ABSTRACT
The current study aimed to evaluate the efficacy of orally administered rapid mini-tablets containing atomoxetine hydrochloride (ODMT) relative to the conventional capsule formulation of atomoxetine hydrochloride (ATO). To mask the bitter taste of ATO and render it more palatable for pediatric administration in individuals with Attention Deficit Hyperactivity Disorder (ADHD), an inclusion complex of ATO with ß-cyclodextrin (ß-CD) was synthesized. The ODMT and conventional capsule ATO formulations were administered orally to a cohort of ADHD rat pups born to nicotine-exposed dams, facilitating an in vivo efficacy assessment. Behavioral assays, including the open field test, novel object recognition test, and Barnes maze test, were conducted pre- and post-administration of the therapeutics. The outcomes suggested that the ODMT formulation, incorporating ATO-ß-CD inclusion complexes, shows promise as a viable alternative to the capsule form of ATO. Conclusively, the preparation of the ATO-ß-CD complexes and ODMTs leveraged a factorial experimental design, with the animal model being subjected to nicotine-induced hyperactivity to provide a unique evaluative framework for the ODMT formulation under development.
Subject(s)
Atomoxetine Hydrochloride , Attention Deficit Disorder with Hyperactivity , Disease Models, Animal , Nicotine , beta-Cyclodextrins , Animals , Atomoxetine Hydrochloride/pharmacology , Atomoxetine Hydrochloride/administration & dosage , Attention Deficit Disorder with Hyperactivity/drug therapy , Nicotine/administration & dosage , Rats , beta-Cyclodextrins/pharmacology , beta-Cyclodextrins/administration & dosage , Male , Administration, Oral , Female , Behavior, Animal/drug effects , Rats, Sprague-Dawley , Adrenergic Uptake Inhibitors/pharmacology , Adrenergic Uptake Inhibitors/administration & dosageABSTRACT
Piroxicam (PX) is a nonsteroidal anti-inflammatory drug (NSAID) commonly associated with gastrointestinal (GI) injuries, including dyspepsia, heartburn, inflammation, bleeding, ulceration, and life-threatening perforation. The ß-cyclodextrin (ß-CD)-based PX formulation (PX@CD) has been shown to reduce gastric side effects by improving PX's solubility and dissolution rates. However, the solubility of PX can only be increased to a limited extent by ß-CD, due to the low binding constant between PX and ß-CD (â¼100 M-1). As a result, adverse reactions such as epigastric pain and pyrosis are still commonly reported. Cucurbit[7]uril (CB[7]) is a synthetic macrocyclic host compound that binds strongly to various drugs. In this study, we demonstrated that CB[7] forms complexes with PX in the gastric acid environment with a binding constant approximately 70 times higher than that between ß-CD and PX. The PX@CB[7] inclusion complexes exhibited rapid dissolution rates in the gastric environment. In addition, PX@CB[7] showed significantly higher oral bioavailability and maximum concentration (Cmax) compared to PX and PX@CD (1:2.5), resulting in improved anti-inflammatory effects in both mouse and rat models. Moreover, PX@CB[7] (1:2.5) had the least adhesion to the gastric mucosa and caused the mildest gastric side effects in rat models when compared to PX, PX@CD (1:2.5), and PX@CB[7] (1:1). Lastly, CB[7] demonstrated good oral biocompatibility in a subacute toxicity evaluation study. These findings indicate that CB[7] could be used as an excipient to improve treatment effectiveness and decrease adverse reactions in orally administered formulations with a favorable safety profile.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal , Biological Availability , Bridged-Ring Compounds , Imidazoles , Piroxicam , Solubility , beta-Cyclodextrins , Animals , Piroxicam/administration & dosage , Piroxicam/chemistry , Piroxicam/pharmacokinetics , Piroxicam/adverse effects , Imidazoles/chemistry , Imidazoles/administration & dosage , Imidazoles/pharmacokinetics , Imidazoles/adverse effects , Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/administration & dosage , Bridged-Ring Compounds/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , beta-Cyclodextrins/chemistry , beta-Cyclodextrins/administration & dosage , Male , Mice , Rats, Sprague-Dawley , Rats , Drug Liberation , Administration, Oral , Heterocyclic Compounds, 2-Ring , Macrocyclic Compounds , ImidazolidinesABSTRACT
The nasal administration route has been studied for the delivery of active molecules directed to the Central Nervous System, thanks to the anatomical connection between the nasal cavity and the brain. Dimethyl fumarate is used to treat relapsing-remitting multiple sclerosis, with a role as an immunomodulator towards T- T-cells and a cytoprotector towards neurons and glial cells. Its use in therapy is hindered by its low aqueous solubility, and low stability, due to hydrolysis and sublimation at room temperature. To overcome this limitation, in this study we evaluated the feasibility of using two amorphous ß-cyclodextrin derivatives, namely hydroxypropyl ß-cyclodextrin and methyl ß-cyclodextrin, to obtain a nasally administrable powder with a view to nose-to-brain administration. Initially, the interaction product was studied using different analytical methods (differential scanning calorimetry, Fourier transform infrared spectroscopy and powder X-ray diffraction) to detect the occurrence of binary product formation, while phase solubility analysis was used to probe the complexation in solution. The dimethyl fumarate-cyclodextrin binary product showing best solubility and stability properties was subsequently used in the development of a chitosan-based mucoadhesive nasally administrable powder comparing different preparative methods. The best performance in terms of both hydrolytic stability and DMF recovery was achieved by the powder obtained via freeze-drying.
