Prevention of the proliferation of oral pathogens due to prolonged mask use based on α-cyclodextrin and hydroxytyrosol mouthwash.

OBJECTIVE: Face masks help contain the aerosol-mediated transmission of infectious viral particles released from individuals via cough and sneezes. However, the prolonged use of face masks has raised concerns regarding oral hygiene. Here, we present a mouthwash formulation based on α-cyclodextrin and hydroxytyrosol that can maintain healthy oral microbiota. MATERIALS AND METHODS: We isolated and cultured Candida albicans, Staphylococcus aureus, and a mix of Streptococcus sp., Staphylococcus sp. and Neisseria sp. from oral and throat swabs. The microorganisms were cultured in a standard medium with or without the mouthwash. To evaluate the effect of the mouthwash on the oral microbiota, the DNA from the saliva of 3 volunteers that used the mouthwash was extracted. Then, the DNA was amplified using primer pairs specific for bacterial and fungal DNA. Twelve further volunteers were offered to use the mouthwash and a questionnaire was submitted to them to assess the possible beneficial effects of mouthwash on halitosis and other oral disturbances. RESULTS: The bacteria and fungi cultured in media containing the mouthwash showed a growth reduction ranging from 20 to 80%. The PCR amplification of fungal and bacterial DNA extracted from volunteers that used the mouthwash showed a reduction of both bacteria and fungi. Volunteers that used the mouthwash reported a tendency towards a reduction of halitosis, gingival and mouth inflammation, and dry mouth. CONCLUSIONS: The use of a mouthwash containing α-cyclodextrin and hydroxytyrosol is not aggressive against oral mucosa; it is safe and effective to reduce the bacterial and fungal load due to the continuous use of face masks.

In vitro and clinical studies on the efficacy of α-cyclodextrin and hydroxytyrosol against SARS-CoV-2 infection.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new coronavirus responsible for the current pandemic of coronavirus disease 2019 (COVID-19). This virus attacks cells of the airway epithelium by binding transmembrane angiotensin-converting enzyme 2 (ACE2). Hydroxytyrosol has anti-viral properties. Alpha-cyclodextrin can deplete sphingolipids and phospholipids from cell membranes. The aim of the present experimental study was to evaluate the efficacy of α-cyclodextrin and hydroxytyrosol in improving defenses against SARS-CoV-2 infection in in vitro cell models and humans. PATIENTS AND METHODS: For in vitro experiments on Vero E6 cells, RNA for RT-qPCR analysis was extracted from Caco2 and human fibroblast cell lines. For study in humans, the treatment group consisted of 149 healthy volunteers in Northern Cyprus, considered at higher risk of SARS-CoV-2 infection than the general population. The volunteers used nasal spray containing α-cyclodextrin and hydroxytyrosol for 4 weeks. The control group consisted of 76 healthy volunteers who did not use the spray. RESULTS: RT-qPCR experiments on targeted genes involved in endocytosis showed a reduction in gene expression, whereas cytotoxicity and cytoprotective tests showed that the compounds exerted a protective effect against SARS-CoV-2 infection at non-cytotoxic concentrations. None of the volunteers became positive to SARS-CoV-2 RT-qPCR assay during the 30 days of treatment. CONCLUSIONS: Treatment with α-cyclodextrin and hydroxytyrosol nasal spray improved defenses against SARS-CoV-2 infection and reduced synthesis of viral particles.

Study protocol for SFX-01 after subarachnoid haemorrhage (SAS): a multicentre randomised double-blinded, placebo controlled trial.

