Use of neuromuscular blockade for neck dissection and association with iatrogenic nerve injury.

BACKGROUND: Cranial nerve injury is an uncommon but significant complication of neck dissection. We examined the association between the use of intraoperative neuromuscular blockade and iatrogenic cranial nerve injury during neck dissection. METHODS: This was a single-center, retrospective, electronic health record review. Study inclusion criteria stipulated patients > 18 years who had ≥ 2 neck lymphatic levels dissected for malignancy under general anesthesia with a surgery date between 2008 - 2018. Use of neuromuscular blockade during neck dissection was the primary independent variable. This was defined as any use of rocuronium, cisatracurium, or vecuronium upon anesthesia induction without reversal with sugammadex prior to surgical incision. Univariate tests were used to compare variables between those patients with, and those without, iatrogenic cranial nerve injury. Multivariable logistic regression determined predictors of cranial nerve injury and was performed incorporating Firth's estimation given low prevalence of the primary outcome. RESULTS: Our cohort consisted of 925 distinct neck dissections performed in 897 patients. Neuromuscular blockade was used during 285 (30.8%) neck dissections. Fourteen instances (1.5% of surgical cases) of nerve injury were identified. On univariate logistic regression, use of neuromuscular blockade was not associated with iatrogenic cranial nerve injury (OR: 1.73, 95% CI: 0.62 - 4.86, p = 0.30). There remained no significant association on multivariable logistic regression controlling for patient age, sex, weight, ASA class, paralytic dose, history of diabetes, stroke, coronary artery disease, carotid atherosclerosis, myocardial infarction, and cardiac arrythmia (OR: 1.87, 95% CI: 0.63 - 5.51, p = 0.26). CONCLUSIONS: In this study, use of neuromuscular blockade intraoperatively during neck dissection was not associated with increased rates of iatrogenic cranial nerve injury. While this investigation provides early support for safe use of neuromuscular blockade during neck dissection, future investigation with greater power remains necessary.

Postoperative recurarization after sugammadex administration in two patients who received neoadjuvant chemotherapy: case reports and literature review.

BACKGROUND: Preoperative neoadjuvant chemotherapy plays a critical role in multidisciplinary therapy for a variety of malignant tumours. Although oncologists consider myocardial injury to be the most concerning side effect of chemotherapy, unique chemotherapy-mediated skeletal muscular damage has received attention recently. CLINICAL FEATURES: We report two unusual cases of postoperative delayed respiratory failure following administration of the recommended sugammadex dosage for patients undergoing lengthy operations with deep neuromuscular blockade (NMB) after neoadjuvant chemotherapy. Based on clinical outcomes, especially the comparison of muscle imaging results in patients at different treatment time points, we concluded that NMB recurrence had a possible correlation with neoadjuvant chemotherapy-induced muscular damage. CONCLUSION: The early identification of neoadjuvant chemotherapeutic side effects on NMB could be instrumental for clinical safety, especially in cases of major surgery requiring deep NMB. Thus, the timing of NMB antagonism and the recommended dosage of sugammadex warrant special consideration in these patients. In addition to neuromuscular monitoring during the operation, a more extended and closer observation period in the postanesthesia care unit is warranted.

RéSUMé: CONTEXTE: La chimiothérapie néoadjuvante préopératoire joue un rôle crucial dans le traitement multidisciplinaire de diverses tumeurs malignes. Bien que les oncologues considèrent les lésions myocardiques comme l'effet secondaire le plus inquiétant de la chimiothérapie, des lésions musculosquelettiques spécifiques induites par la chimiothérapie ont récemment fait l'objet d'une attention plus précise. CARACTéRISTIQUES CLINIQUES: Nous signalons deux cas inhabituels d'insuffisance respiratoire postopératoire retardée suite à l'administration de la posologie recommandée de sugammadex chez des patient·es bénéficiant d'opérations prolongées avec blocage neuromusculaire (BNM) profond après une chimiothérapie néoadjuvante. Sur la base des résultats cliniques, en particulier de la comparaison des résultats d'imagerie musculaire chez les patient·es à différents moments du traitement, nous avons conclu que la récurrence du BNM avait une corrélation intéressante avec les lésions musculaires induites par la chimiothérapie néoadjuvante. CONCLUSION: L'identification précoce des effets secondaires de la chimiothérapie néoadjuvante sur le BNM pourrait jouer un rôle déterminant dans l'innocuité clinique, en particulier en cas de chirurgie majeure nécessitant un BNM profond. Ainsi, le moment de l'antagonisme du BNM et la posologie recommandée de sugammadex nécessitent une attention particulière chez ces patient·es. En plus du monitorage neuromusculaire pendant l'opération, une période d'observation plus longue et plus étroite en salle de réveil est justifiée.

