does not suggest a basis for concern regarding the impact of sugammadex on contraception in the perioperative setting.

Intracerebroventricular 2-hydroxypropyl-γ-cyclodextrin alleviates hepatic manifestations without distributing to the liver in a murine model of Niemann-Pick disease type C.

Niemann-Pick disease type C (NPC) is a lysosomal lipid storage disorder characterized by progressive neurodegeneration and hepatic dysfunction. A cyclic heptasaccharide, 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD), is currently under clinical investigation for NPC, but its adverse events remain problematic. We previously identified that a cyclic octasaccharide, 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), also ameliorated NPC manifestations with higher biocompatibility than HP-ß-CD. However, preclinical studies describing the associations between the biodistribution and pharmacodynamics of these compounds, which are essential for clinical application, are still lacking. Here, we investigated these properties of HP-γ-CD by measuring its organ biodistribution and therapeutic effect after systemic and central administration. The effect of HP-γ-CD on disturbed cholesterol homeostasis appeared within several hours after exposure and persisted for several days in NPC model cells and mice. Tissue distribution indicated that only a small fraction of subcutaneously administered HP-γ-CD rapidly distributed to peripheral organs and contributed to disease amelioration. We found that a subcutaneous dose of HP-γ-CD negligibly ameliorated neurological characteristics because it has limited penetration of the blood-brain barrier; however, an intracerebroventricular microdose unexpectedly attenuated hepatic dysfunction without the detection of HP-γ-CD in the liver. These results demonstrate that central administration of HP-γ-CD can indirectly attenuate peripheral manifestations of NPC.

γ-Cyclodextrin hydrogel for the sustained release of josamycin for potential ocular application.

Glaucoma is the leading cause of blindness worldwide. However, its surgical treatment, in particular via trabeculectomy, can be complicated by fibrosis. In current clinical practice, application of the drug, Mitomycin C, prevents or delays fibrosis, but can lead to additional side effects, such as bleb leakage and hypotony. Previous in silico drug screening and in vitro testing has identified the known antibiotic, josamycin, as a possible alternative antifibrotic medication with potentially fewer side effects. However, a suitable ocular delivery mechanism for the hydrophobic drug to the surgical site does not yet exist. Therefore, the focus of this paper is the development of an implantable drug delivery system for sustained delivery of josamycin after glaucoma surgery based on crosslinked γ-cyclodextrin. γ-Cyclodextrin is a commonly used solubilizer which was shown to complex with josamycin, drastically increasing the drug's solubility in aqueous solutions. A simple γ-cyclodextrin crosslinking method produced biocompatible hydrogels well-suited for implantation. The crosslinked γ - cyclodextrin retained the ability to form complexes with josamycin, resulting in a 4-fold higher drug loading efficiency when compared to linear dextran hydrogels, and prolonged drug release over 4 days.

Direct electrospinning for producing multiple activity nanofibers consisting of aggregated luteolin/hydroxypropyl-gamma-cyclodextrin inclusion complex.

Hydroxypropyl-gamma-cyclodextrin (HPγCD) inclusion complex nanofibers (Lut/HPγCD-IC-NF) containing Luteolin (Lut) were prepared by electrospinning technology. Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD) spectra confirmed the formation of Lut/HPγCD-IC-NF. Scanning electron microscopy (SEM) images showed that the morphology of Lut/HPγCD-IC-NF was uniform and bead-free, suggesting that self-assembled aggregates, macromolecules with higher molecular weights, were formed by strong hydrogen bonding interactions between the cyclodextrin inclusion complexes. Confocal laser scanning microscopy (CLSM) images showed that Lut was distributed in Lut/HPγCD-IC-NF. Proton nuclear magnetic resonance (1H NMR) spectroscopy revealed the change in chemical shift of the proton peak between Lut and HPγCD, confirming the formation of inclusion complex. Thermogravimetric analysis (TGA) proved that Lut/HPγCD-IC-NF had good thermal stability. The phase solubility test confirmed that HPγCD had a solubilizing effect on Lut. When the solubility of HPγCD reached 10 mM, the solubility of Lut increased by 15-fold. The drug loading test showed that the content of Lut in fibers reached 8.57 ± 0.02 %. The rapid dissolution experiment showed that Lut/HPγCD-IC-NF dissolved within 3 s. The molecular simulation provides three-dimensional evidence for the formation of inclusion complexes between Lut and HPγCD. Antibacterial experiments showed that Lut/HPγCD-IC-NF had enhanced antibacterial activity against S. aureus. Lut/HPγCD-IC-NF exhibited excellent antioxidant properties with a free radical scavenging ability of 89.5 ± 1.1 %. In vitro release experiments showed Lut/HPγCD-IC-NF had a higher release amount of Lut. In conclusion, Lut/HPγCD-IC-NF improved the physicochemical properties and bioavailability of Lut, providing potential applications of Lut in the pharmaceutical field.

