RESUMEN

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder. Approximately, around 2% to 3% percent of the general population experience symptoms of OCD over the course of their lifetime. OCD can lead to economic burden, poor quality of life, and disability. The characteristic features exhibited generally in OCD are continuous intrusive thoughts and periodic ritualized behaviours. Variations in genes, pathological function of Cortico-Striato-Thalamo-Cortical (CSTC) circuits and dysregulation in the synaptic conduction have been the major factors involved in the pathological progression of OCD. However, the basic mechanisms still largely unknown. Current therapies for OCD largely target monoaminergic neurotransmitters (NTs) in specific dopaminergic and serotonergic circuits. However, such therapies have limited efficacy and tolerability. Drug resistance has been one of the important reasons reported to critically influence the effectiveness of the available drugs. Inflammation has been a crucial factor which is believed to have a significant importance in OCD progression. A significant number of proinflammatory cytokines have been reportedly amplified in patients with OCD. Mechanisms of drug treatment involve attenuation of the symptoms via modulation of inflammatory signalling pathways, modification in brain structure, and synaptic plasticity. Hence, targeting inflammatory signaling may be considered as a suitable approach in the treatment of OCD. The present review focuses mainly on the significant findings from the animal and human studies conducted in this area, that targets inflammatory signaling in neurological conditions. In addition, it also focusses on the therapeutic approaches that target OCD via modification of the inflammatory signaling pathways.

Asunto(s)

Trastorno Obsesivo Compulsivo , Calidad de Vida , Animales , Humanos , Trastorno Obsesivo Compulsivo/diagnóstico , Transducción de Señal , Encéfalo/metabolismo , Cognición

RESUMEN

Diseases related to the lungs are among the most prevalent medical problems threatening human life. The treatment options and therapeutics available for these diseases are hindered by inadequate drug concentrations at pathological sites, a dearth of cell-specific targeting and different biological barriers in the alveoli or conducting airways. Nanostructured delivery systems for lung drug delivery have been significant in addressing these issues. The strategies used include surface engineering by altering the material structure or incorporation of specific ligands to reach prespecified targets. The unique characteristics of nanoparticles, such as controlled size and distribution, surface functional groups and therapeutic release triggering capabilities, are tailored to specific requirements to overcome the major therapeutic barriers in pulmonary diseases. In the present review, the authors intend to deliver significant up-to-date research in nanostructured therapies in inflammatory lung diseases with an emphasis on biocomposite-based nanoparticles.

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Lung-related disorders such as asthma, chronic obstructive pulmonary diseases and pulmonary fibrosis are the result of inflammatory processes in the human body. The causes of these lung diseases can vary from unknown to specific. Chronic obstructive pulmonary disease is most commonly caused by smoking, whereas asthma may be caused by allergens, infections, cold air or smoke. Targeting these lung-related diseases with biologically degradable polymeric nanoparticles has recently been proposed as an effective treatment. These nanoparticles can be made by combining different materials to form biocomposite nanoparticles. Different drugs can be loaded into nanoparticles, and the surface of nanoparticles can be modified to change their properties; for example, to make them target diseased parts of the lung. In this article, the authors discuss current trends in nanoparticle treatment of inflammatory lung diseases, including the significance of biologically degradable materials.

Asunto(s)

Enfermedades Pulmonares , Nanopartículas , Sistemas de Liberación de Medicamentos , Humanos , Pulmón/metabolismo , Enfermedades Pulmonares/tratamiento farmacológico , Nanopartículas/química

