Current Therapeutic Strategies for the Management of Benzodiazepine (BZD) Withdrawal Syndrome: A Review.

Benzodiazepines are commonly prescribed drugs for numerous indications such as epilepsy, anti-anxiety, sleep aids, sedatives, and hypnotics. Although the well-tolerated effects of benzodiazepine are seen in many clinical instances, the severity of side effects reduces its quantifiable use. Benzodiazepines, which are medically useful but theoretically unsafe, are frequently recommended by medical practitioners for psychotic patients but have misuse and dependence liabilities. It is impelled as a debateable topic globally about which no one talks. These drugs are also known as silent killers because abruptly stopping them can result in tremors, muscle spasticity, and life-frightening seizures. These drugs are beneficial as well as risky. Nonclinical treatment is simple and well suited and provides support for patients suffering from side effects generated by benzodiazepine withdrawal. This review mainly focuses on antipsychotic drugs and their mechanisms, mortality, withdrawal, abuse, and management via clinical and nonclinical therapies.

Formulation and Characterization of Glucosamine Sulphate Potassium Chloride (GSPC) Loaded Emulgel for the Treatment of Osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is becoming a major medical burden worldwide due to changing lifestyles and aging populations. Osteoarthritis is a disease characterized by a variety of anatomic and physiological changes to joints, including cartilage degradation, bone remodeling, and the formation of osteophytes. These changes cause pain, stiffness, swelling, and limitations in joint function. Glucosamine serves as a fundamental constituent for cartilage, the resilient connective tissue responsible for cushioning joints. Glucosamine Sulphate Potassium Chloride (GSPC) supplementation is widely employed to mitigate symptoms linked to osteoarthritis, a degenerative joint disorder hallmarked by cartilage degradation. AIM: Palliative care aims at minimizing pain and disability and improving function, performance, and quality of life. In this study, the emulgel formulation of GSPC was developed and checked for its potential. OBJECTIVE: Currently, OA does not have a definitive treatment. Since conventional dosage forms cannot deliver the active drug content at a predefined target site in a predictable manner throughout the treatment period, a new carrier system is always required. Considering their reduced size, targeting potential, and site specificity, nanocarrier-based approaches could hold an answer to shortcomings associated with conventional routes. Thus, the objective of the current study was to formulate and characterize glucosamine sulphate potassium chloride-loaded emulgel for the treatment of osteoarthritis. METHODS: Microemulsion of glucosamine sulphate potassium chloride was formulated using a spontaneous emulsification method comprising of oleic acid (oil phase), Tween 80, Tween 20 (surfactant) and PEG 400, Span 80 (co-surfactant), and distilled water (aqueous phase). The microemulsions were evaluated for surface morphology, globule size, poly-dispersibility index (PDI), zeta potential, and viscosity, and the final batch of microemulsions was selected. RESULT: The optimized microemulsion contained 35% co-surfactant (propylene glycol), 20% surfactant (Tween 20), and 15% oil (oleic acid) and glucosamine sulphate potassium chloride in a dose of 60 mg, which has sufficient drug loading capacity with a droplet size of 182 nm for optimized formulation. The optimized microemulsion formulation was added to gel prepared by Carbopol 934 in a 1:1 (w/w) ratio, leading to the formulation of glucosamine sulphate potassium chloride- containing emulgel. The prepared emulgel was further evaluated for viscosity, drug content, pH, and in-vitro drug release. Emulgel formulation (F6) showed 88% drug release after 6 hours, and it followed the Higuchi model. CONCLUSION: Glucosamine Sulphate Potassium Chloride (GSPC) is used in the treatment of OA by increasing the production of proteoglycans, which can cause the cartilage to break down. Emulgel formulation (F3) showed 75.41% drug release, and formulation (F6) showed 88% drug release after 6 h. Therefore, it may be concluded that an emulgel of GSPC can be used as a controlled-release dosage form of the drug for local application in OA.

Role of Nanoformulations in the Treatment of Lung Cancer.