Effect of Sugammadex During Transcranial Electrical Motor Evoked Potentials Monitoring in Spinal Surgery: A Randomized Controlled Trial.

INTRODUCTION: Neuromuscular blockade suppresses transcranial electrical motor evoked potential (TceMEP) amplitude and is usually avoided during TceMEP monitoring. In this randomized controlled trial, we investigated whether rocuronium-induced suppression of TceMEP amplitude could be reversed by sugammadex in patients undergoing spine surgery. METHODS: Seventy-six patients undergoing spinal surgery were randomly allocated into sugammadex and control groups. In the sugammadex group, a rocuronium infusion was titrated to maintain moderate neuromuscular blockade (2 twitches on train-of-four) until dural opening when the rocuronium infusion was discontinued and 2 mg/kg sugammadex administered. In the control group, no neuromuscular blockade was administered after induction of anesthesia. The primary outcome was a comparison between sugammadex and control groups of mean TceMEP amplitudes in the abductor pollicis brevis muscles of both upper extremities 5 minutes after dural. Secondary outcomes included TceMEP amplitudes at 10, 20, 30, and 60 minutes after dural opening. RESULTS: Sixty-six patients were included in the analysis. TceMEP amplitudes were significantly greater in the sugammadex group (629 µV, interquartile range: 987 µV) than in the control group (502 µV, interquartile range: 577 µV; P =0.033) at 5 minutes after dural opening. TceMEP amplitudes were also greater in the sugammadex group at 10 minutes ( P =0.0010), 20 minutes ( P =0.003), 30 minutes ( P =0.001), and 60 minutes ( P =0.003) after dural opening. CONCLUSIONS: Moderate neuromuscular blockade induced by continuous infusion of rocuronium was effectively reversed by sugammadex. This suggests that sugammadex could be used to enhance TceMEP waveform monitoring during spine surgery requiring muscle relaxation.

Population Pharmacokinetic-Pharmacodynamic Modeling and Probability of Target Attainment Analysis of Rocuronium and Sugammadex in Children Undergoing Surgery.

BACKGROUND AND OBJECTIVES: Probability of target attainment (PTA) curves are commonly used to support dose recommendations of antibiotics for different patient groups. In this study we propose PTA analysis to optimize sugammadex dosing in children. METHODS: This study involved data from an observational cohort study of 30 American Society of Anesthesiologists (ASA) Physical Status I and II children undergoing surgery requiring muscle relaxation. All patients received 0.6 mg/kg rocuronium, with sugammadex administered at the end of surgery in three different doses (0.5, 1.0, and 2.0 mg/kg) to reverse the neuromuscular blockade. RESULTS: The data were analyzed using a population Bayesian-based approach. The developed model was used to simulate pharmacokinetic-pharmacodynamic profiles for different patient groups and dosing regimens before the PTA analysis was performed to translate these simulations into a clinically useful measure. The target was defined as neuromuscular blockade reversal measured by Train-of-Four (TOF ratio > 90%) at 1.5, 3, and 5 min post sugammadex dose. The sugammadex doses leading to 90% PTA were determined for different patients' body weights, rocuronium doses, and time gaps between rocuronium and sugammadex administration assuming the model, priors, and gathered data. For comparison, PTA curves for a range of clinical scenarios are provided to illustrate the usefulness of PTA analysis in selecting the appropriate dose for a given patient. CONCLUSIONS: The proposed PTA analysis is useful to support the sugammadex dose selection in different clinical scenarios. TRIAL REGISTRATION: The study was registered by ClinicalTrials.gov under number NCT04851574 on 21 April 2021.