RESUMEN

The major challenge associated with the treatment of neurological disorders is the inefficiency of drugs to enter the Central Nervous System (CNS). Polymer-drug conjugates are now being tailored to overcome this hindrance associated with conventional drugs. The study aimed at developing polymer hybrid nasal nanocomposite for enhanced delivery of Centella to the CNS. Thiolated chitosan was complexed with Centella to form a composite using EDAC hydrochloride. The composite was characterized by FTIR, XRD, NMR, and MS. Further, this composite was converted into a nanoformulation by the ionic-gelation method, characterized, and subjected to ex vivo permeation studies. Additionally, MTT assay was performed using Human Uumbilical cord Vein Endothelial Cells (HUVECs) mimicking Blood-Brain Barrier (BBB) to establish the safety of nanocomposite. The targeting efficacy was predicted by molecular docking studies against receptors associated with BBB. The FTIR, XRD, NMR, and MS studies confirmed the chemical conjugation of thiolated chitosan with Centella. Nanocomposite characterization through SEM, AFM, and DLS confirmed the size and stability of the developed nanocomposite having a zeta potential of - 14.5 mV and PDI of 0.260. The nanocomposite showed no signs of nasal ciliotoxicity and good permeation of 89.44 ± 1.75% (mean ± SD, n = 3) at 8 h across the nasal mucosa. MTT assay showed that the nanocomposite had lesser toxicity compared to the free drug (IC50 of Centella-269.1 µg/mL and IC50 of CTC nanocomposite-485.375 µg/mL). The affinity of polymer to the BBB receptors as proved by docking studies suggests the ability of polymer-based nanocomposite to concentrate in the brain post nasal administration.

Asunto(s)

Centella , Quitosano , Nanocompuestos , Nanopartículas , Administración Intranasal , Barrera Hematoencefálica , Células Endoteliales , Humanos , Simulación del Acoplamiento Molecular , Mucosa Nasal

RESUMEN

The present work investigates the targeting efficacy of a novel thiolated polymer-based nanocomposite reinforced with glycyrrhetinic acid (GA) and loaded with 5-fluorouracil in hepatocellular carcinoma (HCC). The thiolated polymers were synthesized by EDAC-mediated conjugation reactions and lyophilization. The nanoparticles were prepared by solvent diffusion and high-pressure homogenization method. The prepared nanocomposite was characterized by Fourier transform infrared (FTIR) radiation, x-ray diffraction (XRD), dynamic light scattering (DLS), scanning electron microscopy (SEM) and atomic force microscopy (AFM) techniques. Pharmacological evaluation of the formulation was carried out on a rat model of diethylnitrosamine (DEN), and carbon tetrachloride (CCl4)-induced HCC and MTT assay was carried out with HEP-G2 cell line. In silico studies were conducted to investigate the probable mechanistic pathway of the nanocomposite. FTIR and XRD analysis indicated the successful thiolation of the polymers and confirmed the formation of the nanocomposite without any incompatibilities. DLS, SEM/EDX and AFM characterization confirmed that the nanoparticles were within the nano-size range. MTT assay implied the cytotoxic nature of the nanocomposite against hepatic carcinoma cells. The in vivo study revealed that serum SGOT, SGPT, ALP, GGT and total bilirubin levels were significantly reduced, in comparison with disease control and the result was confirmed by histopathology studies. The results of the HPLC analysis of liver homogenate confirmed the liver targeting ability of the nanocomposite. In silico studies exhibited significant binding affinity of GA and thiolated Eudragit towards liver homolog receptor-1 (LRH-1) suggesting that the developed nanocomposite could be a potential material for the treatment of HCC.

Asunto(s)

Carcinoma Hepatocelular , Ácido Glicirretínico , Neoplasias Hepáticas , Animales , Carcinoma Hepatocelular/tratamiento farmacológico , Fluorouracilo , Ácido Glicirretínico/química , Neoplasias Hepáticas/tratamiento farmacológico , Polímeros/uso terapéutico , Ratas , Espectroscopía Infrarroja por Transformada de Fourier/métodos

RESUMEN

Delivery of bisphosphonates-like risedronate has been a major challenge till date due to its poor bioavailability and gastrointestinal tract adverse effects. In this study, we explored the prospective use of risedronate functionalised chitosan nanoparticle (RISCN) for management and treatment of osteoporosis. The prepared nanoparticle was characterised by using scanning electron microscopy, atomic force microscopy, and dynamic light scattering technique. Osteoporosis was induced on quarantined female Wistar rats and treated with RISCN. Docking studies were performed to establish the molecular mechanism of RISCN in improving the bone microarchitecture. Results indicated that there was a significant improvement in bone mineral density and healing of trabecular microarchitecture with less cortical porosity on the bone surfaces of the treatment groups. Docking studies indicated a high affinity and binding of chitosan and RISCN towards the human farnesyl diphosphate synthase (FDPS). Thus, a novel risedronate-loaded chitosan nanoparticle revealed promising results in an effective bone bridging process and osteoporosis treatment.