Lung cancer is the second deadliest disease in the world. A major portion of deaths related to cancer are due to lung cancer in both males and females. Interestingly, unbelievable advances have occurred in recent years through the use of nanotechnology and development in both the diagnosis and treatment of lung cancer. Due to their in vivo stability, the nanotechnology-based pharmacological system gained huge attractiveness, solubility, absorption from the intestine, pharmacological effectiveness, etc. of various anticancer agents. However, this field needs to be utilized more to get maximum results in the treatment of lung cancer, along with wider context medicines. In the present review, authors have tried to concentrate their attention on lung cancer`s difficulties along with the current pharmacological and diagnostic situation, and current advancements in approaches based on nanotechnology for the treatment and diagnosis of lung cancer. While nanotechnology offers these promising avenues for lung cancer diagnosis and treatment, it is important to acknowledge the need for careful evaluation of safety, efficacy, and regulatory approval. With continued research and development, nanotechnology holds tremendous potential to revolutionize the management of lung cancer and improve patient outcomes. The review also highlights the involvement of endocrine systems, especially estrogen in lung cancer proliferation. Some of the recent clinical trials and patents on nanoparticle-based formulations that have applications in the treatment and diagnosis of lung cancer are also discussed.

Wheatgrass (Triticum Aestivum) Extract Loaded Chitosan Solid Lipid Nanoparticles: Formulation, Physicochemical Characterisation and Cytotoxic Potential.

BACKGROUND: The prevalence of cancer is around the world, and is identified as a multifarious ailment. Amongst the most common reasons for cancer in the world is oxidative stress, and this can be overcome by taking the herbal plant wheatgrass in any form. AIM AND OBJECTIVE: The aim of the present work is to formulate wheatgrass extract-loaded solid lipid nanoparticles using Box-Behnken design and to investigate the effect of formulation variables. METHODS: Using the hot homogenisation method, the current work plan aimed to develop wheatgrassfilled chitosan solid lipid nanoparticles by means of a Box-Behnken design. This study investigated the effect of three formulation variables on particle size and entrapment efficiency, namely the sodium alginate concentration, the chitosan concentration, and the sonication time. Extraction of wheatgrass was done in a soxhlet extractor, using methanolic extract. Furthermore, the authors have examined recent patents associated with wheatgrass to enhance their comprehension of this herbal plant. RESULTS: The hot homogenisation technique was used to prepare Triticum aestivum extract loaded with solid lipid nanoparticles (SLNs). For BBD, all formulations were analysed for particle size, which ranged from 394.4 to 911.2 nm, and for polydispersity index, which ranged from 0.527 to 1.0. Batch code BB SLN-8 was found to be the finest suitable because of a maximum loading capacity of 58.23 ±0.11 % (w/w), maximum entrapment efficiency of 55.12±0.17 % (w/w), and minimum particle size of 394.4nm by using sodium alginate as a surface stabiliser at sonication time ~ 10 min and having maximum percentage yield of 49.87%. During characterisation studies and MCF-6 cell line studies, it was found that wheatgrass has antioxidant potential and is potent against breast cancer. CONCLUSION: As an alternative medicine for cancer, wheatgrass is considered to be effective due to its high antioxidant content.

Enhanced Efficacy of Carvedilol by Utilization of Solid Dispersion and Other Novel Strategies: A Review.

Carvedilol is classified as a second class drug of Biopharmaceutical classification system (BCS), and it is an excellent beta blocker and vasodilating agent. It is used in a diverse range of disease states. Despite having tremendous advantages, the drug cannot be used effectively and productively due to aquaphobicity and poor bioavailability. To overcome this limitation, numerous novel approaches and tactics have been introduced over the past few years, such as Selfmicro emulsifying drug delivery systems (SMEDDS), nanoparticles, solid dispersions and liposomal drug delivery. The present review aims to accentuate the role of solid dispersion in improving the dissolution profile and aqua solubility of carvedilol and also to emphasize other novel formulations of carvedilol proposed to prevail the limitations of carvedilol. Solid dispersion and other novel approaches were found to play a significant role in overcoming the drawbacks of carvedilol, among which solid dispersion is the most feasible and effective approach being used worldwide. Reduced particle size, more wettability, and large surface area are obtained by the implementation of solid dispersion technique, hence improving carvedilol solubility and bioavailability.

Nanotheranostics: The Fabrication of Theranostics with Nanoparticles and their Application to Treat the Neurological Disorders.