Subject(s)
Administration, Intranasal , Chitosan , Dimethyl Fumarate , Drug Stability , Powders , Solubility , beta-Cyclodextrins , Dimethyl Fumarate/administration & dosage , Dimethyl Fumarate/chemistry , Dimethyl Fumarate/pharmacokinetics , Chitosan/chemistry , Chitosan/administration & dosage , beta-Cyclodextrins/chemistry , beta-Cyclodextrins/administration & dosage , Brain/metabolism , 2-Hydroxypropyl-beta-cyclodextrin/chemistry , Spectroscopy, Fourier Transform Infrared/methods , Calorimetry, Differential Scanning , X-Ray Diffraction/methodsABSTRACT
PURPOSE/BACKGROUND: Brexanolone is approved for postpartum depression (PPD) by the United States Food and Drug Administration. Brexanolone has outperformed placebo in clinical trials, but less is known about the efficacy in real-world patients with complex social and medical histories. Furthermore, the impact of brexanolone on large-scale brain systems such as changes in functional connectivity (FC) is unknown. METHODS/PROCEDURES: We tracked changes in depressive symptoms across a diverse group of patients who received brexanolone at a large medical center. Edinburgh Postnatal Depression Scale (EPDS) scores were collected through chart review for 17 patients immediately prior to infusion through approximately 1 year postinfusion. In 2 participants, we performed precision functional neuroimaging (pfMRI), including before and after treatment in 1 patient. pfMRI collects many hours of data in individuals for precision medicine applications and was performed to assess the feasibility of investigating changes in FC with brexanolone. FINDINGS/RESULTS: The mean EPDS score immediately postinfusion was significantly lower than the mean preinfusion score (mean change [95% CI]: 10.76 [7.11-14.40], t (15) = 6.29, P < 0.0001). The mean EPDS score stayed significantly lower at 1 week (mean difference [95% CI]: 9.50 [5.23-13.76], t (11) = 4.90, P = 0.0005) and 3 months (mean difference [95% CI]: 9.99 [4.71-15.27], t (6) = 4.63, P = 0.0036) postinfusion. Widespread changes in FC followed infusion, which correlated with EPDS scores. IMPLICATIONS/CONCLUSIONS: Brexanolone is a successful treatment for PPD in the clinical setting. In conjunction with routine clinical care, brexanolone was linked to a reduction in symptoms lasting at least 3 months. pfMRI is feasible in postpartum patients receiving brexanolone and has the potential to elucidate individual-specific mechanisms of action.
Subject(s)
Depression, Postpartum , Feasibility Studies , Pregnanolone , beta-Cyclodextrins , Humans , Female , Adult , Pregnanolone/administration & dosage , Pregnanolone/pharmacology , Pilot Projects , Depression, Postpartum/drug therapy , beta-Cyclodextrins/administration & dosage , beta-Cyclodextrins/pharmacology , Functional Neuroimaging , Drug Combinations , Young Adult , Treatment Outcome , Brain/drug effects , Brain/diagnostic imaging , Magnetic Resonance ImagingABSTRACT
Febuxostat (FBX), a potent xanthine oxidase inhibitor, is widely used as a blood uric acid-reducing agent and has recently shown a promising repurposing outcome as an anti-cancer. FBX is known for its poor water solubility, which is the main cause of its weak oral bioavailability. In a previous study, we developed a binary system complex between FBX and sulfobutylether-ß-cyclodextrin (SBE7-ßCD) with improved dissolution behavior. The aim of the current study was to investigate the effect of incorporating a water-soluble polymer with a binary system forming a ternary one, on further enhancement of FBX solubility and dissolution rate. In vivo oral bioavailability was also studied using LC-MS/MS chromatography. The polymer screening study revealed a marked increment in the solubility of FBX with SBE7-ßCD in the presence of 5% w/v polyethylene glycol (PEG 6000). In vitro release profile showed a significant increase in the dissolution rate of FBX from FBX ternary complex (FTC). Oral in vivo bioavailability of prepared FTC showed more than threefold enhancement in Cmax value (17.05 ± 2.6 µg/mL) compared to pure FBX Cmax value (5.013 ± 0.417 µg/mL) with 257% rise in bioavailability. In conclusion, the association of water-soluble polymers with FBX and SBE7-ßCD system could significantly improve therapeutic applications of the drug.