INTRODUCTION: Subarachnoid haemorrhage (SAH) from a ruptured cerebral aneurysm carries high morbidity and mortality. Despite huge advances in techniques to secure the aneurysm, there has been little progress in the treatment of the deleterious effects of the haemorrhage.Sulforaphane is an Nrf2 inducer with anti-oxidant and anti-inflammatory properties. It has been shown to improve clinical outcome in experimental models of SAH, but is unstable. SFX-01 (Evgen Pharma) is a novel composition comprised of synthetic sulforaphane stabilised within an α-cyclodextrin complex. On ingestion, the complex releases sulforaphane making SFX-01 an ideal vehicle for delivery of sulforaphane. METHODS AND ANALYSIS: The objective of the study is to assess the safety, pharmacokinetics and efficacy of SFX-01. This is a prospective, multicentre, randomised, double-blind placebo-controlled trial in patients aged 18-80 years with aneurysmal subarachnoid haemorrhage in the previous 48 hours. 90 patients will be randomised to receive SFX-01 (300 mg) or placebo two times per day for up to 28 days.Safety will be assessed using blood tests and adverse event reporting.Pharmacokinetics will be assessed based on paired blood and cerebrospinal fluid (CSF) sulforaphane levels on day 7. A subgroup will have hourly samples taken during 6 hours post-dosing on days 1 and 7. Pharmacodynamics will be assessed by haptoglobin and malondialdehyde levels, and maximum flow velocity of middle cerebral artery will be measured by transcranial Doppler ultrasound.Clinical outcomes will be assessed at days 28, 90 and 180 with modified Rankin Scale, Glasgow Outcome Score, SAH Outcome Tool, Short Form-36, Brain Injury Community Rehabilitation Outcome Scales and Check List for Cognitive and Emotional consequences following stroke. MRI at 6 months including quantitative susceptibility mapping and volumetric T1 will measure iron deposition and cortical volume.Safety, CSF sulforaphane concentration and middle cerebral artery flow velocity will be primary outcomes and all others secondary. ETHICS AND DISSEMINATION: Ethical approval was obtained from South Central Hampshire A committee. Outcomes of the trial will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02614742.

Highly efficient photocontrolled targeted delivery of siRNA by a cyclodextrin-based supramolecular nanoassembly.

In this study, we have constructed a binary supramolecular nanoassembly composed of α-cyclodextrin-modified hyaluronic acid and an azobenzene-modified diphenylalanine derivative with a positively charged imidazole group. This nanoassembly can bind with siRNA through electrostatic interactions and efficiently delivered them into cancer cells and inhibited their growth.

Alpha-cyclodextrin as a new functional ingredient in low-fat chicken frankfurter.

1. The current consumer preference for healthier meat products is associated with less additives in manufacturing (so-called 'clean-label') or the addition of non-meat ingredients with functional properties, recognised as improving specific technological properties in meat products.2. This study evaluated the effect of the addition of alpha-cyclodextrin and wheat fibre to low-fat chicken frankfurters containing 35% mechanically deboned chicken meat on the technological and sensorial properties during refrigerated storage.3. The results showed that the addition of dietary fibres (alpha-cyclodextrin and wheat fibre) in low-fat chicken frankfurters improved emulsion stability, hardness, chewiness and reduced cohesiveness.4. Alpha-cyclodextrin helped the retention of fat globules in the microstructure and affected colour in the sensorial evaluation.5. The use of alpha-cyclodextrin, in combination with wheat fibre, as a new ingredient to substitute fat in emulsified meat products containing mechanically deboned chicken, improved emulsion stability and texture.6. Alpha-cyclodextrin and wheat fibre were effective in contributing to fat reduction without affecting the sensory properties of the product.

Effects of alpha-cyclodextrin on cholesterol control and Compound K on glycaemic control in people with pre-diabetes: Protocol for a Phase III randomized controlled trial.

The prevalence of pre-diabetes and of type 2 diabetes mellitus is increasing. Preventing disease progression is important to improve outcomes. Natural products are becoming popular alternatives to pharmaceutical products for preventative health and treatment of disease; however, the evidence to support the use of natural alternatives for pre-diabetes and type 2 diabetes is lacking. Two such natural medicines include alpha-cyclodextrin (marketed as FBCx), a fibre derived from corn starch that has been found to bind triglycerides in the intestines to prevent its absorption, aiding weight maintenance and lipid control, and hydrolysed ginseng extract (marketed as GINST15), a formula containing high amounts of Compound K, a metabolite of ginsenosides thought to be an active ingredient contributing to the anti-hyperglycaemic effects of ginseng. This paper describes the rationale and design of a 12-month randomized controlled trial to investigate the metabolic effects of these two products in people with pre-diabetes and overweight or obesity. A total of 400 participants will be randomized to one of four groups (FBCx + GINST15, FBCx + placebo, placebo + GINST15, placebo + placebo) for 6 months, followed by 6 months of follow-up. Participants will also receive lifestyle advice for healthy eating and weight loss. Data collected during the trial will include weight, waist circumference, body composition and blood pressure. Blood samples will also be collected to measure lipid profile and glycaemia. If the products are found to improve lipid and glucose levels, it will provide evidence for their use in people with pre-diabetes to help reduce the risk of progression to type 2 diabetes.