Case Report: Successful Reversal of Residual Block with Sugammadex in a Patient Not Known to Have Myasthenia Gravis.

BACKGROUND Incomplete recovery from residual neuromuscular block agent (NMBA) after anesthesia is a serious adverse event in the post-anesthesia care unit. Acetylcholinesterase neostigmine is usually used to reverse residual neuromuscular blockade and facilitate spontaneous breathing and endotracheal extubation. CASE REPORT A 40-year-old woman received general anesthesia for strabismus correction surgery. At the end of surgery, repeated doses of neostigmine up to 85 µg/kg failed to reverse the residual neuromuscular blockade (train-of-four [TOF] ratio below 21%). Sugammadex (200 mg) provided immediate reversal, with the TOF ratio up to 100%. The patient regained spontaneous breathing, and the endotracheal tube was removed. After surgery, myasthenia gravis was diagnosed. CONCLUSIONS When unexpected prolonged neuromuscular blockade presents, the TOF ratio should be used to detect its depth and guide a reasonable dose of reversal agents. Anticholinesterase has a ceiling effect; once acetylcholinesterase activity is fully inhibited, administration of additional anticholinesterase can result in no further recovery. Furthermore, excessive acetylcholine can cause muscle weakness. In contrast, sugammadex is a selective reversal agent for steroidal NMBA, which works by encapsulation via tight water-soluble complexes with amino steroids (eg, rocuronium) rather than increasing acetylcholine at the neuromuscular junction. In this case, the recovery from moderate neuromuscular blockade by sugammadex was more effective and rapid than that by neostigmine. When refractory and prolonged residual neuromuscular blockade presents after repeated doses of anticholinesterase, sugammadex should be considered as an effective reversal agent. Particularly in cases of myasthenia gravis, sugammadex is superior to neostigmine for reversing rocuronium-induced NMBA in patients undergoing surgery.

Retrospective observational study of the effects of residual neuromuscular blockade and sugammadex on motor-evoked potential monitoring during spine surgery in Japan.

Given neuromuscular blockade (NMB) can affect the amplitude and detection success rate of motor-evoked potentials (MEP), sugammadex may be administered intraoperatively. We evaluated the factors affecting the degree of residual NMB (i.e., the train-of-four [TOF] ratio) and the relationship between TOF ratio and MEP detection success rate in Japanese patients undergoing spine surgery. This single-center retrospective observational study included adults who underwent spine surgery under propofol/remifentanil anesthesia, received rocuronium for intubation, and underwent myogenic MEP monitoring after transcranial stimulation. TOF ratios were assessed using electromyography. Sugammadex was administered after finishing the MEP setting and the TOF ratio was ≤0.7. To identify factors affecting the TOF ratio, TOF ratio and MEP detection success rate were simultaneously measured after finishing the MEP setting; to compare the time from intubation to the start of MEP monitoring after NMB recovery between sugammadex and spontaneous recovery groups, multivariable analyses were performed. Of 373 cases analyzed, sugammadex was administered to 221 (59.2%) cases. Age, blood pressure, hepatic impairment, and rocuronium dose were the main factors affecting the TOF ratio. Patients with higher TOF ratios (≥0.75) had higher MEP detection success rates. The time from intubation to the start of MEP monitoring after NMB recovery was significantly shorter in patients administered sugammadex versus patients without sugammadex (P < .0001). The MEP detection success rate was higher in patients with a TOF ratio of ≥0.75. Sugammadex shortened the time from intubation to the start of MEP monitoring after NMB recovery.

Optimizing Reversal of Neuromuscular Block in Older Adults: Sugammadex or Neostigmine.