Subject(s)
Biological Availability , Febuxostat , Polyethylene Glycols , Solubility , beta-Cyclodextrins , Febuxostat/pharmacokinetics , Febuxostat/chemistry , Febuxostat/administration & dosage , Animals , beta-Cyclodextrins/chemistry , beta-Cyclodextrins/pharmacokinetics , beta-Cyclodextrins/administration & dosage , Male , Polyethylene Glycols/chemistry , Polyethylene Glycols/pharmacokinetics , Polyethylene Glycols/administration & dosage , Administration, Oral , Water/chemistry , Drug Liberation , Rats, Sprague-Dawley , RatsABSTRACT
Stigmasterol, a plant-derived sterol, sharing structural similarity with cholesterol, has demonstrated anti-osteoarthritis (OA) properties, attributed to its antioxidant and anti-inflammatory capabilities. Given that OA often arises in weight bearing or overused joints, prolonged localized treatment effectively targets inflammatory aspects of the disease. This research explored the impact of stigmasterol-loaded nanoparticles delivered via intra-articular injections in an OA rat model. Employing mesoporous silica nanomaterials (MSNs) combined with ß-cyclodextrin (ß-CD) as a vehicle, stigmasterol was loaded in conjunction with tannic acid, forming stigmasterol/ß-CD-MSNs to facilitate a sustained stigmasterol release. The study employed RAW 264.7 cells to examine the in vitro cytotoxicity and anti-inflammatory effect of stigmasterol/ß-CD-MSNs. For in vivo experimentation, we used healthy control rats and monosodium iodoacetate (MIA)-induced OA rats, separated into five groups, varying the injection substances. In vitro findings indicated that stigmasterol/ß-CD-MSNs suppressed the mRNA expression of key pro-inflammatory mediators such as interleukin-6, tumor necrosis factor-α, and matrix metalloproteinase-3 in a dose-dependent manner. In vivo experiments revealed a substantial decrease in the mRNA levels of pro-inflammatory factors in the stigmasterol(50 µg)/ß-CD-MSN group compared to the others. Macroscopic, radiographic, and histological evaluations established that intra-articular injections of stigmasterol/ß-CD-MSNs inhibited cartilage degeneration and subchondral bone deterioration. Therefore, in a chemically induced OA rat model, intra-articular stigmasterol delivery was associated with reduction in both local and systemic inflammatory responses, alongside a slowdown in joint degradation and arthritic progression.
Subject(s)
Anti-Inflammatory Agents , Nanoparticles , Osteoarthritis , Stigmasterol , Animals , Stigmasterol/administration & dosage , Stigmasterol/pharmacology , Osteoarthritis/drug therapy , Osteoarthritis/chemically induced , Injections, Intra-Articular , Nanoparticles/administration & dosage , Pilot Projects , RAW 264.7 Cells , Mice , Male , Anti-Inflammatory Agents/administration & dosage , Inflammation/drug therapy , Inflammation/chemically induced , Rats , Pain/drug therapy , Pain/chemically induced , Disease Models, Animal , beta-Cyclodextrins/administration & dosage , beta-Cyclodextrins/chemistry , Rats, Sprague-Dawley , Silicon Dioxide/administration & dosage , Silicon Dioxide/chemistry , Iodoacetic Acid , Joints/drug effects , Joints/pathologyABSTRACT
In this study, a biodegradable photodynamic antibacterial film (Car-Cur) was prepared using casting method with κ-Carrageenan (κ-Car) as film-forming substrate and curcumin-ß-cyclodextrin (Cur-ß-CD) complex as photosensitizer. The comprehensive performance of this Car-Cur film was investigated. The obtained results showed that the concentration of Cur-ß-CD was an important factor determining the properties of film including tensile strength (TS) elongation at break (EB), water vapor permeability (WVP), water content (WC) and thermal stability. When the concentration of Cur-ß-CD is 1%, the film demonstrated the maximum TS and EB, increased thermal stability, with desirable WVP and WC. Furthermore, this film also showed good photodynamic antibacterial potential against Staphylococcus aureus and Escherichia coli upon irradiation of blue LED light. Moreover, the film can be degraded in the soil in one week. In conclusion, our results suggested Car-Cur photodynamic film could be developed as biodegradable antimicrobial packaging material for food preservation.
Subject(s)
Anti-Bacterial Agents , Carrageenan , Curcumin , Escherichia coli/drug effects , Photosensitizing Agents , Staphylococcus aureus/drug effects , beta-Cyclodextrins , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/radiation effects , Carrageenan/administration & dosage , Carrageenan/chemistry , Carrageenan/radiation effects , Curcumin/administration & dosage , Curcumin/chemistry , Curcumin/radiation effects , Escherichia coli/growth & development , Food Packaging , Hot Temperature , Light , Photosensitizing Agents/administration & dosage , Photosensitizing Agents/chemistry , Photosensitizing Agents/radiation effects , Staphylococcus aureus/growth & development , Steam , Tensile Strength , beta-Cyclodextrins/administration & dosage , beta-Cyclodextrins/chemistry , beta-Cyclodextrins/radiation effectsABSTRACT
Reactive oxygen species (ROS) are aerobic products generated during cellular respiration, but in the case of oxidative stress, they become key factors in the development of inflammatory processes and chronic diseases such as diabetes and rheumatoid arthritis. In this work, Euterpe oleracea oil (EOO), as well as the complexes produced by slurry (S) and kneading (K), were analyzed for antioxidant capacity in vitro, while only the ß-cyclodextrin complex obtained by kneading (EOO-ßCD-K), which showed better complexation, was selected for anti-inflammatory assays in vivo. In the scavenging activity of OH·, the hydroxypropyl-ß-cyclodextrin complex obtained by kneading (EOO-HPßCD-K) exhibited an activity 437% higher than the pure oil. In the paw edema assay, EOO-ßCD-K reduced edema by 200% and myeloperoxidase (MPO) activity by 112%. In an air pouch model, this treatment showed a reduction in leukocyte, MPO, and Interleukin-1ß (IL-1ß) levels; meanwhile those of glutathione and IL-10 were increased, demonstrating its ability to potentiate the anti-inflammatory effect of EOO.