Interaction Studies Between Levodopa and Different Excipients to Develop Coground Binary Mixtures for Intranasal Application.

Levodopa (LEVO) as the gold standard in the treatment of Parkinson's disease is usually administrated per os but its bioavailability is low. The intranasal administration is a potential alternative route to increase bioavailability of the drug and treat the off period. Our aim was to develop LEVO-containing binary nasal powders with different excipients by dry cogrinding process. The interactions between the components were examined. The optimized cogrinding process parameters (LEVO:excipient ratio and grinding time) resulted in the desired particle size range (5-40 µm). The α-cyclodextrin and poly(vinylpyrrolidone) (PVP) had an intensive crystallinity degree reducing effect on LEVO measured by XRPD, and they functioned as cogrinding agents. Hydroxypropyl methylcellulose, poly (vinyl alcohol) (PVA), and D-mannitol associate around the LEVO crystals preventing its crystalline structure. Hydrogen bonding was detected only for LEVO-PVP and LEVO-D-mannitol used Fourier-transformed infrared spectroscopy. Chemical degradation of LEVO in the products was not detected even after the accelerated stability test. The dissolution profile of the products can be characterized by the first-order kinetic model with different dissolution rate. The dissolution rate of LEVO was increased with α-cyclodextrin and PVP, and the drug release decreased in the case of hydroxypropyl methylcellulose, PVA, and D-mannitol compared to the LEVO powder.

The Soluble Fiber α-Cyclodextrin Does Not Increase the Fecal Losses of Dietary Fat in Adults-A Double-Blind, Randomized, Placebo-Controlled, Crossover Trial.

Background: α-Cyclodextrin (α-CD), a soluble dietary fiber, may improve abnormal plasma lipids and promote weight loss. Preliminary evidence suggests that it may exert these effects by binding dietary fat and reducing absorption; this has not been tested in humans. Objective: The primary objective was to test whether supplemental α-CD increases fecal content of dietary lipid in humans. Methods: This was a randomized, double-blind, placebo-controlled, crossover study completed at the Mayo Clinic. Eight healthy volunteers, 5 premenopausal women and 3 men ages 23-54 y with body mass index (BMI; kg/m2) 18-27, underwent 2 separate study visits with a ≥2-wk washout period. The first morning of each visit volunteers consumed a standardized breakfast (14.5% protein, 27.5% fat, 60% carbohydrate, and 1.5 kcal/mL) containing [14C]tripalmitin and [3H]triolein with 2 g of α-CD or placebo, followed by 2 g of α-CD or placebo per meal for 2 more days. Volunteers consumed 100 g/d of dietary fat. Feces were collected for 72 h after the labeled breakfast to measure radiotracer content and total fecal fat. Radiotracer appearance in plasma TGs was measured at intervals after the labeled meal as a secondary outcome. Results: Virtually no 3H radiotracer, but an average of ∼20% of the 14C radiotracer was recovered in fecal lipids, with no difference between α-CD and placebo. Total fecal fat content and radiotracer appearance in postprandial plasma TGs did not differ between the α-CD and placebo treatments. Plasma appearance of 14C-TG was 37% ± 14% less (P < 0.0001) than 3H-TG. Conclusions: α-CD supplementation did not increase loss of dietary lipid in stool or total fecal fat compared with placebo in healthy adults. Greater stool loss and lesser appearance in plasma TGs of tripalmitin-derived [14C] compared with triolein-derived [3H] TGs imply different metabolic handling of these 2 dietary fat tracers. This trial was registered at www.clinicaltrials.gov as NCT03002168.

Complex polymorphisms in endocytosis genes suggest alpha-cyclodextrin as a treatment for breast cancer.