CD-MOF-1 Growth on Polysaccharide Gels through Only C2-OH/C3-OH or C5-O/C6-OH Group Formed Four-Coordinated K+ Ions for Developing Porous Biogels.

The γ-cyclodextrin (γ-CD) metal-organic frameworks (CD-MOF-1) consist of γ-CD and potassium (K+) ions through coordinating an eight-coordinated K+ ion with two C5-linked oxygen and C6-linked hydroxyl (C5-O/C6-OH) groups in the primary faces of adjacent γ-CD units and two C2- and C3-linked hydroxyl (C2-OH/C3-OH) groups in the secondary faces. Herein, we found polysaccharide gels with only C2-OH/C3-OH or C5-O/C6-OH groups in pyranoid rings can form four-coordinated K+ ions and then coordinate γ-CD in a KOH solution for CD-MOF-1 growth. Exposure of C2-OH/C3-OH or C5-O/C6-OH groups in polysaccharide gels is important to form active four-coordinated K+ ions. Mechanism supporting this work is that four-coordinated K+ ion sites are first formed after coordinating C2-OH/C3-OH groups in pectin and then coordinating C5-O/C6-OH groups in the primary faces of γ-CD units. Alternatively, four-coordinated K+ ions with C5-O/C6-OH groups in chitosan can coordinate the C2-OH/C3-OH groups in the secondary faces of γ-CD units. Mechanism of CD-MOF-1 growing on pectin and chitosan gels through the proposed four-coordinated K+ ions is also universally applicable to other polysaccharide gels with similar C2-OH/C3-OH or C5-O/C6-OH groups such as alginate gel. Based on this mechanism, we developed pectin and chitosan gel-based CD-MOF-1 composites and exemplified applications of them in antibacterial and organic dye removal. To help future research and applications of this mechanism, we share our theoretical assumption for further investigations that any matrices with an ortho-hydroxyl carbon chain or ortho-hydroxyl ether structures may form four-coordinated K+ ions for CD-MOF-1 growth. The proposed mechanism will broaden the development of novel CD-MOF-1 composites in various fields.

Enhanced Stability and Solidification of Volatile Eugenol by Cyclodextrin-Metal Organic Framework for Nasal Powder Delivery.

Eugenol (Eug) holds potential as a treatment for bacterial rhinosinusitis by nasal powder drug delivery. To stabilization and solidification of volatile Eug, herein, nasal inhalable γ-cyclodextrin metal-organic framework (γ-CD-MOF) was investigated as a carrier by gas-solid adsorption method. The results showed that the particle size of Eug loaded by γ-CD-MOF (Eug@γ-CD-MOF) distributed in the range of 10-150 µm well. In comparison to γ-CD and ß-CD-MOF, γ-CD-MOF has higher thermal stability to Eug. And the intermolecular interactions between Eug and the carriers were verified by characterizations and molecular docking. Based on the bionic human nasal cavity model, Eug@γ-CD-MOF had a high deposition distribution (90.07 ± 1.58%). Compared with free Eug, the retention time Eug@γ-CD-MOF in the nasal cavity was prolonged from 5 min to 60 min. In addition, the cell viability showed that Eug@γ-CD-MOF (Eug content range 3.125-200 µg/mL) was non-cytotoxic. And the encapsulation of γ-CD-MOF could not reduce the bacteriostatic effect of Eug. Therefore, the biocompatible γ-CD-MOF could be a potential and valuable carrier for nasal drug delivery to realize solidification and nasal therapeutic effects of volatile oils.

Oral Synergism of Egg-White-Derived Peptides (EWDP) and Curcumin for Colitis Mitigation via Polysaccharide/Cyclodextrin Metal-Organic Framework-Based Assemblies.