Subject(s)
Euterpe/chemistry , Plant Oils/chemistry , Plant Oils/pharmacology , 2-Hydroxypropyl-beta-cyclodextrin/administration & dosage , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antioxidants/administration & dosage , Antioxidants/chemistry , Antioxidants/pharmacology , Edema/drug therapy , Female , In Vitro Techniques , Male , Mice , Phytochemicals/administration & dosage , Phytochemicals/chemistry , Phytochemicals/pharmacology , Plant Oils/administration & dosage , Plants, Medicinal/chemistry , beta-Cyclodextrins/administration & dosageABSTRACT
P-glycoprotein (P-gp) plays a critical role in drug oral bioavailability, and modulation of this transporter can alter the safety and/or efficacy profile of substrate drugs. Individual oral molecular excipients that inhibit P-gp function have been considered a mechanism for improving drug absorption, but a systematic evaluation of the interaction of excipients with P-gp is critical for informed selection of optimal formulations of proprietary and generic drug products. A library of 123 oral molecular excipients was screened for their ability to inhibit P-gp in two orthogonal cell-based assays. ß-Cyclodextrin and light green SF yellowish were identified as modest inhibitors of P-gp with IC50 values of 168 µM (95% CI, 118-251 µM) and 204 µM (95% CI, 5.9-1745 µM), respectively. The lack of effect of most of the tested excipients on P-gp transport provides a wide selection of excipients for inclusion in oral formulations with minimal risk of influencing the oral bioavailability of P-gp substrates.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Excipients/pharmacology , Administration, Oral , Excipients/administration & dosage , Humans , Inhibitory Concentration 50 , Lissamine Green Dyes/administration & dosage , Lissamine Green Dyes/pharmacology , beta-Cyclodextrins/administration & dosage , beta-Cyclodextrins/pharmacologyABSTRACT
OBJECTIVE: This paper reviews the current literature available for the efficacy and safety of allopregnanolone agonists and discusses considerations for their place in therapy. LITERATURE SEARCH: A literature search was conducted utilizing PubMed, clinicaltrials.gov, and the manufacturer's website. DATA SYNTHESIS: One phase II trial and two phase III trials evaluating the efficacy and safety of brexanolone were identified. Brexanolone demonstrated efficacy through significantly reduced Hamilton Depression Rating Scale (HAM-D) scores compared to placebo in the treatment of postpartum depression (PPD). Noted adverse effects were somnolence and dizziness, excessive sedation, and loss of consciousness. One published phase II study and the interim results of two phase III trials and one phase II trial on zuranolone were included in this review. Zuranolone, an oral allopregnanolone agonist, is given as a single, 14-day course. A significant reduction in HAM-D scores was demonstrated in patients with major depressive disorder (MDD) at 15 and 28 days compared to placebo. Interim results for zuranolone in PPD and bipolar disorder (BPD) show promising reductions in HAM-D scores. Adverse effects included sedation, dizziness, and headache. PLACE IN THERAPY: Allopregnanolone agonists seem to have a role in PPD when weighing the quick onset of action and potential risks of untreated PPD. The class of medications is limited by the single course for this indication and may fit as a bridge to maintenance therapy with selective serotonin reuptake inhibitors (SSRIs). Brexanolone, specifically, is hindered by the long infusion time, hospitalization associated with administration, and risk evaluation and mitigation strategy program. Zuranolone may also have a role in MDD or BPD, but more data are needed. CONCLUSION: Allopregnanolone agonists present a novel mechanism of action in the treatment of depressive disorders. Clinical trials and interim results support significant reductions in depression scores for brexanolone in PPD, and for zuranolone in PPD, MDD, and BPD.