Asunto(s)

Conservadores de la Densidad Ósea/administración & dosificación , Quitosano/química , Portadores de Fármacos/química , Nanopartículas/química , Osteoporosis/tratamiento farmacológico , Ácido Risedrónico/administración & dosificación , Animales , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/uso terapéutico , Femenino , Ratas Wistar , Ácido Risedrónico/uso terapéutico

RESUMEN

OBJECTIVE: In this study, we investigated the potential of thiolated chitosan-based mucoadhesive film, loaded with risedronate sodium in the treatment of osteoporosis. SIGNIFICANCE: Risedronate sodium is a bisphosphonate derivative having very low bioavailability when administered through the oral route. Moreover, the adverse effects associated with the drug when administered through GIT necessitate an alternative and feasible route which can improve its bioavailability and therapeutic efficacy. METHODS: Thiolation of chitosan was interpreted by different analytical techniques. The mucoadhesive films were prepared by the solvent evaporation method and evaluated for drug content analysis, swelling degree, mucoadhesive parameters, and permeation characterization. For the screening of preclinical efficacy and pharmacodynamic parameters, a methylprednisolone induced osteoporotic rat model was used. The trabecular microarchitecture and biochemical markers were evaluated for determination of bone resorption. RESULTS: The different analytical characterization of synthesized thiolated chitosan revealed that chitosan was successfully incorporated with thiol groups. The formulation containing 2:1 ratio of thiolated chitosan and HPMC-4KM was found to have the maximum swelling degree, mucoadhesive strength with a good force of adhesion and better in vitro permeability compared to the marketed formulation. With respect to trabecular microarchitecture, the drug-loaded film formulation showed superior and promising results. Furthermore, the film formulation also improved the serum level of biomarkers better than the marketed formulation. CONCLUSIONS: The results significantly suggest that risedronate loaded novel mucoadhesive film formulation could be a logical approach in the therapeutic intervention of osteoporosis.

Asunto(s)

Huesos/efectos de los fármacos , Quitosano/química , Metilprednisolona/toxicidad , Osteoporosis/tratamiento farmacológico , Ácido Risedrónico/química , Animales , Huesos/diagnóstico por imagen , Huesos/patología , Modelos Animales de Enfermedad , Composición de Medicamentos , Femenino , Microscopía Electrónica de Rastreo , Osteoporosis/inducido químicamente , Osteoporosis/patología , Ratas , Espectroscopía Infrarroja por Transformada de Fourier , Termogravimetría

RESUMEN

The plant Euphorbia tirucalli Linn has been successfully used as a tribal folk medicine in India and Africa for the management of acute inflammatory, arthritic, nociceptive pain and asthmatic symptoms. The present study was conducted to assess the anti-inflammatory, analgesic, anti-asthmatic and anti-arthritic role of the total steroid and terpenoid rich fractions of the hydro-alcoholic extract of E. tirucalli root (STF-HAETR). STF-HAETR fraction demonstrated 71.25 ± 2.5 and 74.25 ± 5.1% protection against acetic acid-induced pain and central neuropathic pain at 75 and 100 mg/kg doses, respectively. It showed 96.97% protection against acute inflammation at 100 mg/kg with 1.6-fold better activity than the standard drug. The fraction exhibited such efficacy via inhibition of proinflammatory cytokines TNF-α, IFN-γ, by 61.12 and 65.18%, respectively, at 100 µg/mL. Inhibition of cyclooxygenase and Nitric oxide synthase in a dose-dependent manner affirms its analgesic and anti-inflammatory activity. The spectrophotometric analysis reveals that STF-HAETR induces ameliorative effect against heat-induced denaturation of Bovine serum albumin (BSA) and exhibits significant anti-proteinase activity. The plant fraction also demonstrated anti-asthmatic activity by displaying 62.45% protection against histamine induced bronchoconstriction or dyspnoea. Our findings suggest that STF-HAETR could be an effective safe therapeutic agent to treat nociceptive pain, acute inflammation, asthma, and arthritis which may authenticate its traditional use.