BACKGROUND: Theranostics is a method that focuses on providing patient-centred care and is evolving as a targeted, safe, and effective pharmacotherapy. Nanotheranostics combines diagnosis and therapeutic modalities that bridge traditional treatment and personalised medicine. Theranostics provides novel ideas for nanotechnology. This review describes the current state of nanotechnology-based therapies used to treat neurological illnesses. Some patents on theranostics are also discussed in this review. OBJECTIVE: This study aims to provide a more comprehensive review of the diagnosis and therapeutic properties of nanotheranostics, the present state of nanotechnology-based treatment of neurological disorders, and the future potential of theranostics. METHOD: The phrase "theranostics" refers to a treatment strategy that integrates therapeutics and diagnostics to monitor treatment response and enhance drug efficacy and safety. Theranostics is a crucial component of personalised medicine and calls for significant advancements in predictive medicine. The term "theranostics" refers to a diagnosis that screens patients for potential adverse drug reactions and targets drug delivery depending on the test results. Theranostics treats neurological disorders (like brain tumours (glioma), Parkinson's disease, Alzheimer's disease, and neurovascular diseases). Many review articles on Google Scholar, PubMed, Google Patents, and Scopus were used to gather information for this review. Data acquired from many sources was compiled in this review to provide more information on theranostics. RESULT: The role of various nanocarrier systems as theranostic agents for neurological illnesses and the fabrication of nanomaterials for theranostics are discussed in this article after evaluating a substantial number of review articles. CONCLUSION: The distinctive intrinsic features of nanoparticles make them useful for functionalization and imaging. Theranostics in nuclear medicine include diagnostic imaging and therapy using the same molecule that is radiolabeled differently or the same medication at various doses. It is possible to determine if a patient will benefit from a given treatment by visualising potential targets. Targeted nuclear therapy has been shown to be beneficial in patients if chosen carefully and has a good safety profile.

Nanocrystals: A Deep Insight into Formulation Aspects, Stabilization Strategies, and Biomedical Applications.

BACKGROUND: Drugs with poor solubility exhibit hurdles in their formulation due to poor dissolution and low bioavailability. Nanocrystallization is a great technique for incorporating poorly soluble drugs and is associated with many benefits. OBJECTIVE: The objective of the present review is to discuss formulation techniques for the generation of Nanocrystals (NCs) and illustrate the various advantages of NCs. It also explains commonly used stabilizers and guidelines for their safe use for enhancing NCs and provides a deep insight into various biomedical applications of NCs. METHODS: The review was extracted from the study carried out in the general literature to emphasize the importance of NCs in various formulations. RESULTS: NCs are a widely accepted approach to enhancing drug solubility. There are so many marketed products of nanocrystal drug formulations that are being used to treat life-threatening disorders. Two techniques can be used to formulate NCs, i.e., the bottom-up method and the top-down method. Their main biomedical applications are found in oral, parenteral, pulmonary, ocular, dermal, and mucosal formulations. CONCLUSION: In the present review, different formulation methods of NCs have been discussed in detail, followed by explaining the advantages and various targeted drug delivery systems covered by NCs formulations. The development of NCs-based formulation avoids the limitations of other systems used for targeted drug delivery.

Solid Lipid Nanoparticles: Peculiar Strategy to Deliver Bio-Proactive Molecules.

BACKGROUND: Novel Drug Delivery Systems (NDDS) provide numerous benefits compared to conventional dosage forms. Poor aqueous solubility, low bioavailability, frequent dosing, and particular hydrophilic lipophilic character of the drug are the biological factors associated with the traditional systems leading to the development of SLNs. OBJECTIVE: For improving the solubility profile, enhancing the bioavailability, and attaining the best possible therapeutic effect of lipid inclined or aqueous inclined drug, formulating solid lipid nanoparticles is the best choice. METHODS: Solid Lipid Nanoparticles (SLNs) have been projected as a colloidal carrier system with a size of 50-1,000 nm, collectively combining the benefits of other colloidal systems like liposomes, emulsions, etc., for delivering the drug at the target site. High absorption, high stability, and efficient drug packing enhance the pharmacokinetic and pharmacodynamic properties of the packed drug. RESULT: Solid Lipid Nanoparticles can be developed in different dosage forms and administered via routes such as nasal, rectal, oral, topical, vaginal, ocular, and parenteral. They have higher physicochemical stability and the batch size can be easily scaled up at a low cost. Lipophilic as well as hydrophilic drugs can be easily incorporated into solid lipid nanoparticles. CONCLUSION: In this manuscript, the authors have reviewed different aspects of solid lipid nanoparticles, major principles behind mechanism methods, recent patents, applications, and therapeutic potentials of solid lipid nanoparticles.