Most breast cancer deaths are caused by metastasis and treatment options beyond radiation and cytotoxic drugs, which have severe side effects, and hormonal treatments, which are or become ineffective for many patients, are urgently needed. This study reanalyzed existing data from three genome-wide association studies (GWAS) using a novel computational biostatistics approach (muGWAS), which had been validated in studies of 600-2000 subjects in epilepsy and autism. MuGWAS jointly analyzes several neighboring single nucleotide polymorphisms while incorporating knowledge about genetics of heritable diseases into the statistical method and about GWAS into the rules for determining adaptive genome-wide significance. Results from three independent GWAS of 1000-2000 subjects each, which were made available under the National Institute of Health's "Up For A Challenge" (U4C) project, not only confirmed cell-cycle control and receptor/AKT signaling, but, for the first time in breast cancer GWAS, also consistently identified many genes involved in endo-/exocytosis (EEC), most of which had already been observed in functional and expression studies of breast cancer. In particular, the findings include genes that translocate (ATP8A1, ATP8B1, ANO4, ABCA1) and metabolize (AGPAT3, AGPAT4, DGKQ, LPPR1) phospholipids entering the phosphatidylinositol cycle, which controls EEC. These novel findings suggest scavenging phospholipids as a novel intervention to control local spread of cancer, packaging of exosomes (which prepare distant microenvironment for organ-specific metastases), and endocytosis of ß1 integrins (which are required for spread of metastatic phenotype and mesenchymal migration of tumor cells). Beta-cyclodextrins (ßCD) have already been shown to be effective in in vitro and animal studies of breast cancer, but exhibits cholesterol-related ototoxicity. The smaller alpha-cyclodextrins (αCD) also scavenges phospholipids, but cannot fit cholesterol. An in-vitro study presented here confirms hydroxypropyl (HP)-αCD to be twice as effective as HPßCD against migration of human cells of both receptor negative and estrogen-receptor positive breast cancer. If the previous successful animal studies with ßCDs are replicated with the safer and more effective αCDs, clinical trials of adjuvant treatment with αCDs are warranted. Ultimately, all breast cancer are expected to benefit from treatment with HPαCD, but women with triple-negative breast cancer (TNBC) will benefit most, because they have fewer treatment options and their cancer advances more aggressively.

α-Amylase triggered carriers based on cyclodextrin anchored hollow mesoporous silica for enhancing insecticidal activity of avermectin against Plutella xylostella.

α-Amylase-responsive carrier for controlled release of avermectin (AVM) was prepared based on α-cyclodextrin (α-CD) anchored hollow mesoporous silica (HMS) using α-CD as a capping molecule. The release of AVM was studied at different temperatures, pH values and in the presence or absence of α-amylase. The results revealed that the AVM-encapsulated controlled release formulation (AVM-CRF) has a drastic enzymatic dependence, an excellent encapsulation efficacy reaching 38%, and outstanding UV and thermal shielding ability. The AVM-CRF biological activity survey shows excellent toxicological properties against Plutella xylostella larvae, which confirms that α-CD caps could be uncapped enzymatically in vivo and release AVM, inducing P. xylostella larval death. AVM-CRF has a notable capability to keep 0.6 mg L-1 AVM biologically active until 14th day with 83.33% mortality of the target insect, which was 40% higher than that of treated with AVM commercial formulation. The study provides a theoretical basis for the application of pesticide reduction.

Development of pre-activated α-cyclodextrin as a mucoadhesive excipient for intra-vesical drug delivery.

The study was designed to synthesize and characterize pre-activated α-cyclodextrin (α-CD) derivatives as mucus adhering excipients for intra-vesical drug delivery. Sodium periodate (NaIO4) was used to oxidize α-CD and subsequently cysteamine was covalently attached to carbonyl groups of oxidized α-CD via reductive amination to produce thiolated α-CD. l-cysteine-2-mercaptonicotinic acid conjugate (Cys-MNA) was covalently attached to carbonyl groups of oxidized α-CD to produce pre-activated α-CD having enhance stability against oxidation at higher pH. Thiolated and pre-activated α-CD derivatives were quantitatively assayed for the attached thiol groups and MNA groups, respectively. Cell viability and tolerability was evaluated via resazurin assay and via red blood cells (RBC) lysis assay, respectively. Mucoadhesive properties were evaluated on porcine bladder mucosa. Trimethoprim (TMP) was encapsulated into thiolated and pre-activated α-CD derivatives and the dissolution behavior was evaluated in vitro. Thiol groups attached to thiolated α-CD derivatives α-CD-SH780 and α-CD-SH1426 were 780±68µmol/g and 1426±66µmol/g, respectively. For the entirely pre-activated α-CD derivatives, α-CD-MNA3609 and α-CD-MNA4285 number of attached MNA groups were 3609±19µmol/g and 4285±43µmol/g, respectively. Thiolated and pre-activated derivatives of α-CD did not show adverse effects to cells determined via resazurin and RBC lysis assays. Mucoadhesion on porcine bladder mucosa was significantly improved for thiolated and pre-activated α-CD derivatives. Thiolated α-CD-SH1426 showed 15-fold and pre-activated α-CD-MNA4285 showed 25-fold improved mucoadhesion compared to unmodified α-CD. Further, pre-activated α-CD-MNA4285 showed 2-fold enhanced dissolution of encapsulated TMP compared to free TMP over 3 h. The study shows that pre-activated α-CD could be an excipient of the choice for the formulations of mucoadhesive intra-vesical drug delivery systems.