Residual neuromuscular paralysis, the presence of clinically significant weakness after administration of pharmacologic neuromuscular blockade reversal, is associated with postoperative pulmonary complications and is more common in older patients. In contemporary anesthesia practice, reversal of neuromuscular blockade is accomplished with neostigmine or sugammadex. Neostigmine, an acetylcholinesterase inhibitor, increases the concentration of acetylcholine at the neuromuscular junction, providing competitive antagonism of neuromuscular blocking drug and facilitating muscle contraction. Sugammadex, a modified gamma-cyclodextrin, antagonizes neuromuscular blockade by encapsulating rocuronium and vecuronium in a one-to-one ratio for renal clearance, a pharmacokinetic property that led to the recommendation that sugammadex not be administered to those with end-stage renal disease. While data are limited, reports suggest sugammadex is efficacious and well tolerated in individuals with reduced renal function. Sugammadex provides a more rapid and complete reversal of neuromuscular blockade than neostigmine. There is also accumulating evidence that sugammadex may provide a protective effect against the development of postoperative pulmonary complications, nausea, and vomiting, and that it may have beneficial effects on the rate of bowel and bladder recovery after surgery. Accordingly, sugammadex administration is beneficial for most older patients undergoing surgery.

Adamgammadex in patients to reverse a moderate rocuronium-induced neuromuscular block.

AIMS: The aim of this study was to investigate the effectiveness, safety and pharmacokinetics of adamgammadex in surgical patients. METHODS: Forty-eight patients aged 18-64 years old were randomized to receive adamgammadex (2, 4, 6, and 8 mg.kg-1 ) or placebo at a ratio of 10:2 for reversal of 0.6 mg.kg-1 rocuronium-induced neuromuscular block. Neuromuscular function was monitored by TOF-Watch® SX. When the T2 of train-of-four (TOF) reappeared at the end of surgery, patients received an intravenous administration of adamgammadex or placebo. RESULTS: The recovery time of the TOF ratio to 0.9 decreased significantly from 39.3 [29.5, 50.2] minutes in the group that received placebo to 3.0 [2.3, 3.9] minutes, P < .0001; 2.1 [1.5, 3.0] minutes, P < .0001; 2.1 [1.8, 3.3] minutes, P < .0001; and 1.8 [1.5, 2.2] minutes, P < .0001 in the 2, 4, 6 and 8 mg.kg-1 adamgammadex groups, respectively. Then, adamgammadex also showed a shortened recovery time for the TOF ratio recovered to 0.8 and 0.7. Adamgammadex was well tolerated, and no cases of anaphylactic reactions, post-operative bleeding, recurarization, abnormal basic vital signs and prolonged QT intervals were observed. The pharmacokinetics of adamgammadex in plasma increased in dose-dependent manner. The 24-hour cumulative fraction of adamgammadex in urine was 65-83%, and that of rocuronium was increased after using adamgammadex from 15% to about 25-30%. CONCLUSION: Adamgammadex was found to be effective for reversal of rocuronium-induced neuromuscular block, and it was safe and well tolerated in patients.

Carboxymethyl-γ-cyclodextrin, a novel selective relaxant binding agent for the reversal of neuromuscular block induced by aminosteroid neuromuscular blockers: an ex vivo laboratory study.

BACKGROUND: Residual neuromuscular block at the end of surgery may compromise the patient's safety. The risk of airway complications can be minimized through monitoring of neuromuscular function and reversal of neuromuscular block if needed. Effective reversal can be achieved with selective relaxant binding agents, however, sugammadex is the only clinically approved drug in this group. We investigated the concentration-response properties of a novel selective relaxant binding agent, carboxymethyl-γ-cyclodextrin for the reversal of neuromuscular block. We evaluated the hypothesis that it is equally potent for reversing neuromuscular block as sugammadex. METHODS: Phrenic nerve - hemidiaphragm tissue preparations were isolated from male Wistar rats and suspended in a tissue holder allowing electrical stimulation of the nerve and monitoring of muscle contraction force. Concentration-response relationships were constructed for the neuromuscular blocking agents rocuronium, pipecuronium, and vecuronium. The half-effective concentrations of sugammadex and carboxymethyl-γ-cyclodextrin for reversal of neuromuscular block were determined. RESULTS: The half effective concentrations (95% confidence interval, CI) were 7.50 (6.93-8.12) µM for rocuronium, 1.38 (1.33-1.42) µM for pipecuronium, and 3.69 (3.59-3.80) µM for vecuronium. The half effective concentrations (95% CI) of carboxymethyl-γ-cyclodextrin and sugammadex were 35.89 (32.67-39.41) µM and 3.67 (3.43-3.92) µM, respectively, for the reversal of rocuronium-induced block; 10.14 (9.61-10.70) µM and 0.67 (0.62-0.74) µM, respectively, for the reversal of pipecuronium-induced block; and 376.1 (341.9-413.8) µM and 1.45 (1.35-1.56) µM, respectively, for the reversal of vecuronium-induced block. CONCLUSIONS: Carboxymethyl-γ-cyclodextrin is an effective, but less potent agent for reversal of neuromuscular block than sugammadex.