Recently, oral deliverable strategies of multiple nutraceuticals for ulcerative colitis (UC) mitigation have attracted increasing attention. This study aimed to fabricate facile oral assemblies loaded with egg-white-derived peptides (EWDP) and curcumin based on carboxymethyl chitosan (CMCS) and an γ-cyclodextrin metal-organic framework (MOF). Herein, outer CMCS could coassemble with EWDP (both nutraceuticals and building blocks) into cobweb-like fibrils to promote bridging with inner MOF via coordinative noncovalent interactions (hydrogen bonding, hydrophobic interaction, and electrostatic interaction). Compared with conventional γ-cyclodextrin/MOF-based composites, the above coassembly could also endow the biocompatible assemblies with superior nanoscale colloidal properties, processing applicability (curcumin storage stability, bioaccessibility, and aqueous solubility), and bioactivity. Moreover, the oral synergism of EWDP and curcumin (initially nonsynergistic) for UC mitigation was achieved by alleviating inflammatory damage and gut microbiota imbalance. Overall, the novel assemblies could be a promising amplifier and platform to facilitate oral formulations of various nutraceuticals for food processing and UC relief.

Determination of Acetylamantadine by γ-Cyclodextrin-Assisted α-HL Nanopore for Potential Cancer Prediagnosis.

The high expression of Spermidine/spermine N1-acetyltransferase (SSAT-1) is an important indicator in early cancer diagnosis. Here, we developed a nanopore-based methodology with γ-cyclodextrin as an adaptor to detect and quantify acetylamantadine, the specific SSAT-1-catalyzed product from amantadine, to accordingly reflect the activity of SSAT-1. We employ γ-cyclodextrin and report that amantadine cannot cause any secondary signals in γ-cyclodextrin-assisted α-HL nanopore, while its acetylation product, acetylamantadine, does. This allows γ-cyclodextrin to practically detect acetylamantadine in the interference of excessive amantadine, superior to the previously reported ß-cyclodextrin. The quantification of acetylamantadine was not interfered with even a 50-fold amantadine and displayed no interference in artificial urine sample analysis, which indicates the good feasibility of this nanopore-based methodology in painless cancer prediagnosis. In addition, the discrimination mechanism is also explored by 2-D nuclear magnetic resonance (NMR) and nanopore experiments with a series of adamantane derivatives with different hydrophilic and hydrophobic groups. We found that both the hydrophobic region matching effect and hydrophilic interactions play a synergistic effect in forming a host-guest complex to further generate the characteristic signals, which may provide insights for the subsequent design and study of drug-cyclodextrin complexes.

Effect of cinnamon essential oil/γ-cyclodextrin inclusion complex on papaya quality and shelf-life.

BACKGROUND: Papaya, a highly nutritious and economically significant fruit, is susceptible to infections caused by phytopathogenic fungi. Cinnamon essential oil, derived from Cinnamomum cassia (CC), shows promise in preserving papaya due to its antifungal properties. However, CC is volatile, sensitive to environmental factors, and carries a strong aroma. γ-Cyclodextrin (γ-CD) is known for encapsulating hydrophilic molecules, shielding them from environmental influences, reducing odor, and enabling controlled release due to its unique channel structure. This study aimed to tackle these challenges by preparing and characterizing an inclusion complex of CC with γ-CD (CC-γ-CD), and subsequently evaluating its efficacy in preserving papaya fruits. RESULTS: Analyses, including Fourier-infrared, powder X-ray diffraction, thermal gravity analysis, differential scanning calorimeter, and scanning electron microscopy, revealed successful encapsulation of CC components within the γ-CD cavity. Evaluations of the CC-γ-CD complex's impact on papaya fruit shelf life and quality showed notable enhancements. Fruits treated with CC-γ-CD inclusion complex at a dose of 10 g kg-1 exhibited a 55% extension in shelf-life, evidenced by reduced disease severity index compared with untreated fruit in the same storage conditions. Detailed physicochemical and bromatological assessments highlighted significant improvements, particularly in fruit treated with CC-γ-CD inclusion complex at a dose of 10 g kg-1. CONCLUSION: The application of CC-γ-CD inclusion complex at 10 g kg-1 extended the shelf-life of papaya fruit, significantly and markedly improved the overall quality. These findings underscore the potential of the CC-γ-CD inclusion complex as an effective preservative for papaya, offering a promising solution for its postharvest management and marketability. © 2024 Society of Chemical Industry.

Exploring oral drug delivery: In vitro release and mathematical modeling of hydrophobic drug (Na-L-thyroxine) and its cyclodextrin inclusion complex in chitosan microparticles.

