Cannabis Sativa in Phytotherapy: Reappraisal of Therapeutic Potential and Regulatory Aspects.

Cannabis sativa is widely used as a folk medicine in many parts of the globe and has been reported to be a treasure trove of phytoconstituents, including cannabinoids, terpenoids, and flavonoids. Accumulating evidence from various pre-clinical and clinical studies revealed the therapeutic potential of these constituents in various pathological conditions, including chronic pain, inflammation, neurological disorders, and cancer. However, the psychoactive effect and addiction potential associated with cannabis use limited its clinical application. In the past two decades, extensive research on cannabis has led to a resurgence of interest in the clinical application of its constituents, particularly cannabinoids. This review summarizes the therapeutic effect and molecular mechanism of various phytoconstituents of cannabis. Furthermore, recently developed nanoformulations of cannabis constituents have also been reviewed. Since cannabis is often associated with illicit use, regulatory aspects are of vital importance and this review therefore also documented the regulatory aspects of cannabis use along with clinical data and commercial products of cannabis.

Engineering biosafe cisplatin loaded nanostructured lipid carrier: optimisation, synthesis, pharmacokinetics and biodistribution.

Low aqueous solubility, adverse effects of Cisplatin includes hepatotoxicity and nephrotoxicity necessitates development of nanoparticulate drug delivery. The study pertains to development of CisNLC (Cisplatin loaded Nanostructured Lipid Carrier) by ultrasonication. Physical characterisation includes particle size, zeta potential, TEM, SEM-EDX, DSC. Its ex vivo biocompatibility, pharmacokinetics and biodistribution along with acute toxicity induced oxidative stress in Balb/c mice were evaluated. The mean particle diameter of CisNLC was observed to be 141.5 ± 3.86 nm with zeta potential of -41.5 ± 1.62 mV. In vitro release studies at pH 7.4 and 5.8 showed burst release following a sustained release pattern post-72 h. CisNLC showed anticancer efficacy against PA-1. Negligible ex vivo haemolysis indicated bio-compatibility. Improved pharmacokinetics of CisNLC was observed. Acute toxicity and oxidative stress evaluation proved negligible toxicity by CisNLC. The formulated CisNLC had a good physical stability, biocompatible, indicated enhanced circulation and caused negligible toxicity on liver and kidney as compared to pure Cis.

WITHDRAWN: Cannabis Sativa In Phytotherapy : Reappraisal Of Therapeutic Potential And Regulatory Aspects

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Role of triggering receptor expressed on myeloid cells 2 (TREM2) in neurodegenerative dementias.

Neurodegeneration is a debilitating condition that causes nerve cell degeneration or death. Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), and Lewy body dementia (LBD) are posing a larger population burden of dementia worldwide. Neurodegenerative dementia is one of the main challenges in public health with its main characteristics being permanent loss of memory, impairment in cognition, and impaired daily functions. The published literature about genetic studies of these disorders suggests genetic underpinning in the pathogenesis of neurodegenerative dementia. In the process of underlining the pathogenesis of NDD, growing evidence has related genetic variations in the triggering receptor expressed on myeloid cells 2 (TREM2). This review paper aims to provide a detailed information regarding the association of TREM2 and NDDs leading to dementia. A central consideration is AD that accounts for almost 50%-70% of all late-life dementias alone or in combination with other neurological disorders. Other prevalent neurodegenerative conditions that lead to dementia are also discussed. Such studies are important as they can give a comprehensive knowledge of TREM2's role in various NDDs, in order to maximize the potential for developing new therapeutic approaches.

Deciphering the Role of Aberrant Protein Post-Translational Modification in the Pathology of Neurodegeneration.

Neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Huntington's Disease (HD), are characterized by progressive neuronal dysfunction and death. Recent studies have established detrimental modifications in the structure and function of brain proteins, which stimulate their aggregation, misfolding and deposition in and around the neurons an important hallmark of neurodegenerative diseases. Post-Translational Modification (PTM) of proteins, including phosphorylation, acetylation, glycosylation, palmitoylation, SUMOylation, and ubiquitination, are important regulators of protein characteristics, including stability, intracellular distribution, activity, interactions, aggregation and clearance. Despite clear evidence that altered protein modifications emerging from impromptu chemical modifications to side chains of amino acid are associated with neurodegeneration, the underlying mechanisms that promote aberrant PTM remain poorly understood. Therefore, elucidating PTM of specific disease-associated proteins can prove to be a significant step in evaluating the functional alteration of proteins and their association with neurodegeneration. This review describes how aberrant PTM of various proteins is linked with the neurodegenerative disease pathogenesis, as well as molecular strategies targeting these modifications for treating such diseases, which are yet incurable.

Lipid-nanopotentiated combinatorial delivery of tamoxifen and sulforaphane: ex vivo, in vivo and toxicity studies.

Aim: This study aims to load tamoxifen (TAM) and sulforaphane (SFN) into nanostructured lipid carriers (NLCs) to enhance their oral delivery. Materials & methods: TAM-SFN-NLCs were prepared using Precirol® ATO5 and Transcutol® HP, characterized and evaluated in vitro and ex vivo to assess the drug release profile and intestinal permeability, respectively. In vivo pharmacokinetic and acute toxicity assessment was performed in Wistar rats. Results: Optimized TAM-SFN-NLCs exhibited a particle size of 121.9 ± 6.42 nm and zeta potential of -21.2 ± 2.91 mV. The NLCs enhanced intestinal permeability of TAM and SFN and augmented oral bioavailability of TAM and SFN 5.2-fold and 4.8-fold, respectively. SFN significantly reduced TAM-associated toxicity in vivo. Conclusion: This coencapsulation of a chemotherapeutic agent with a herbal bioactive in NLCs could pave a novel treatment approach against cancer.

Nanostructured lipid carrier potentiated oral delivery of raloxifene for breast cancer treatment.

Nanotherapeutics in cancer treatment are dominating global science and research, and have been recognized as the pioneering medical care regimen. Raloxifene (RLN) has been used for its anti-proliferative action on mammary tissue, however, it suffers from poor oral bioavailability. This investigation gives an account of the design and development of RLN-loaded nanostructured lipid carriers (RLN-NLCs) using a simple and scalable ultrasonication method for improved oral efficacy and limited offsite toxicity using Compritol® 888 ATO as a solid lipid and Transcutol® HP as a liquid lipid. In addition, the optimized RLN-NLCs were in the nanometric range (121 nm) with high % entrapment efficiency (%EE) (81%) for RLN, and were further freeze-dried in the presence of mannitol to enhance the stability of RLN-NLCs in the dry state for long-term use. Morphological observation under a transmission electron microscope and scanning electron microscope revealed the spherical smooth surface nanometric size of RLN-NLCs. Powder x-ray diffraction confirmed the encapsulation of RLN into the RLN-NLC's matrix with reduced crystallinity of the drug. The in vitro release study showed a burst release for an initial 4 h, and sustained release for up to 24 h. Furthermore, the RLN-NLCs showed higher cytotoxicity towards MCF-7 cells in vitro in comparison to RLN suspension, and an ex vivo intestinal permeation study demonstrated improved intestinal permeability of RLN-NLCs. Moreover, the in vivo pharmacokinetic study in female Wistar rats showed a 4.79-fold increment in oral bioavailability of RLN from RLN-NLCs compared to RLN suspension. Taken together, our results pave the way for a new nanotherapeutic approach towards breast cancer treatment.

PEGylated Nanoliposomes Potentiated Oral Combination Therapy for Effective Cancer Treatment.