Subject(s)
Antidepressive Agents/pharmacology , Depressive Disorder/drug therapy , Pregnanolone/agonists , Antidepressive Agents/administration & dosage , Antidepressive Agents/adverse effects , Bipolar Disorder/drug therapy , Bipolar Disorder/physiopathology , Depression, Postpartum/drug therapy , Depressive Disorder/physiopathology , Drug Combinations , Female , Humans , Pregnancy , Pregnanes/administration & dosage , Pregnanes/adverse effects , Pregnanes/pharmacology , Pregnanolone/administration & dosage , Pregnanolone/adverse effects , Pregnanolone/pharmacology , Psychiatric Status Rating Scales , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyrazoles/pharmacology , beta-Cyclodextrins/administration & dosage , beta-Cyclodextrins/adverse effects , beta-Cyclodextrins/pharmacologyABSTRACT
The purpose of this study was to investigate the impact of anticancer drug erlotinib-randomly methylated-ß-cyclodextrin complex (ERL-RAMEB CD) on drug solubility and dissolution rate. Phase solubility study showed erlotinib displayed maximum solubility in RAMEB CD solution and the stability constant (Kc) was calculated to be 370 ± 16 M-1. The optimal formulation was obtained with ERL-RAMEB CD in a 1:1 molar ratio using the co-lyophilization technique. Differential scanning calorimetry (DSC) and Scanning electron microscopy (SEM) verified the inclusion of complex formation. In vitro dissolution study confirmed ERL-RAMEB CD as a favorable approach to increase drug dissolution with a 1.5-fold increase than free ERL at 1 h. An improved dissolution with â¼88.4% drug release at 1 h was observed, in comparison with Erlotinib with â¼58.7% release in 45 min. The in vitro cytotoxicity results indicated that the ERL-RAMEB CD inclusion complex reduced cell viability than free erlotinib. Caco-2 cell uptake that is indicative of drug intestinal permeability resulted in a 5-fold higher uptake of ERL-RAMEB CD inclusion complex than the ERL solution. Hence, ERL-RAMEB CD complexation displays a strong potential to increase dissolution and permeability of erlotinib leading eventually to enhanced oral bioavailability.
Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Erlotinib Hydrochloride/administration & dosage , Lung Neoplasms/drug therapy , A549 Cells/drug effects , Animals , Antineoplastic Agents/therapeutic use , Caco-2 Cells/drug effects , Calorimetry, Differential Scanning , Cell Line, Tumor/drug effects , Drug Liberation , Erlotinib Hydrochloride/therapeutic use , Humans , Intestinal Absorption , Methylation , Mice , Microscopy, Electron, Scanning , Solubility , Treatment Outcome , beta-Cyclodextrins/administration & dosage , beta-Cyclodextrins/therapeutic useABSTRACT
Protocatechuic aldehyde (PCAL) and protocatechuic acid (PCAC) are catechol derivatives and have broad therapeutic effects associated with their antiradical activity. Their pharmacological and physicochemical properties have been improved via the cyclodextrin (CD) encapsulation. Because the characteristics of ß-CD inclusion complexes with PCAL (1) and PCAC (2) are still equivocal, we get to the bottom of the inclusion complexation by an integrated study of single-crystal X-ray diffraction and DFT full-geometry optimization. X-ray analysis unveiled that PCAL and PCAC are nearly totally shielded in the ß-CD wall. Their aromatic rings are vertically aligned in the ß-CD cavity such that the functional groups on the opposite side of the ring (3,4-di(OH) and 1-CHO/1-COOH groups) are placed nearby the O6-H and O2-H/O3-H rims, respectively. The preferred inclusion modes in 1 and 2 help to establish crystal contacts of OHâ â â O H-bonds with the adjacent ß-CD OH groups and water molecules. By contrast, the DFT-optimized structures of both complexes in the gas phase are thermodynamically stable via the four newly formed host-guest OHâ¯O H-bonds. The intermolecular OHâ â â O H-bonds between PCAL/PCAC 3,4-di(OH) and ß-CD O6-H groups, and the shielding of OH groups in the ß-CD wall help to stabilize these antioxidants in the ß-CD cavity, as observed in our earlier studies. Moreover, PCAL and PCAC in distinct lattice environments are compared for insights into their structural flexibility.
Subject(s)
Antioxidants/chemistry , Benzaldehydes/chemistry , Catechols/chemistry , Hydroxybenzoates/chemistry , beta-Cyclodextrins/chemistry , Antioxidants/administration & dosage , Benzaldehydes/administration & dosage , Catechols/administration & dosage , Crystallography, X-Ray , Drug Delivery Systems/methods , Hydrogen Bonding , Hydroxybenzoates/administration & dosage , Thermodynamics , beta-Cyclodextrins/administration & dosageABSTRACT
In this study, two hydrophilic polymers hydroxypropyl methyl cellulose and beta-cyclodextrin (ß-CD) are used to synthesize highly responsive and spongy polymeric matrices. Porous and stimulus-responsive polymeric network was developed to improve the solubility of acyclovir (ACV) at significant level. Grafting was successfully carried out by free radical polymerization technique. Spongy matrices were characterized by percentage entrapment efficiency, drug loading, solubility studies, FTIR, powder X-ray diffraction, TGA, DSC, XRD, SEM, swelling studies, and in vitro studies. Acute oral toxicity studies were conducted to determine the safety of oral administration of prepared HPMC-ßCD-g-poly(AMPS) formulation. Porous and spongy structures were depicted in SEM images. Complex formation and thermal stability of constituents and drug (ACV) were analyzed by FTIR, TGA, and DSC spectra. XRD analysis revealed reduction in acyclovir crystallinity in spongy matrices. Particle size of optimized formulation was found in the range of 197 ± 2.55 nm. The momentous difference with reference product committed that drug solubility and release characteristics were markedly enhanced by the developed spongy matrices. Toxicity studies endorsed that developed spongy matrices were non-toxic and compatible to biological system. The efficient method of preparation, enhanced solubility, excellent physico-chemical characteristics, high dissolution, and non-toxic HPMC-ßCD-g-poly(AMPS) spongy matrices may be a promising approach for oral delivery of poorly soluble drugs.