Exploring Charged Polymeric Cyclodextrins for Biomedical Applications.

Over the years, cyclodextrin uses have been widely reviewed and their proprieties provide a very attractive approach in different biomedical applications. Cyclodextrins, due to their characteristics, are used to transport drugs and have also been studied as molecular chaperones with potential application in protein misfolding diseases. In this study, we designed cyclodextrin polymers containing different contents of ß- or γ-cyclodextrin, and a different number of guanidinium positive charges. This allowed exploration of the influence of the charge in delivering a drug and the effect in the protein anti-aggregant ability. The polymers inhibit Amiloid ß peptide aggregation; such an ability is modulated by both the type of CyD cavity and the number of charges. We also explored the effect of the new polymers as drug carriers. We tested the Doxorubicin toxicity in different cell lines, A2780, A549, MDA-MB-231 in the presence of the polymers. Data show that the polymers based on γ-cyclodextrin modified the cytotoxicity of doxorubicin in the A2780 cell line.

Delivering Crocetin across the Blood-Brain Barrier by Using γ-Cyclodextrin to Treat Alzheimer's Disease.

Crocetin (CRT) has shown various neuroprotective effects such as antioxidant activities and the inhibition of amyloid ß fibril formation, and thus is a potential therapeutic candidate for Alzheimer's disease (AD). However, poor water solubility and bioavailability are the major obstacles in formulation development and pharmaceutical applications of CRT. In this study, a novel water-soluble CRT-γ-cyclodextrin inclusion complex suitable for intravenous injection was developed. The inclusion complex was nontoxic to normal neuroblastoma cells (N2a cells and SH-SY5Y cells) and AD model cells (7PA2 cells). Furthermore, it showed stronger ability to downregulate the expression of C-terminus fragments and level of amyloid ß in 7PA2 cell line as compared to the CRT free drug. Both inclusion complex and CRT were able to prevent SH-SY5Y cell death from H2O2-induced toxicity. The pharmacokinetics and biodistribution studies showed that CRT-γ-cyclodextrin inclusion complex significantly increased the bioavailability of CRT and facilitated CRT crossing the blood-brain barrier to enter the brain. This data shows a water-soluble γ-cyclodextrin inclusion complex helped to deliver CRT across the blood-brain barrier. This success should fuel further pharmaceutical research on CRT in the treatment for AD, and it should engender research on γ-cyclodextrin with other drugs that have so far not been explored.

Potency estimation of sugammadex for the reversal of moderate rocuronium-induced neuromuscular block: a non-randomized dose-response study.

PURPOSE: There is no report investigating the precise potency of sugammadex for antagonizing various intensities of rocuronium-induced neuromuscular block. The aim of this study was to evaluate the ED95 of reversibility of sugammadex and reveal the safety factor of 2 mg/kg of sugammadex for moderate rocuronium-induced neuromuscular block. METHODS: Fifteen patients were enrolled in this study. After induction of anesthesia, we recorded the adductor pollicis muscle response to ulnar nerve stimulation using acceleromyography. All patients received 0.6 mg/kg rocuronium. When the first twitch (T1) of the train-of-four (TOF) response reappeared, rocuronium infusion was commenced to maintain T1 at 10% of the control. After the surgery was completed and infusion of rocuronium was stopped, patients were given sugammadex by a cumulative dose technique. The effective doses of sugammadex that led to recovery of the amplitude of T1 and the TOF ratio by 95% (ED95) were calculated from the regression lines of least-squares regression analysis. RESULTS: The mean ED95 of sugammadex for recovery of T1 and the TOF ratio from rocuronium-induced moderate neuromuscular block was 1.34 (0.24) and 1.14 (0.24) mg/kg, respectively. CONCLUSIONS: The ED95 of sugammadex for the recovery of T1 was significantly greater than that for the TOF ratio. However, a sugammadex dose of 2 mg/kg is equivalent to about 1.5 times the ED95 of sugammadex for reversal of moderate rocuronium-induced block, indicating its safety margin.