Asunto(s)

Antiinflamatorios/farmacología , Euphorbia/química , Inflamación/tratamiento farmacológico , Dolor Nociceptivo/tratamiento farmacológico , Raíces de Plantas/química , Esteroides/farmacología , Terpenos/farmacología , Ácido Acético/farmacología , Analgésicos/farmacología , Animales , Artritis/tratamiento farmacológico , Artritis/metabolismo , Línea Celular Tumoral , Citocinas/metabolismo , Edema/tratamiento farmacológico , Edema/metabolismo , Femenino , Inflamación/metabolismo , Masculino , Medicina Tradicional/métodos , Ratones , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/metabolismo , Dolor Nociceptivo/metabolismo , Fitoterapia/métodos , Extractos Vegetales/farmacología , Prostaglandina-Endoperóxido Sintasas/metabolismo , Células RAW 264.7 , Ratas

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Gelsemium sempervirens (L.) J.St.-Hil is a herb used for the treatment of various neuroses in both homeopathic and Ayurvedic systems. The present study examines whether Gelsemium reconstituted tincture can protect against scopolamine induced cognitive discrepancies in amnesic mouse model. In order to investigate the protective mechanism of Gelsemium against dementia, in vitro acetyl cholinesterase and ß-secretase enzyme inhibition and estimation of glutathione level in mouse brain were carried out. MATERIALS AND METHODS: The inhibition study on acetyl cholinesterase and ß-secretase enzyme was conducted on brain homogenate supernatant spectrophotometrically using specific substrate. Cognitive enhancement activity was assessed by elevated plus maze and passive avoidance study in scopolamine induced dementia mouse model. Glutathione, an anti-oxidant, was measured spectrophotometrically from scopolamine induced amnesic mice brain supernatant using 5,5'-dithiobis 2-nitrobenzoic acid in the presence and absence of Gelsemium tincture. RESULTS: Significant inhibition was found with Gelsemium on AChE and ß-secretase enzyme with an IC50 of 9.25 and 16.25 µg/ml, respectively, followed by increasing glutathione levels in comparison to the untreated dementia group. The effect of Gelsemium of scopolamine-induced cognitive deficits was determined by measuring the behavioral parameters and the antioxidant status of the brain after scopolamine (1mg/kg i.p.) injected amnesic mice. Gelsemium significantly demonstrated in vivo anti-dementia activity (60% protection) and increased exploratory behavior. CONCLUSION: Our investigations indicated that alkaloid, iridoids and coumarin enriched reconstituted Gelsemium tincture extract displays promising cognitive enhancement in adult mice after short-term oral treatment. Hence, Gelsemium can be a promising anti-dementia agent, mediating the protection against amnesia, attention disorders and learning dysfunctions through dual inhibition of both acetyl cholinesterases (no false positive effect was shown), ß-secretase and antioxidant activity.

Asunto(s)

Trastornos del Conocimiento/tratamiento farmacológico , Demencia/tratamiento farmacológico , Gelsemium , Memoria/efectos de los fármacos , Fitoterapia , Preparaciones de Plantas/uso terapéutico , Acetilcolinesterasa/genética , Acetilcolinesterasa/metabolismo , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/metabolismo , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Trastornos del Conocimiento/inducido químicamente , Demencia/inducido químicamente , Glutatión/metabolismo , Masculino , Ratones , Preparaciones de Plantas/farmacología , Preparaciones de Plantas/toxicidad , ARN Mensajero/metabolismo , Escopolamina , Pruebas de Toxicidad Aguda

RESUMEN

The objective of this study is to evaluate the effect of formulation variables on different evaluation properties such as cumulative percentage release and swelling index in development of two layered buccal mucoadhesive system consisting of a highly water soluble drug risedronate sodium. The mucoadhesive systems were developed with varied concentrations of the polymers (1-2%) using plasticizer/permeation enhancer (25-50% w/w of polymer). Two layered films comprised of risedronate sodium with chitosan (85% deacetylated) and hydroxypropylmethyl cellulose (HPMC 4KM) interpolymer complex of different ratios were prepared by solvent casting method. An impermeable backing membrane of ethyl cellulose was incorporated into the films. The study shows the effect of multipolymeric films on the release of a bisphosphonates derivative. The optimized formulations showed films with uniform drug content (90.91 ± 0.17-105.53% ± 2.15), thickness (0.22 ± 0.01 mm to 0.31 ± 0.06 mm), mucoadhesivity (26 ± 3.61-42.33 ± 2.82 g), and controlled drug release profile up to a period of 10 hours. The films were also studied for swelling index, moisture uptake, viscosity, folding endurance, water vapor transmission rate, and mucoadhesive time.