The conventional treatment regimen for cancer with a single chemotherapeutic agent is far behind the clinical expectations due to the complexity of cancer biology and is also associated with poor Quality of Life (QOL) due to off-site toxicity and multidrug resistance. In recent years, nanopotentiated combination therapy has shown significant improvement in cancer treatment via a synergistic approach. However, being synthetic in nature, nanocarriers have been associated with the activation of the Complement (C) activation system resulting in serious hypersensitivity reactions known as CActivation Related Pseudoallergy (CARPA) effect once given via intravenous injection. On the other hand, nanopotentiated oral drug delivery offers several advantages for the effective and safe delivery of the drug to the target site. This hypothesis aims to put forward wherein Exemestane (chemotherapeutic agent) and lycopene (herbal bioactive) co-laden into PEGylated liposomes and delivered to the breast cancer via the oral route. PEGylation of the liposomes would prevent both molecules from the harsh microenvironment of the Gastrointestinal Tract (GIT) and would eventually promote their intestinal absorption via the lymphatic pathway to the systemic circulation. Lycopene being a potent antioxidant and anti-cancer herbal bioactive would promote the therapeutic efficacy of the Exemestane via a synergistic approach. This nanopotentiated oral combination therapy would pave the path for the safe and effective treatment of cancer.

Development and validation of a high throughput bioanalytical UPLC-MS/MS method for simultaneous determination of tamoxifen and sulphoraphane in rat plasma: Application to an oral pharmacokinetic study.

Tamoxifen (TAM) is the choice of a drug approved by the Food and Drug Administration (FDA) for the treatment of estrogen-positive receptor (ER+) breast cancer. Sulphoraphane (SFN), a natural plant antioxidant compound, also acts on estrogen-positive breast cancer receptor. Thus, a combination of TAM with SFN is preferred as it helps to minimize the drug-related toxicity and increases the therapeutic efficacy by providing synergistic anticancer effects of both drugs. In the present study, a new simple, sensitive, precise, and selective UPLC-MS/MS method was developed for the simultaneous quantification of tamoxifen and sulphoraphane using propranolol as an internal standard (IS) in rat plasma. Chromatographic separation was achieved on reverse phase Acquity UPLC BEH C18 column (50 mm × 2.1 mm, i.d., 1.7 µm) with an isocratic mobile phase composed of solvent A (0.1% formic acid in acetonitrile) and B (0.1% formic acid in water) (80:20, v/v) at a flow-rate of 0.4 mL/min. The detection and quantification of analytes was performed on Waters ZsprayTM Xevo TQD using selected-ion monitoring operated under a positive electrospray ionization mode. The transitions were m/z = 372.0 [M+H]+ → 71.92 for tamoxifen, m/z = 177.9 [M+H]+ → 113.9 for sulphoraphane and m/z = 260.3 [M+H]+ → 116.1 for propranolol. The method was linear over the concentration range of 8-500 ng/mL (r2 = 0.9996) for tamoxifen, 30-2000 ng/mL (r2 = 0.9998) for sulphoraphane with insignificant matrix effect and high extraction recovery on spiked quality control (QC) samples. The intra- and inter-batch precisions and accuracy were within the acceptable limits, and both the analytes were found to be stable throughout the short term, long term and freeze thaw stability studies. The validated method was successfully applied for the simultaneous estimation of TAM and SFN in an oral pharmacokinetic study in female Wistar rats. This developed UPLC-MS/MS method could be a valuable tool for future pharmacokinetic interaction, therapeutic drug monitoring and pharmacokinetic characterization of novel formulations.

Insights into Nanotherapeutic Strategies as an Impending Approach to Liver Cancer Treatment.

Liver cancer, being the utmost prevalent fatal malignancy worldwide, is ranked as the fifth leading cause of deaths associated with cancer. Patients with liver cancer are diagnosed often at an advanced stage, contributing to poor prognosis. Of all forms of liver cancer, hepatocellular carcinoma (HCC) contributes to 90% of cases, with chemotherapy being the treatment of choice. However, unfavorable toxicity of chemotherapy drugs and the vulnerability of nucleic acid-based drugs to degradation, have limited their application in clinical settings. So, in order to improvise their therapeutic efficacy in HCC treatment, various nanocarrier drug delivery systems have been explored. Furthermore, nanoparticle based imaging provides valuable means of accurately diagnosing HCC. Thus, in recent years, the advent of nanomedicine has shown great potential and progress in dramatically altering the approach to the diagnosis as well as treatment of liver cancer. Nanoparticles (NPs) are being explored as potential drug carriers for small molecules, miRNAs, and therapeutic genes used for liver cancer treatment. This review emphasizes on the current developments and applications of nanomedicine based therapeutic and diagnostic approaches in HCC.