Subject(s)
Acrylamides/chemical synthesis , Acyclovir/chemical synthesis , Alkanesulfonates/chemical synthesis , Hypromellose Derivatives/chemical synthesis , Polymerization , beta-Cyclodextrins/chemical synthesis , Acrylamides/administration & dosage , Acyclovir/administration & dosage , Administration, Oral , Alkanesulfonates/administration & dosage , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/chemical synthesis , Drug Evaluation, Preclinical/methods , Hypromellose Derivatives/administration & dosage , Male , Particle Size , Polymers/administration & dosage , Polymers/chemical synthesis , Rabbits , Solubility , Spectroscopy, Fourier Transform Infrared/methods , X-Ray Diffraction/methods , beta-Cyclodextrins/administration & dosageABSTRACT
Neuropathic pain develops due to injury to the somatosensory system, affecting the patient's quality of life. In view of the ineffectiveness of the current pharmacotherapy, substances obtained from natural products (NPs) are a promising alternative. One NP that has been discussed in the literature is hecogenin acetate (HA), a steroidal sapogenin with anti-inflammatory and antinociceptive activity. However, HA has low water solubility, which affects its bioavailability. Thus, the objective of this study was to evaluate the anti-hyperalgesic activity of pure and complexed hecogenin acetate (HA/ßCD) in an animal model of chronic neuropathic and inflammatory pain. The inclusion complex was prepared at a molar ratio of 1:2 (HA:ßCD) by the lyophilization method. For the induction of chronic inflammatory pain, the mice received an intraplantar injection of CFA (complete Freund's adjuvant), and were evaluated for mechanical hyperalgesia and for the levels of myeloperoxidase (MPO) in the skin of the paw after eight days of treatment. HA and HA/ßCD reduced mechanical hyperalgesia in relation to the vehicle group until the fourth and fifth hours, respectively, in the acute evaluation, with a superior effect of the complexed form over the pure form in the second and third hour after treatment (p < 0.001). In the chronic evaluation, HA and HA/ßCD reduced hyperalgesia in relation to the vehicle in the eight days of treatment (p < 0.001). Both pure (p < 0.01) and complexed (p < 0.001) forms reduced myeloperoxidase activity in the skin of the animals' paw. Groups of animals subjected to the same pharmacological protocol were submitted to the partial sciatic nerve ligation (PSNL) model and evaluated for mechanical and thermal hyperalgesia, and cold allodynia. HA and HA/ßCD reduced mechanical hyperalgesia until the fourth and sixth hours, respectively, and both reduced hyperalgesia in relation to the vehicle in the chronic evaluation (p < 0.001). HA and HA/ßCD also reduced thermal hyperalgesia and cold allodynia (p < 0.05 and p < 0.001, respectively). The analysis of the spinal cord of these animals showed a decrease in the levels of the pro-inflammatory cytokines TNF-α, IL-1ß and IL-6 and a reduction in the phosphorylation of NFκB and p38MAPK, as well as a decrease in microglioses compared to the vehicle group. In addition, HA/ßCD reduced the nociception induced by intraplantar injection of agonist TRPA1 (p < 0.01) and TRPM8 (p < 0.05). Treatment for eight days with HA and HA/ßCD showed no signs of gastric or liver damage. HA and HA/ßCD were, therefore, shown to have antinociceptive effects in chronic pain models. Based on our exploration of the mechanisms of the action of HA, these effects are likely to be related to inhibited leukocyte migration, interaction with the TRPA1 and TRPM8 receptors, reduced pro-inflammatory cytokines levels, microglial expression and suppression of NF-κB p65 and p38 MAPK pathway signaling. Therefore, HA/ßCD has great potential for use in the treatment of chronic pain.