Randomized double blind clinical trial on the effect of oral α-cyclodextrin on serum lipids.

BACKGROUND: This single center, double-blinded, cross-over, placebo controlled clinical trial investigated the effect of oral α-cyclodextrin (α-CD), a soluble dietary fiber, on blood lipid and lipoprotein levels in healthy human subjects. α-CD, a cyclical polymer containing 6 glucose subunits, is currently sold as an over the counter food supplement and is also a common additive in many foods. α-CD forms a hydrophobic central cavity that binds lipids and has been shown in animal studies and in previous clinical trials to alter plasma lipid levels. METHODS: We screened for healthy subjects, males and females, between ages 18 to 75. Out of total 103 subjects interviewed, 75 subjects completed the study. Qualified individuals in each gender group were randomized into two groups in terms of which treatment arm they received first (placebo vs. α-CD, receiving 6 grams P.O. a day, for 12-14 weeks with a 7 day wash out between arms). The primary outcome variable, plasma total cholesterol, as well as other tests related to lipids and lipoprotein and glucose metabolism, were measured at baseline and at the end of each arm of the study. RESULTS: α-CD was well tolerated; no serious adverse events related to α-CD were observed. Approximately 8 % of the subjects on α-CD complained of minor gastrointestinal symptoms versus 3 % on placebo (p = 0.2). Small-LDL particle number decreased 10 % (p < 0.045) for subjects on α-CD versus placebo. Fasting plasma glucose (1.6 %, p < 0.05) and Insulin resistance index (11 %, p < 0.04) were also decreased when on α-CD versus placebo. CONCLUSION: α-CD treatment appears to be safe and well tolerated in healthy individuals and showed a modest reduction in small LDL particles, and an improvement in glucose related parameters. TRIAL REGISTRATION: NCT01131299.

Dual stimuli-responsive multi-drug delivery system for the individually controlled release of anti-cancer drugs.

A dual stimuli-responsive multi-drug delivery system was developed for "cancer cocktail therapy". Upon UV irradiation, microcapsules could rapidly release the small-molecule drugs, and thereafter the macromolecular drugs would be released in the presence of MMP in the tumor cells. This system will find great potential as a novel chemotherapeutic combination for cancer treatment.

Supramolecular gels of poly-α-cyclodextrin and PEO-based copolymers for controlled drug release.

The aim of this work was to prepare syringeable supramolecular gels of α-cyclodextrin-polymer (poly-αCD) with various poly(ethylene oxide) (PEO)-based copolymers, which can be suitable to form depots for controlled drug release. A series of water-soluble poly-αCDs was synthesized from αCD by crosslinking with epichlorohydrin in alkaline medium. The chemical composition of the polymers was characterized by NMR (αCD content>53%) and the molecular weight was evaluated using static light scattering (SLS). Supramolecular assemblies occurred by mixing poly-αCD (20-40% w/v) with a PEO-based polymer (i.e., PEG, Pluronic® F127 or Tetronic® 908) (10-15% w/v). Phase separation was observed and the αCD content in each phase was determined by means of the phenol-sulfuric acid colorimetric method. Formation of poly-αCD/PEO-based polymer 3D-supramolecular complexes was confirmed by diffusion-ordered NMR spectroscopy (DOSY) and X-ray diffractometry. The supramolecular assemblies showed good cytocompatibility against SAOS-2 cells and in the HET-CAM test. The supramolecular gels were able to sustain the release of vancomycin for at least 5 days at 37 °C, more efficiently than dispersions of each polymer component in separate. These results open new possibilities in the design of novel controlled delivery systems for the treatment of bone infections.

Oil-cyclodextrin based beads for oral delivery of poorly-soluble drugs.