Biocompatible Nanovesicular Drug Delivery Systems with Targeting Potential for Autoimmune Diseases.

Autoimmune diseases are collectively addressed as chronic conditions initiated by the loss of one's immunological tolerance, where the body treats its own cells as foreigners or self-antigens. These hay-wired antibodies or immunologically capable cells lead to a variety of disorders like rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis and recently included neurodegenerative diseases like Alzheimer's, Parkinsonism and testicular cancer triggered T-cells induced autoimmune response in testes and brain. Conventional treatments for autoimmune diseases possess several downsides due to unfavourable pharmacokinetic behaviour of drug, reflected by low bioavailability, rapid clearance, offsite toxicity, restricted targeting ability and poor therapeutic outcomes. Novel nanovesicular drug delivery systems including liposomes, niosomes, proniosomes, ethosomes, transferosomes, pharmacosomes, ufasomes and biologically originated exosomes have proved to possess alluring prospects in supporting the combat against autoimmune diseases. These nanovesicles have revitalized available treatment modalities as they are biocompatible, biodegradable, less immunogenic and capable of carrying high drug payloads to deliver both hydrophilic as well as lipophilic drugs to specific sites via passive or active targeting. Due to their unique surface chemistry, they can be decorated with physiological or synthetic ligands to target specific receptors overexpressed in different autoimmune diseases and can even cross the blood-brain barrier. This review presents exhaustive yet concise information on the potential of various nanovesicular systems as drug carriers in improving the overall therapeutic efficiency of the dosage regimen for various autoimmune diseases. The role of endogenous exosomes as biomarkers in the diagnosis and prognosis of autoimmune diseases along with monitoring progress of treatment will also be highlighted.

Decoding Novel Mechanisms and Emerging Therapeutic Strategies in Breast Cancer Resistance.

Breast cancer (BC), an intricate and highly heterogeneous disorder, has presently afflicted 2.09 million females globally. Chemoresistance remains a paramount challenge in the treatment of BC. Owing to its assorted nature, the chemoresistant mechanisms of BC still need intensive research. Accumulating evidence suggests that abnormalities related to the biogenesis of cancer stem cells (CSCs) and microRNAs (miRNAs) are associated with BC progression and chemoresistance. The presently available interventions are inadequate to target chemoresistance, therefore more efficient alternatives are urgently needed to improvise existing therapeutic regimens. A myriad of strategies is being explored, such as immunotherapy, gene therapy, and combination treatment to surmount chemoresistance. Additionally, nanoparticles as chemotherapeutic carriers put forward the options to encapsulate numerous drugs, alone as well as in combination for cancer theranostics. This review summarizes the chemoresistance mechanisms of miRNAs and CSCs as well as the most recently documented therapeutic approaches for the treatment of chemoresistance in BC. By unraveling the underpinning mechanism of BC chemoresistance, researchers could possibly develop more efficient treatment strategies towards BC.

Tamoxifen and Sulphoraphane for the breast cancer management: A synergistic nanomedicine approach.

Breast cancer is second most leading cause of death in all over the world and not only limited to the females. Tamoxifen has been considered as the gold line therapy for estrogen receptor positive breast cancer. However, this chemopreventive approach has been focused at individuals in high risk group and limits its clinical applications to moderate and/or lower risk groups. Moreover, Tamoxifen treatment is associated with a dose related hepatotoxicity and nephrotoxicity and eventually results in poor quality of life of patients. Sulphoraphane, a naturally occurring isothiocyanate derivative has been investigated for its numerous potential biological activities including anticancer effects. The present hypothesis aims to put forward in which Tamoxifen is combined with a natural bioactive Sulphoraphane, both incorporated into a novel lipid based nanocarrier at a reduced dose, which would eventually shuttle the cargo to the target site. At the breast cancer, Sulphoraphane sensitizes the estrogen receptors and ameliorates the binding affinity of Tamoxifen to these receptors, thereby potentiating the anticancer efficacy and reducing the offsite toxicity of Tamoxifen. This dual loaded zero-dimension lipid carrier would be a value addition to the current treatment regimen for breast cancer management.