Antioxidant, antibacterial and anti-cancer activities of ß-and γ-CDs/curcumin loaded in chitosan nanoparticles.

Curcumin, as a naturally occurring polyphenol, has been extensively used as anticancer and antioxidant agent due to its ability to protect cells from oxidative damage. In the present study, we have prepared highly soluble CUR-ß-cyclodextrin (ß-CD) and γ-cyclodextrin (γ-CD) hollow spheres. UV-Vis method was employed to approve the successful formation of the inclusion complex where the aromatic ring of CUR has been encapsulated by the hydrophobic cavity of CDs. CUR-CDs were then encapsulated into positively charged biodegradable chitosan (CUR-CDs-CS) nanoparticles. The CUR-CD-CS were characterized by UV-Vis, FTIR, 1HNMR, XRD, SEM analysis. Antibacterial efficacy was evaluated by measuring the zone of inhibition scale and MIC value which was recorded as 32 µg/mL and 64 µg/mL for both Gram positive S. aureus and Gram negative E. coli bacteria respectively. We tested the efficacy of these CUR-CD-CS nanoparticles in A549 cell lines using MTT assay and investigated its cellular uptake mechanism. Our results demonstrated that CUR-CD-CS nanoparticles showed superior in vitro release performance and higher cytotoxicity in A549 cell line among all tested formulations. Antioxidant activity and release behavior of the curcumin-loaded CDs-CS was investigated. The IC50 value for CUR/CD-CS was estimated based on their inhibition percent-concentration curves using DPPH assay.

Honeycomb-like pH-responsive γ-cyclodextrin electrospun particles for highly efficient tumor therapy.

We report here the tumor-implantable microparticles with a honeycomb-like porous structure. These microparticles were prepared by electrospinning using γ-cyclodextrin (γ-CD) conjugated with 3-(diethylamino)propylamine (DEAP, as a pH-responsive moiety), named γ-CD-DEAP. The resulting microparticles had pore channels (constructed using γ-CD-DEAP) extending into the deep compartment of the microparticles and allowing efficient paclitaxel (PTX, as a chemotherapeutic model drug) entrapment by a simple hole-filling encapsulation process. Importantly, the hydrophobic DEAP (at pH 7.4) in the γ-CD-DEAP microparticles changed to hydrophilic DEAP (at pH 6.8) because of its acidic pH-induced protonation. This phenomenon resulted in an acidic pH-activated particle destruction by a charge-charge repulsion between the protonated DEAP moieties and allowed a pH-triggered release of the encapsulated PTX from the collapsed microparticles. Consequently, γ-CD-DEAP microparticles implanted at the tumor site caused a significant enhancement of the in vitro/in vivo tumor cell ablation, suggesting their significant potential as a chemotherapeutic implant for tumor therapy.

A Molecular Dynamics Study of a Photodynamic Sensitizer for Cancer Cells: Inclusion Complexes of γ-Cyclodextrins with C70.