Na-l-Thyroxine (Na-l-Thy) is a frequently prescribed synthetic hormone for hypothyroidism treatment. Despite its efficacy, its hydrophobic nature poses a challenge for achieving optimal bioavailability. To address this, researchers explored various delivery methods, including micro-formulations and nano-formulations, for precise and prolonged release of hydrophobic and hydrophilic drugs. In this study, we developed micro-formulations with cyclodextrin and chitosan. Docking studies identified γ-cyclodextrin as the preferred option for forming a stable complex with Na-l-Thyroxine compared to α, and ß-cyclodextrins. Two micro-formulations were prepared compared: Na-l-Thyroxine loaded on chitosan (CS + Na-l-Thy) and Na-l-Thyroxine and γ-cyclodextrin inclusion complex (IC) loaded on chitosan (CS + IC). CS + IC exhibited superior encapsulation efficiency (91.25 %) and loading capacity (18.62 %) compared to CS + Na-l-Thy (encapsulation efficiency: 70.24 %, loading capacity: 21.18 %). Characterization using FTIR, SEM, and TGA validated successful encapsulation of Na-l-Thy in spherical microparticles with high thermal stability. In-vitro release studies at pH 1.2 and 7.4 showed that the CS + IC microparticles displayed gradual, consistent drug release compared to CS + Na-l-Thy -Thy. Both formulations showed faster release at pH 1.2 than at pH 7.4. Reaction kinetics analysis of release studies of CS + Na-l-Thy and CS + IC were best described by Higuchi kinetic model and Korsemeyer-Peppas kinetic model respectively. This study suggests that the CS + IC microparticles are an effective and stable delivery system for sustained release of hydrophobic Na-l-Thy.

Unraveling the molecular dynamics of sugammadex-rocuronium complexation: A blueprint for cyclodextrin drug design.

Sugammadex, marketed as Bridion™, is an approved cyclodextrin (CD) based drug for the reversal of neuromuscular blockade in adults undergoing surgery. Sugammadex forms an inclusion complex with the neuromuscular blocking agent (NMBA) rocuronium, allowing rapid reversal of muscle paralysis. In silico methods have been developed for studying CD inclusion complexes, aimed at accurately predicting their structural, energetic, dynamic, and kinetic properties, as well as binding constants. Here, a computational study aimed at characterizing the sugammadex-rocuronium system from the perspective of docking calculations, free molecular dynamics (MD) simulations, and biased metadynamics simulations with potential of mean force (PMF) calculations is presented. The aim is to provide detailed information about this system, as well as to use it as a model system for validation of the methods. This method predicts results in line with experimental evidence for both the optimal structure and the quantitative value for the binding constant. Interestingly, there is a less profound preference for the orientation than might be assumed based on electrostatic interactions, suggesting that both orientations may exist in solution. These results show that this technology can efficiently analyze CD inclusion complexes and could be used to facilitate the development and optimization of novel applications for CDs.

Alizarin-embedded γ-cyclodextrin-based metal-organic framework in a methylcellulose/polyvinyl alcohol film for maintaining and monitoring grass carp freshness.

Multifunctional packaging films that monitor and maintain fish freshness hold significant potential for use in the food industry. This study introduces a multifunctional intelligent packaging film comprising alizarin (ALI)-embedded cubic γ-cyclodextrin metal-organic frameworks (γ-CD-MOFs) (denoted as γ-CD-MOFs@ALI) in a methylcellulose/polyvinyl alcohol (MP)-based matrix to achieve colorimetric monitoring and enhanced preservation of fish freshness. The MP/γ-CD-MOFs@ALI reveals a rapid color transition in 3 min from yellow color progressively darkens to purple as the pH increases from 2.0 to 10.0. And it is proved that the as-prepared film owns high antibacterial activity against Gram-positive bacteria (S. aureus), impressive ABTS+ radical scavenging rates of 85.54 ± 1.25 %, and effective ALI sustained-release properties. The intelligent packaging film exhibits an excellent colorimetric response to total volatile basic nitrogen and provides exceptional freshness preservation performance, effectively prolonging the shelf life of Ctenopharyngodon idella (grass carp) under 25 °C to 42 h.

Trapping and reversing neuromuscular blocking agent by anionic pillar[5]arenes: Understanding the structure-affinity-reversal effects.