Current Cannabidiol Safety: A Review.

BACKGROUND: Marijuana, also known as cannabis, is the second most widely used illegal psychoactive substance smoked worldwide after tobacco, mainly due to the psychoactive effects induced by D-9-tetrahydrocannabinol (9-THC). Cannabidiol (CBD) is extracted from cannabis and may be used as an anti-inflammatory agent. Some patents on cannabidiol are discussed in this review. The cannabinoid is a non-psychoactive isomer of the more infamous tetrahydrocannabinol (THC); and is available in several administration modes, most known as CBD oil. OBJECTIVES: This study aims to provide an enhanced review of cannabidiol properties used in treating inflammation. This review also emphasises the current safety profile of cannabidiol. METHODS: Cannabis is also called Marijuana. It is the second most commonly used illegal psychoactive substance in the universe after tobacco. D-9-tetrahydrocannabinol (9-THC) present in cannabis produces psychoactive effects. Cannabidiol (CBD) extracted from cannabis is used for antiinflammatory purposes. Cannabis smoking causes various types of cancer, such as lung, tongue, and jaw. The current review took literature from Google Scholar, PubMed, and Google Patents. Many clinical investigations are included in this review. RESULT: After analysing the literature on cannabis, it has been suggested that although cannabis is banned in some countries, it may be included in the treatment and mitigation of some diseases and symptoms like pain management, epilepsy, cancer, and anxiety disorder. Mild side effects were frequently observed in cannabis medications, which included infertility in females, liver damage, etc. Conclusion: Cannabis contains chemical compounds such as the cannabinoids delta-9- tetrahydrocannabinol (THC), a psychoactive substance, and non-psychoactive cannabidiol (CBD). Cannabidiol has been confirmed as an efficient treatment of epilepsy in several clinical trials, with one pure CBD product named Epidiolex. It is also used in treating anxiety and acne, as a pain reliever, and has anti-inflammatory properties.

Histone H4 lysine 14 acetylation in Leishmania donovani is mediated by the MYST-family protein HAT4.

Post-translational modifications (PTMs) of histones regulate almost all facets of DNA metabolism in eukaryotes, such as replication, repair, transcription and chromatin condensation. While histone PTMs have been exhaustively examined in yeast and higher eukaryotes, less is known of their functional consequences in trypanosomatids. Trypanosome histones are highly divergent from those of other eukaryotes, and specific PTMs have been identified in histones of Trypanosoma species. The characterization of three MYST-family histone acetyltransferases (HATs) in Trypanosoma brucei had earlier identified the HATs responsible for acetylation of two lysine residues, K4 and K10, in the N-terminal tail of histone H4. This report presents the results of what we believe to be the first study of a HAT in a Leishmania species. The HAT4 gene of Leishmania donovani, the causative pathogen of visceral leishmaniasis, was cloned and expressed in fusion with GFP in Leishmania promastigotes. We found that HAT4-GFP behaves differently from typical eukaryotic MYST-family HATs, which are usually constitutively nuclear, in that it is cytosolic throughout the cell cycle, although the protein is also present in the nucleus in post-mitotic cells. Substrate-specificity analyses revealed that LdHAT4 acetylates the N terminus of histone H4, but not those of H2A, H2B or H3. Nor does it acetylate the C terminus of H2A. The primary target of HAT4-mediated acetylation is the K14 residue of H4, although K2 may be a minor site as well. H4K14 acetylation in Leishmania may occur either in the cytoplasm prior to histone deposition, or soon after mitosis in the nucleus.

Characterization of Leishmania donovani MCM4: expression patterns and interaction with PCNA.