Photodynamic therapy is an emerging treatment of tumor diseases. The complexes with γ-cyclodextrins (γ-CD) and fullerenes or their derivatives can be used as photosensitizers by direct injection into cancer cells. Using molecular mechanics and molecular dynamics methods, the stability and the geometry of the 2:1 complexes [(γ-CD)2/C70] are investigated analyzing the differences with the analogous C60 complexes, studied in a previous theoretical work and experimentally found to be much less efficient in cancer therapy. The inclusion complex of γ-CD and C70 has a 2:1 stoichiometry, the same as C60, but is significantly less stable and displays an unlike arrangement. In vacuo, mimicking an apolar solvent, the complex is compact, whereas in water the two γ-CDs encapsulate C70 forming a relatively stable complex by interacting through their primary rims, however exposing part of C70 to the solvent. Other higher-energy complexes with the γ-CDs facing different rims can form in water, but in all cases part of the hydrophobic C70 surface remains exposed to water. The stability and arrangement of these peculiar amphiphilic inclusion complexes having non-covalent interactions in water can be an important key for cancer therapy to enhance both the solubilization and the fullerene insertion into liposomes or cell membranes.

Cellular delivery and enhanced anticancer activity of berberine complexed with a cationic derivative of γ-cyclodextrin.

A cationic derivative of γ-cyclodextrin (GCD) modified with propylenediamine (PDA) was synthesized. It was shown that the derivative (GCD-PDA) is mucoadhesive and resistant to the digestion with ∝-amylase indicating that it may constitute an efficient oral delivery vehicle. GCD-PDA formed an inclusion complex with berberine (BBR), an alkaloid displaying a multitude of beneficial physiological effects. The complexed BBR penetrates a lipid membrane easier than the free one. Both uncomplexed BBR and that complexed with GCD-PDA was delivered to normal (NMuMG) and cancerous (4T1) murine mammary gland cells. In the normal cells both free and complexed BBR was homogeneously dispersed in the cytoplasm and was nontoxic up to 131 µM. In the cancerous cells uncomplexed BBR was also homogeneously dispersed but it was toxic to about 25% of cells at 131 µM, while the GCD-PDA/BBR complex was preferably localized in lysosomes and its toxicity doubled at this concentration compared to that of free BBR. Moreover, free BBR and GCD-PDA/BBR showed even more efficient inhibitory effect against murine melanoma (B16-F10) cells than against 4T1 cells.

Hydroxypropyl-beta and -gamma cyclodextrins rescue cholesterol accumulation in Niemann-Pick C1 mutant cell via lysosome-associated membrane protein 1.

Niemann-Pick type C (NPC) disease is a fatal hereditary neurodegenerative disorder characterized by a massive accumulation of cholesterol in lysosomes and late endosomes due to a defect in intracellular cholesterol trafficking. Dysfunction in intracellular cholesterol trafficking is responsible for about 50 rare inherited lysosomal storage disorders including NPC. The lysosomal proteins NPC1 and NPC2 play a crucial role in trafficking of cholesterol from late endosomes and lysosomes to other cellular compartments. However, the detailed mechanisms of cholesterol trafficking at the late endosomes/lysosomes (LE/LY) are poorly understood. Studies showed that 2-hydroxypropyl-ß-cyclodextrin (HPßCD) alleviates the cholesterol accumulation defect in animal model and has been approved for a phase 2b/3 clinical trial for NPC. HPßCD is known to bind cholesterol; however, the mechanisms how HPßCD mediates the exit of cholesterol from the LE/LY compartments are still unknown. Further, another cyclodextrin (CD) derivative, 2-hydroxypropyl-γ-cyclodextrin (HPγCD), was shown to reduce intracellular cholesterol accumulation in NPC patient cells and NPC mice model. Herein, we identified a number of candidate proteins differentially expressed in NPC patient-derived cells compared to cells derived from a healthy donor using a proteomic approach. Interestingly, both HPßCD and HPγCD treatments modulated the expression of most of these NPC-specific proteins. Data showed that treatment with both CDs induces the expression of the lysosome-associated membrane protein 1 (LAMP-1) in NPC patient-derived cells. Remarkably, LAMP-1 overexpression in HeLa cells rescued U18666A-induced cholesterol accumulation suggesting a role of LAMP-1 in cholesterol trafficking. We propose that HPßCD and HPγCD facilitate cholesterol export from the LE/LY compartments via the LAMP-1 protein, which may play a crucial role in cholesterol trafficking at the LE/LY compartments when there is no functional NPC1 protein. Together, this study uncovers new cellular mechanisms for cholesterol trafficking, which will contribute to development of novel therapeutic approaches for lysosomal storage diseases.