The main interest of cyclodextrins results from their ability to form inclusion complexes with hydrophobic molecules. This property is employed in pharmaceutical industry to facilitate the formulation of poorly-soluble and/or fragile drugs. Cyclodextrins are also used to form or stabilise dispersed systems. An original multiparticulate system named "beads" is obtained thanks to the interactions occurring between the molecules of α cyclodextrin and the triglycerides of vegetable oils. Beads are prepared by a simple process involving the external shaking of a mixture of an aqueous solution of α cyclodextrin with soybean oil. This is done without any organic solvent or surface-active agent. Once freezedried, beads have a diameter of 1.6 mm and a high lipid content. They consist in a partially crystalline matrix of cyclodextrin surrounding microdomains of oil. The coating of beads with a layer of α cyclodextrin improves their resistance in gastro- intestinal fluids and prolongs the release of drugs. Beads can also be manufactured from mineral oils with α cyclodextrin and from silicone oils with γ cyclodextrin. Poorly-soluble drugs which do not form inclusion complexes with α cyclodextrin are encapsulated in beads with high efficiency and drug loading. In rats, the oral bioavailability of isotretinoin is twofold enhanced with uncoated beads as compared to the lipid content of a soft capsule. The relative oral bioavailability of indomethacin is improved with both coated and uncoated beads versus a commercial hard capsule. Beads demonstrate an important potential for the encapsulation of poorly-soluble and/or fragile compounds and their delivery by oral route.

[Preparation and in vitro evaluation of self-assembled beads drug delivery system of berberine hydrochloride].

The purpose of the present work was to investigate the innovative self-assembling system, "beads", prepared by continuously shaking alpha-cyclodextrin and soybean oil without the use of organic solvents and surfactants at room temperature. Berberine hydrochloride previously dissolved in soybean oil was chosen as a model drug to explore the shape, structure, drug loading and in vitro release of beads. The particle size and drug loading of berberine hydrochloride-loaded beads were (2.25 +/- 0.23) mm and (67.02 +/- 0.64) microg x g(-1), respectively. Confocal microscopy showed that the core-shell structure of beads could contain poorly water soluble drugs or lipophilic drugs in the lipid core. The drug release rate and cumulative releases of beads were both higher than those of raw medicine of berberine hydrochloride in simulated intestinal fluid. These results suggested that beads were the novel and potential lipid-based drug delivery system for lipophilic or poorly water soluble traditional Chinese medicine.

Design and evaluation of polyamidoamine dendrimer conjugate with PEG, α-cyclodextrin and lactose as a novel hepatocyte-selective gene carrier in vitro and in vivo.

To develop a novel hepatocyte-selective gene carrier, we prepared polyamidoamine starburst dendrimer (generation 3, G3) conjugates with three functional molecules, i.e. α-cyclodextrin, polyethylene glycol (PEG, molecular weight = 2170) and lactose (PEG-LαCs), and evaluated gene delivery efficiency of these conjugates in vitro and in vivo. PEG-LαC (G3, degrees of substitution of the PEG moiety (DSP) 2.1) showed higher gene transfer activity than other PEG-LαCs (G3, DSP4.0, 6.2) in HepG2 cells, expressing asialoglycoprotein receptor, and the activity decreased in HeLa cells, non-expressing the receptor and in the presence of asialofetuin. High gene transfer activity of PEG-LαC (G3, DSP2.1) was retained even in the presence of 50% serum, although the activity of α-cyclodextrin/lactosylated dendrimer (G3) conjugate (Lac-α-CDE (G3)), which is lacking a PEG moiety, was severely decreased in the presence of 20% serum. PEG-LαC (G3, DSP2.1) provided negligible cytotoxicity up to a charge ratio of 50 (carrier/pDNA) in HepG2 cells and less acute organ toxicity. PEG-LαC (G3, DSP2.1) showed selective gene transfer activity to hepatic parenchymal cells rather than hepatic non-parenchymal cells. These results suggest that PEG-LαC (G3, DSP2.1) is useful as a hepatocyte-selective gene carrier in vitro and in vivo.

Limaprost alfadex and nonsteroidal anti-inflammatory drugs for sciatica due to lumbar spinal stenosis.