Subject(s)
Hyperalgesia/drug therapy , NF-kappa B/antagonists & inhibitors , Sapogenins/administration & dosage , Spiro Compounds/administration & dosage , Steroids/administration & dosage , beta-Cyclodextrins/administration & dosage , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Acetylation , Animals , Drug Combinations , Hyperalgesia/metabolism , Male , Mice , NF-kappa B/metabolism , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
The aim of present study was to evaluate the feasibility of a naringenin-hydroxypropyl-ß-cyclodextrin (naringenin-HPßCD) inhalation solution for pulmonary delivery. Naringenin, a flavanone derived from citrus fruits, has been proven to exhibit excellent peripheral antitussive effect. To address the limitation of its poor oral bioavailability and low local concentration in the lung, a naringenin-HPßCD inhalation solution was prepared for pulmonary delivery. The aerosolization performance of formulation was evaluated by next generation impactor (NGI). Both dose-dependent and time-dependent antitussive effects of naringenin-HPßCD inhalation solution on acute cough induced by citric acid in guinea pigs were investigated. In vitro toxicity of naringenin-HPßCD inhalation solution in pulmonary Calu-3 cells was evaluated by MTS assay, and in vivo local toxicity investigation was achieved by assessing bronchoalveolar lavage (BALF) and lung histology after a 7-day inhalation treatment in guinea pigs. Fine particle fraction (FPF) of the formulation was determined as 53.09%. After inhalation treatment of 15 min, naringenin-HPßCD inhalation solution within the studied range of 0.2-3.6 mg/kg could dose-dependently reduce the cough frequency with the antitussive rate of 29.42-39.42%. Naringenin-HPßCD inhalation solution in concentration range of 100-400 µM did not decrease cell viability of Calu-3 cells, and the maximum effective dose (3.6 mg/kg) was non-toxic during the short-term inhalation treatment for guinea pigs. In conclusion, naringenin-HPßCD inhalation solution was capable for nebulization and could provide rapid response with reduced dose for the treatment of cough.
Subject(s)
2-Hydroxypropyl-beta-cyclodextrin/administration & dosage , Aerosols/chemistry , Antitussive Agents/administration & dosage , Flavanones/administration & dosage , 2-Hydroxypropyl-beta-cyclodextrin/chemistry , Administration, Inhalation , Animals , Biological Availability , Flavanones/chemistry , Guinea Pigs , Lung , beta-Cyclodextrins/administration & dosageABSTRACT
Osteoporosis is a skeletal disorder characterized by a low bone mass and density. Alendronate (Alen), a second-generation bisphosphonate drug, was indicated as the first-line regimen for the treatment of osteoporosis. However, the use of Alen has been limited due to its low bioavailability and gastrointestinal side effects. Herein, Alen-decorated nanoparticles were prepared through ionic cross-linking between poly (lactic-co-glycolic acid), ß-cyclodextrin-modified chitosan (PLGA-CS-CD), and Alen-modified alginate (ALG-Alen) for Alen loading and bone-targeted delivery. Alen was selected as a therapeutic drug and a bone-targeting ligand. The nanoparticles have negatively charged surfaces, and sustained release of Alen from the nanoparticles can be observed. Cytotoxicity detected using cell counting kit-8 (CCK-8) assay and lactate dehydrogenase release test on MC3T3 cells showed that the nanoparticles had good cytocompatibility. A hemolysis test showed that the hemolysis ratios of nanoparticles were <5%, indicating that the nanoparticles had no significant hemolysis effect. Moreover, the Alen-decorated nanoparticles exhibited enhanced binding affinity to the hydroxyapatite (HAp) disks compared with that of nanoparticles without Alen modification. Thus, the Alen-decorated nanoparticles might be developed as promising bone-targeted carriers for the treatment of osteoporosis.
Subject(s)
Alendronate , Bone Density Conservation Agents , Drug Carriers , Nanoparticles , Alendronate/administration & dosage , Alendronate/chemistry , Alginates/administration & dosage , Alginates/chemistry , Animals , Bone Density Conservation Agents/administration & dosage , Bone Density Conservation Agents/chemistry , Bone and Bones , Cell Line , Cell Survival/drug effects , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/chemistry , Drug Carriers/administration & dosage , Drug Carriers/chemistry , Drug Liberation , Durapatite/chemistry , Erythrocytes/drug effects , Goats , Hemolysis , Mice , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Osteoporosis/drug therapy , Polylactic Acid-Polyglycolic Acid Copolymer/administration & dosage , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , beta-Cyclodextrins/administration & dosage , beta-Cyclodextrins/chemistryABSTRACT
OBJECTIVES: - To describe the evolution of the SARS-CoV-2 salivary viral load of patients infected with Covid-19, performing 7 days of tri-daily mouthwashes with and without antivirals. - To compare the evolution of the SARS-CoV-2 nasal and salivary viral load according to the presence or absence of antivirals in the mouthwash. TRIAL DESIGN: This is a multi-center, randomised controlled trial (RCT) with two parallel arms (1:1 ratio). PARTICIPANTS: Inclusion criteria - Age: 18-85 years old - Clinical diagnosis of Covid-19 infection - Clinical signs have been present for less than 8 days - Virological confirmation - Understanding and acceptance of the trial - Written agreement to participate in the trial Exclusion criteria - Pregnancy, breastfeeding, inability to comply with protocol, lack of written agreement - Patients using mouthwash on a regular basis (more than once a week) - Patient at risk of infectious endocarditis - Patients unable to answer questions - Uncooperative patient The clinical trial is being conducted with the collaboration of three French hospital centers: Hospital Center Emile Roux (Le Puy en Velay, France), Clinic of the Protestant Infirmary (Lyon, France) and Intercommunal Hospital Center (Mont de Marsan, France). INTERVENTION AND COMPARATOR: Eligible participants will be allocated to one of the two study groups. Intervention group: patients perform a tri-daily mouthwash with mouthwash containing antivirals (ß-cyclodextrin and Citrox®) for a period of 7 days. CONTROL GROUP: patients perform a tri-daily mouthwash with a placebo mouthwash for a period of 7 days. MAIN OUTCOMES: Primary Outcome Measures: Change from Baseline amount of SARS-CoV-2 in salivary samples at 4 and 9 hours, 1, 2, 3, 4, 5 and 6 days. Real-time PCR assays are performed to assess salivary SARS-CoV 2 viral load. SECONDARY OUTCOME MEASURES: Change from Baseline amount of SARS-CoV-2 virus in nasal samples at 6 days. Real-time PCR assays are performed to assess nasal SARS-CoV-2 viral load. RANDOMISATION: Participants meeting all eligibility requirements are allocated to one of the two study arms (mouthwash with ß-cyclodextrin and Citrox® or mouthwash without ß-cyclodextrin and Citrox®) in a 1:1 ratio using simple randomisation with computer generated random numbers. BLINDING (MASKING): Participants, doctors and nurses caring for participants, laboratory technicians and investigators assessing the outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Both the intervention and control groups will be composed of 103 participants, so the study will include a total of 206 participants. TRIAL STATUS: The current protocol version is 6, August 4th, 2020. Recruitment began on April 6, 2020 and is anticipated to be complete by April 5, 2021. As of October 2, 2020, forty-two participants have been included. TRIAL REGISTRATION: This trial was registered on 20 April 2020 at www.clinicaltrials.gov with the number NCT04352959 . FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol." The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2)."