Selective relaxant binding agents (SRBA) have great potential in clinical surgeries for the precise reversal of neuromuscular blockades. Understanding the relationship between the structure-affinity-reversal effects of SRBA and neuromuscular blockade is crucial for the design of new SRBAs, which has rarely been explored. Seven anionic pillar[5]arenes (AP5As) with different aliphatic chains and anionic groups at both edges were designed. Their binding affinities to the neuromuscular blocking agent decamonium bromide (DMBr) were investigated using 1H NMR, isothermal titration calorimetry (ITC), and theoretical calculations. The results indicate that the capture of DMBr by AP5As is primarily driven by electrostatic interactions, ion-dipole interactions and C-H‧‧‧π interactions. The optimal size matching between the carboxylate AP5As and DMBr was ∼0.80. The binding affinity increased with an increase in the charge quantity of AP5As. Further animal experiments indicated that the reversal efficiency increased with increasing binding affinity for carboxylate or phosphonate AP5As. However, phosphonate AP5As exhibited lower reversal efficiencies than carboxylate AP5As, despite having stronger affinities with DMBr. By understanding the structure-affinity-reversal relationships, this study provides valuable insights into the design of innovative SRBAs for reversing neuromuscular blockade.

Covalent modification of γ-cyclodextrin with geraniol: An antibacterial agent with good thermal stability, solubility and biocompatibility.

Geraniol (Ger) is an essential oil molecule with excellent biological activity. High hydrophobicity and volatility limit its practical application. Cyclodextrins (CDs) are water-soluble cyclic oligosaccharides with hydrophobic cavities. Physical encapsulation of CDs to improve the solubility and stability of essential oil molecules is not satisfactory. Therefore, this study synthesized the γ-CD derivative (γ-CD-Ger) by grafting Ger onto γ-CD using a bromide-mediated method. Compared to the inclusion complexes (γ-CD/Ger) formed by both, the derivatives exhibit better solubility and thermal stability. The derivative has better antibacterial activity when the ratio of γ-CD to Ger was 1:2. In addition, the derivatives did not exhibit cytotoxic and hemolytic properties. These results indicate that this research provides a water-soluble antibacterial agent with a wide range of promising applications and offers new ideas for the application of alcohol hydrophobic molecules in aqueous systems.

Sugammadex shortens operation time and improves operation turnover efficacy in video-assisted thoracoscopic surgery.

BACKGROUND: This study compared sugammadex and neostigmine as agents for routine neuromuscular blockade reversal in video-assisted thoracoscopic surgery (VATS) to determine the optimal choice that achieves a shorter operation time and improved turnover efficiency while enhancing postoperative outcomes and ensuring patient safety during thoracic surgery. METHODS: This prospective study, conducted from July 2022 to March 2023, compared the effect of sugammadex and neostigmine on operation time and turnover efficiency in VATS, involving 60 participants randomly assigned to either group, with the primary objective of identifying the optimal anesthesia reversal choice for improved outcomes and patient safety during thoracic surgery. RESULTS: In the study, the sugammadex group showed a significantly shorter total operation room occupancy time (130 ± 7 vs 157 ± 7 minutes; p = 0.009) than the neostigmine group. Patients in the neostigmine group had higher mean pulse rates when leaving the operation room (85 ± 3 vs 73 ± 3 beats/min; p = 0.002) and 120 minutes later in the postanesthesia care unit (76 ± 2 vs 68 ± 2; p = 0.016). CONCLUSION: This study's findings suggest that sugammadex may enhance total operating room occupancy time, operation turnover efficacy, and respiratory recovery outcomes in VATS, potentially improving patient care and anesthesia management.

Macrocycles and Acyclic Cucurbit[n]urils as Pseudo[2]catenane Partners for Long-Acting Neuromuscular Blocks and Rapid Reversal In Vivo.

Long-acting neuromuscular blocks followed by rapid reversal may provide prolonged surgeries with improved conditions by omitting repetitive or continuous administration of the neuromuscular blocking agent (NMBA), eliminating residual neuromuscular block and minimizing postoperative recovery, which, however, is not clinically available. Here, we demonstrate that imidazolium-based macrocycles (IMCs) and acyclic cucurbit[n]urils (ACBs) can form such partners by functioning as long-acting NMBAs and rapid reversal agents through a pseudo[2]catenation mechanism based on stable complexation with Ka values of over 109 M-1. In vivo experiments with rats reveal that, at the dose of 2- and 3-fold ED90, one IMC attains a duration of action corresponding to 158 or 442 min for human adults, covering most of prolonged surgeries. The block can be reversed by one ACB with recovery time significantly shorter than that achieved by sugammadex for reversing the block of rocuronium, the clinically most widely used intermediate-acting NMBA.