Events leading to origin firing and fork elongation in eukaryotes involve several proteins which are mostly conserved across the various eukaryotic species. Nuclear DNA replication in trypanosomatids has thus far remained a largely uninvestigated area. While several eukaryotic replication protein orthologs have been annotated, many are missing, suggesting that novel replication mechanisms may apply in this group of organisms. Here, we characterize the expression of Leishmania donovani MCM4, and find that while it broadly resembles other eukaryotes, noteworthy differences exist. MCM4 is constitutively nuclear, signifying that, unlike what is seen in S.cerevisiae, varying subcellular localization of MCM4 is not a mode of replication regulation in Leishmania. Overexpression of MCM4 in Leishmania promastigotes causes progress through S phase faster than usual, implicating a role for MCM4 in the modulation of cell cycle progression. We find for the first time in eukaryotes, an interaction between any of the proteins of the MCM2-7 (MCM4) and PCNA. MCM4 colocalizes with PCNA in S phase cells, in keeping with the MCM2-7 complex being involved not only in replication initiation, but fork elongation as well. Analysis of a LdMCM4 mutant indicates that MCM4 interacts with PCNA via the PIP box motif of MCM4--perhaps as an integral component of the MCM2-7 complex, although we have no direct evidence that MCM4 harboring a PIP box mutation can still functionally associate with the other members of the MCM2-7 complex- and the PIP box motif is important for cell survival and viability. In Leishmania, MCM4 may possibly help in recruiting PCNA to chromatin, a role assigned to MCM10 in other eukaryotes.

Kinetoplast morphology and segregation pattern as a marker for cell cycle progression in Leishmania donovani.

Trypanosomatids are typified by uniquely configured mitochondrial DNA--the kinetoplast. The replication timing of kinetoplast DNA (kDNA) is closely linked to nuclear S phase, but nuclear and kinetoplast compartments display staggered timing of segregation, post-replication. Kinetoplast division is completed before nuclear division in Trypanosoma species while nuclear division is completed first in Crithidia species. Leishmania donovani is the causative agent of visceral leishmaniasis, a form of leishmanial infection that is often fatal. Cell cycle related studies in Leishmania are hampered by difficulties in synchronizing these cells. This report examines the replication/segregation pattern and morphology of the kinetoplast in L. donovani with the aim of determining if these traits can be used to assign cell cycle stage to individual cells. By labeling replicating cells with bromodeoxyuridine after synchronization with hydroxyurea, we find that although both nuclear and kDNA initiate replication in early S phase, nuclear division precedes kinetoplast segregation in 80% of the cells. The kinetoplast is roundish/short rod-like in G1 and in early to mid-S phase, but prominently elongated/bilobed in late S phase and early G2/M. These morphological traits and segregation pattern of the kinetoplast can be used as a marker for cell cycle stage in a population of asynchronously growing L. donovani promastigotes, in place of cell synchronization procedures or instead of using antibody staining for cell cycle stage marker proteins.

The distribution pattern of proliferating cell nuclear antigen in the nuclei of Leishmania donovani.

DNA replication in eukaryotes is a highly conserved process marked by the licensing of multiple origins, with pre-replication complex assembly in G1 phase, followed by the onset of replication at these origins in S phase. The two strands replicate by different mechanisms, and DNA synthesis is brought about by the activity of the replicative DNA polymerases Pol delta and Pol epsilon. Proliferating cell nuclear antigen (PCNA) augments the processivity of these polymerases by serving as a DNA sliding clamp protein. This study reports the cloning of PCNA from the protozoan Leishmania donovani, which is the causative agent of the systemic disease visceral leishmaniasis. PCNA was demonstrated to be robustly expressed in actively proliferating L. donovani promastigotes. We found that the protein was present primarily in the nucleus throughout the cell cycle, and it was found in both proliferating procyclic and metacyclic promastigotes. However, levels of expression of PCNA varied through cell cycle progression, with maximum expression evident in G1 and S phases. The subnuclear pattern of expression of PCNA differed in different stages of the cell cycle; it formed distinct subnuclear foci in S phase, while it was distributed in a more diffuse pattern in G2/M phase and post-mitotic phase cells. These subnuclear foci are the sites of active DNA replication, suggesting that replication factories exist in Leishmania, as they do in higher eukaryotes, thus opening avenues for investigating other Leishmania proteins that are involved in DNA replication as part of these replication factories.

Acid phosphatase production by recombinant Arxula adeninivorans.

Acid phosphatase production by recombinant Arxula adeninivorans was carried out in submerged fermentation. Using the Plackett-Burman design, three fermentation variables (pH, sucrose concentration, and peptone concentration) were identified to significantly affect acid phosphatase and biomass production, and these were optimized using response surface methodology of central composite design. The highest enzyme yields were attained in the medium with 3.9% sucrose and 1.6% peptone at pH 3.8. Because of optimization, 3.86- and 4.19-fold enhancement in enzyme production was achieved in shake flasks (17,054 U g(-1) DYB) and laboratory fermenter (18,465 U g(-1) DYB), respectively.