Nanostructured Lipid Carriers for Oral Bioavailability Enhancement of Exemestane: Formulation Design, In Vitro, Ex Vivo, and In Vivo Studies.

Exemestane (EXE) is a novel oral steroidal aromatase inhibitor approved for the treatment of breast cancer. However, its oral clinical application is limited because of low aqueous solubility and low oral bioavailability. Here, we aim to design and fabricate nanostructured lipid carriers (NLCs) using Precirol® ATO 5 and flaxseed oil as the solid lipid and liquid lipid, respectively. EXE-loaded NLCs were spherical in shape and with a hydrodynamic diameter of 131.3 ± 2.43 nm, polydispersity index 0.205 ± 0.06, and percentage entrapment efficiency 85.6 ± 1.20%. In vitro release study demonstrated a sustained release pattern for 24 h, with relative burst release at the initial time point. Differential scanning calorimetry and powder X-ray diffraction studies showed reduced crystallinity and complete encapsulation of drug within the lipid matrix. Ex vivo gut permeation study and confocal laser scanning microscopy revealed that NLCs comprising a lipid blend and surfactant enhanced intestinal permeability of EXE. Moreover, in vivo pharmacokinetic study on female Wistar rats found to augment 3.9-fold in oral bioavailability of EXE through NLCs compared with EXE suspension. Herein, we depict that loading of EXE into NLCs hold promising approach for the oral delivery of EXE in cancer therapy.

Development and validation of stability indicating reversed-phase liquid chromatographic method for simultaneous quantification of methotrexate and teriflunomide in nanoparticles and marketed formulation.

Methotrexate (MTX) and teriflunomide (TEF) are the two most effective disease-modifying antirheumatic drugs used as combination therapy for rheumatoid arthritis and no robust high-performance liquid chromatography (HPLC) method is available for their simultaneous estimation to date. Therefore, we have developed and validated an isocratic reversed-phase HPLC method for simultaneous analysis of MTX and TEF spiked in the form of active pharmaceutical ingredients, tablets and nanoformulations. The best separation was achieved on a BDS, C18 , 4.6 × 250 mm, 5 µm analytical column (Thermo Hypersil) with methanol-ethylammonium formate-potassium dihydrogen phosphate buffer (55 mm, pH 3.5; 65:5:30, v/v) as mobile phase at a flow rate of 0.8 mL/min. All the samples were subjected to force degradation studies. Responses of MTX and TEF were found to be a linear function of concentration over the range 1-50 µg/mL (r2 = 0.9976 and 0.9982). The limits of detection and limit of quantification were 7.74 and 25.82 ng/mL and 10.74 and 35.80 ng/mL, respectively. Degradation products produced under the stress studies did not interfere with the detection of MTX and TEF and therefore the developed method can be regarded as stability indicating.

Lipid Based nanoformulation of lycopene improves oral delivery: formulation optimization, ex vivo assessment and its efficacy against breast cancer.

This study aims at developing an optimised nanostructured lipid carrier (NLC) of lycopene for efficient absorption following oral administration. The optimised formulation showed an average particle size of 121.9 ± 3.66 nm, polydispersity index (PDI) 0.370 ± 0.97 and zeta potential -29.0 ± 0.83 mV. Encapsulation Efficiency (% EE) and drug loading (% DL) was found to be 84.50% ± 4.38 and 9.54% ± 2.65, respectively. In vitro release studies demonstrated the burst release within 4-9 h followed by sustained release over 48 h. The IC50 value of lycopene extract and optimised NLC for ABTS+• were found to be 172.37 µg Trolox equivalent and 184.17 µg Trolox equivalent whereas, for DPPH•, 117.76 µg Trolox equivalent and 143.08 µg Trolox equivalent respectively. Ex vivo studies and MTT assay revealed that the NLC had better permeation and cause sufficiently more cytotoxicity as compared to drug extract due to higher bioavailability and greater penetration.