PURPOSE: Limaprost, a prostaglandin E1 analog, has vasodilatory properties and increases blood flow of the nerve root. However, it has not been clarified whether limaprost affects pain sensation associated with radiculopathy due to lumbar spinal stenosis (LSS). The aim of this study was to compare the efficacy of oral limaprost with nonsteroidal anti-inflammatory drugs (NSAIDs) for radiculopathy. METHODS: We performed a multicenter prospective randomized trial. Patients with LSS who had radicular-type neurologic intermittent claudication assessed based on a self-reported diagnostic support tool were randomized into three treatment groups. Limaprost, NSAIDs, or limaprost plus NSAIDs were administered orally for 6 weeks. Leg pain, low back pain (LBP) and the associated symptoms were assessed by a numerical rating scale (NRS) both at rest and on movement as well as the Roland-Morris Disability Questionnaire (RDQ) and Short Form (SF)-36. RESULTS: Sixty-one patients were enrolled in the study. Each treatment finally reduced radicular pain, and the improvement was prominent in a combination treatment. There were no significant differences in radicular pain among three groups at final follow-up. LBP was not influenced by limaprost, and a significant reduction of LBP and RDQ was confirmed in a combination treatment compared with limaprost. Physical function of the SF-36 subscales after a combination treatment showed a marked alleviation compared with NSAIDs. CONCLUSIONS: These obtained findings suggest that the effects of limaprost seem to be limited to radicular pain, not for LBP. Overall, a combination treatment might be more effective in the management of radiculopathy induced by LSS than monotherapy with either agent.

Folate-PEG-appended dendrimer conjugate with α-cyclodextrin as a novel cancer cell-selective siRNA delivery carrier.

We previously reported that of the various polyamidoamine (PAMAM) STARBURST dendrimer (generation 3, G3) (dendrimer) conjugates with cyclodextrins (CyDs), the dendrimer (G3) conjugate with α-CyD having an average degree of substitution of 2.4 (α-CDE (G3)) has the greatest potential for a novel carrier for siRNA in vitro and in vivo. To improve the siRNA transfer activity and the lack of target specificity of α-CDE (G3), we prepared folate-polyethylene glycol (PEG)-appended α-CDEs (G3) (Fol-PαCs) with various degrees of substitution of folate (DSF) and evaluated their siRNA transfer activity to folate receptor (FR)-overexpressing cancer cells in vitro and in vivo. Of the three Fol-PαCs (G3, DSF 2, 4 and 7), Fol-PαC (G3, DSF 4) had the highest siRNA transfer activity in KB cells (FR-positive). Fol-PαC (G3, DSF 4) was endocytosed into KB cells through FR. No cytotoxicity of the siRNA complex with Fol-PαC (G3, DSF 4) was observed in KB cells (FR-positive) or A549 cells (FR-negative) up to the charge ratio of 100/1 (carrier/siRNA). In addition, the siRNA complex with Fol-PαC (G3, DSF 4) showed neither interferon response nor inflammatory response. Importantly, the siRNA complex with Fol-PαC (G3, DSF 4) tended to show the in vivo RNAi effects after intratumoral injection and intravenous injection in tumor cells-bearing mice. The FITC-labeled siRNA and TRITC-labeled Fol-PαC (G3, DSF 4) were actually accumulated in tumor tissues after intravenous injection in the mice. In conclusion, the present results suggest that Fol-PαC (G3, DSF 4) could potentially be used as a FR-overexpressing cancer cell-selective siRNA delivery carrier in vitro and in vivo.

α-Cyclodextrin dimer complexes of dopamine and levodopa derivatives to assess drug delivery to the central nervous system: ADME and molecular docking studies.

This paper attempts to predict and emphasize molecular interactions of dopamine, levodopa, and their derivatives (Dopimid compounds) containing 2-phenyl-imidazopyridine moiety with the α-cyclodextrin dimer in order to assess and improve drug delivery to the central nervous system. The molecular docking method is used to determine the energetic profiles, hydrogen bond formation, and hydrophobic effect of 14 host-guest complexes. The results show that the "chemical branching" represented by additional ethyl-acetate residue is energetically unfavorable and promotes a conformational shift due to the high root mean square deviation levels. This phenomenon is characterized by a low number of H-bonds and a significant decrease of the host-guest hydrophobic potential surface. Finally, the overall docking procedure presents a powerful rationale for screening and analyzing various sets of promising drug-like chemical compounds in the fields of supramolecular chemistry, molecular sensing, synthetic receptors, and nanobiotechnology.