Subject(s)
Betacoronavirus , Clinical Laboratory Techniques/methods , Coronavirus Infections , Mouthwashes , Nasal Cavity/virology , Pandemics , Pneumonia, Viral , Saliva/virology , Adult , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Betacoronavirus/drug effects , Betacoronavirus/isolation & purification , COVID-19 , COVID-19 Testing , Coronavirus Infections/diagnosis , Coronavirus Infections/therapy , Drug Monitoring/methods , Female , Humans , Male , Mouthwashes/administration & dosage , Mouthwashes/adverse effects , Pneumonia, Viral/diagnosis , Pneumonia, Viral/therapy , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome , Viral Load , beta-Cyclodextrins/administration & dosage , beta-Cyclodextrins/adverse effectsSubject(s)
Depression, Postpartum/drug therapy , Guidelines as Topic , Pregnanolone/administration & dosage , Pregnanolone/adverse effects , beta-Cyclodextrins/administration & dosage , beta-Cyclodextrins/adverse effects , Administration, Intravenous , Adult , Depression, Postpartum/psychology , Drug Combinations , Female , Humans , Infant, Newborn , Maternal-Child Health Services/standards , Maternal-Child Health Services/trends , Patient Safety/standards , Pregnanolone/therapeutic use , beta-Cyclodextrins/therapeutic useSubject(s)
Antidepressive Agents/administration & dosage , Depression, Postpartum/drug therapy , Pregnanolone/administration & dosage , beta-Cyclodextrins/administration & dosage , Drug Combinations , Female , Health Personnel , Humans , Infant, Newborn , Infusions, Intravenous/methods , Length of Stay , Mothers , Patient Safety/standards , Severity of Illness Index , WorkforceABSTRACT
The objective of this study is to explore the associations between the patient-reported Edinburgh Postnatal Depression Scale (EPDS) and Patient Health Questionnaire (PHQ)-9 and clinician-reported 17-item Hamilton Depression Rating Scale (HAMD-17) in order to facilitate clinical decision-making. An integrated efficacy dataset of three randomized placebo-controlled trials (NCT02614547, NCT02942004, and NCT02942017) evaluating brexanolone injection, a neuroactive steroid chemically identical to allopregnanolone, in women with postpartum depression was used for this post hoc analysis. Data were pooled across treatment arms. Associations were assessed at day 30 (end-of-trial follow-up). Pearson correlation assessed the relationship between EPDS and PHQ-9 item and total scores and HAMD-17 total score. Cohen's kappa assessed agreement of EPDS remission (score < 10) and PHQ-9 remission (score < 5) with HAMD-17 remission (score ≤ 7). Ordinary least squares (OLS) regression models were used to develop equations estimating HAMD-17 total scores from EPDS and PHQ-9 scores, respectively. The total scores showed large correlations (HAMD-17/EPDS: r = 0.71, p < 0.001; HAMD-17/PHQ-9: r = 0.75, p < 0.001). Individual EPDS and PHQ-9 items significantly correlated (r= 0.35 to 0.67, all p < 0.001) with HAMD-17 total score. EPDS had 79% sensitivity and 67% specificity to detect HAMD-17 remission; corresponding estimates for PHQ-9 were 76% and 78%. OLS models yielded the following equations: HAMD-17 total = 2.66 + (EPDS total × 0.87) and HAMD-17 total = 3.99 + (PHQ-9 total × 0.97). There were large and statistically significant associations between patient-reported outcomes (EPDS, PHQ-9) and clinician-reported outcomes (HAMD-17) as clinical improvements were associated with patient-reported symptom improvement. These results provide tools to help translate clinical trial data to clinical practice, thus aiding shared decision-making for this critical population.