Train-of-four guard-controlled sugammadex reversal in patients with multiple sclerosis.

OBJECTIVE: Multiple sclerosis (MS) is a chronic inflammatory and demyelinating autoimmune disease of the central nervous system. It is known that the disease, which is manifested by a wide variety of symptoms, may exacerbate after anesthesia and show different responses to muscle relaxants in the normal population. It is planned to measure train-of-four (TOF) values of MS patients to be operated under general anesthesia before sugammadex application. MATERIALS AND METHODS: With the approval of the local ethics committee of the University of Health Sciences Bagcilar Training and Research Hospital and with written consents of participants, we anesthetized ten patients (from April 2014 to March 2017) with MS and ten American Society of Anesthesiologists I-III patients without MS. Neuromuscular conduction was assessed by the acceleromyometric method using a TOF-Guard apparatus (Organon, Holland). The patients were extubated after recovery of TOF higher than 0.9. The primary efficacy variable was the time from the start of administration of sugammadex to recovery of the TOF ratio to 0.9. RESULTS: The demographic characteristics of both groups, the type and duration of surgery and anesthesia applied, and the temperature of the operation room were similar. Similar characteristics of both groups were of concern for postoperative residual paralysis, and therefore we did not notice any difference between time to TOF> 90/s for both groups. CONCLUSION: Sugammadex and TOF patients will increase patient safety in general anesthesia practice.

Method for Prediction of Efficacy of Sugammadex Administered to Recover from Rocuronium-Induced Neuromuscular Blockade in Gynecological Laparoscopic Surgery Cases.

Sugammadex (SDX), a neuromuscular blocking-reversal agent, quickly reverses neuromuscular blockade induced by rocuronium (RCR). SDX dosage is set according to the state of neuromuscular blockade determined with a neuromuscular monitoring device. However, in clinical situations, such a devise is not frequently used. Here, we report construction of a method for theoretically setting SDX dose by which the optimum reverse time (RT) can be obtained for individual patients even when the device is not available. The subjects were 42 adult female patients who underwent laparoscopic surgery from 1 August 2015 to 31 March 2016, during which RCR and SDX were administered. We formulated an equation for theoretically calculating the RCR residual ratio (RR) in blood after SDX administration. Furthermore, we examined the relationship between RR and RT. Based on the results obtained, we developed a method for predicting RT using RR. We excluded 1 subject as the RT value was detected as an outlier in our analysis. Multiple regression analysis was performed using standard body weight, serum creatinine, total bilirubin, and RR as explanatory variables. The number of subjects with a prediction error of RT within ±1 min was 36 (87.8%) of 41 in multiple regression analysis. We could predict RT following SDX administration by using the RT prediction expression with RR obtained for subjects administered RCR during the surgery. Furthermore, our results suggest that the SDX dose able to achieve optimum RT may be set prior to surgery on the basis of the present methodology.

Supramolecular cyclodextrin-based metal-organic frameworks as efficient carrier for anti-inflammatory drugs.

Drug delivery systems have been used to reduce adverse effects and improve the efficacy of therapies. Drug carriers have been developed over the years, but they have limitations. γ-cyclodextrin-based metal-organic frameworks (γ-CD-MOF) have significant advantages due to their biocompatibility and environmental safety, besides crystallinity and porosity. Herein, γ-CD-MOFs were synthesised with different metals as nodes and investigated. Uniform mesoporous γ-CD-MOFs were obtained and showed an absence of toxicity in HepG2 and Caco-2 cells. The longer controlled release was verified for γ-CD-MOFs, with a maximum of 62% released in 12 h. An inflammation experiment was performed in mice and activity equivalent to the positive control was verified. γ-KCD-MOFs and γ-NaCD-MOFs reached activity after 6 h of administration, however this happened after 24 h in γ-FeCD-MOFs, being more effective than the positive control. Considering the ability for drug entrapment, easy preparation and controlled release, this class of material allows potential applications in drug delivery systems.