Comparative evaluation of doxorubicin, cyclophosphamide, 5-fluorouracil, and cisplatin on cognitive dysfunction in rats: Delineating the role of inflammation of hippocampal neurons and hypothyroidism.

Chemotherapeutic agents such as doxorubicin, cyclophosphamide, fluorouracil, and cisplatin are commonly used to treat a variety of cancers and often result in chemobrain, which manifests as difficulties in learning and memory processes that can persist in the years following treatment. The current study aims to evaluate the cognitive function following treatment with these agents and the underlying mechanisms using a rat model of neuroinflammation and possible implication of thyroid toxicity in chemotherapy induced cognitive dysfunction. Wistar female rats were treated with a single dose of doxorubicin (DOX, 25 mg/kg), 5-fluorouracil (5-FU, 100 mg/kg), cisplatin (8 mg/kg), and cyclophosphamide (CYP, 200 mg/kg) by intraperitoneal injection. The cognitive performance of rats was then evaluated in spatial memory tasks using the Y-maze, novel object recognition (NOR), and elevated plus maze (EPM) tests. Serum levels of thyroid hormones (T3, T4, FT3, and FT4) and thyroid stimulating hormone (TSH) were measured, followed by estimation of TNFα, IL-6, and IL-1ß in the hippocampal tissue. Results revealed that all the chemotherapeutic agents produced impairment of cognitive function, and significant increase of pro-inflammatory cytokines such as TNFα, IL-6 and IL-1ß in the hippocampal tissues. There was a significant reduction in thyroid hormones (T3, FT3, and T4) and an increase in thyroid stimulating hormone (TSH) in serum, which may also have contributed to the decline in cognitive function. In conclusion, DOX, 5-FU, CYP, and cisplatin produces impairment of spatial memory possibly by inflammation of hippocampal neurons and endocrine disruption (hypothyroidism) in rats.

Biocompatible phospholipid-based nanovesicular drug delivery system of ketoprofen: Systematic development, optimization, and preclinical evaluation.

The present work involved development of phospholipid-based permeation enhancing nanovesicles (PENVs) for topical delivery of ketoprofen. Screening of phospholipids and process parameters was performed. Central composite design was used for optimization of factors, that is, amount (%, w/w) of phospholipid and ethanol at three levels. The optimized nanovesicles (NVs) were loaded with different terpenes and then incorporated into a gel base. Optimized NVs exhibited 69% entrapment efficiency, 51% transmittance, 328 nm mean vesicle size, and polydispersity index of 0.25. In vitro release kinetics evaluation indicated best fitting as per Korsemeyer-Peppa's model and drug release via Fickian-diffusion mechanism. The optimized NVs loaded with mint terpene showed minimal degree of deformability and maximal elasticity as compared with the conventional NVs and liposomes. Rheology and texture analysis indicated pseudoplastic flow and smooth texture of the vesicle gel formulation. Ex vivo permeation studies across Wistar rat skin indicated low penetration (0.43-fold decrease) and high skin retention (4.26-fold increase) of ketoprofen from the optimized PENVs gel vis-à-vis the conventional gel. Skin irritancy study indicated lower scores for PENVs gel construing its biocompatible nature. Stability studies confirmed cold storage is best suitable for vesicle gel, and optimized PENVs were found to be suitable for topical delivery of ketoprofen.

Systematic Development of Solid Lipid Nanoparticles of Abiraterone Acetate with Improved Oral Bioavailability and Anticancer Activity for Prostate Carcinoma Treatment.

In the present work, an attempt was undertaken to improve the oral bioavailability and anticancer activity of abiraterone acetate. Solid lipid nanoparticles (SLNs) were developed using the quality by design (QbD) principles and evaluated through in vitro, ex vivo, and in vivo studies. Solid lipid suitability was evaluated by equilibrium solubility study, while surfactant and cosurfactant were screened based on the ability to form microemulsion with the selected lipid. SLNs were prepared by emulsion/solvent evaporation method using glyceryl monostearate, Tween 80, and Poloxamer 407 as the solid lipid, surfactant, and cosurfactant, respectively. Box-Behnken design was applied for optimization of material attributes and evaluating their impact on particle size, polydispersity index, zeta potential, and entrapment efficiency of the SLNs. In vitro drug release study was evaluated in simulated gastric and intestinal fluids. Cell culture studies on PC-3 cells were performed to evaluate the cytotoxicity of the drug-loaded SLNs in comparison to the free drug suspension. Qualitative uptake was evaluated for Rhodamine B-loaded SLNs and compared with free dye solution. Ex vivo permeability was evaluated on Wistar rat intestine and in vivo pharmacokinetic evaluation on Wistar rats for SLNs and free drug suspension. Concisely, the SLNs showed potential for significant improvement in the biopharmaceutical performance of the selected drug candidate over the existing formulations of abiraterone acetate.

New Paradigms of Old Psychedelics in Schizophrenia.

Psychedelics such as lysergic acid diethylamide (LSD), psilocybin (magic mushrooms), and mescaline exhibit intense effects on the human brain and behaviour. In recent years, there has been a surge in studies investigating these drugs because clinical studies have shown that these once banned drugs are well tolerated and efficacious in medically supervised low doses called microdosing. Psychedelics have demonstrated efficacy in treating neuropsychiatric maladies such as difficult to treat anxiety, depression, mood disorders, obsessive compulsive disorders, suicidal ideation, posttraumatic stress disorder, and also in treating substance use disorders. The primary mode of action of psychedelics is activation of serotonin 5-HT2A receptors affecting cognition and brain connectivity through the modulation of several downstream signalling pathways via complex molecular mechanisms. Some atypical antipsychotic drugs (APDs) primarily exhibit pharmacological actions through 5-HT2A receptors, which are also the target of psychedelic drugs. Psychedelic drugs including the newer second generation along with the glutamatergic APDs are thought to mediate pharmacological actions through a common pathway, i.e., a complex serotonin-glutamate receptor interaction in cortical neurons of pyramidal origin. Furthermore, psychedelic drugs have been reported to act via a complex interplay between 5HT2A, mGlu2/3, and NMDA receptors to mediate neurobehavioral and pharmacological actions. Findings from recent studies have suggested that serotoninergic and glutamatergic neurotransmissions are very closely connected in producing pharmacological responses to psychedelics and antipsychotic medication. Emerging hypotheses suggest that psychedelics work through brain resetting mechanisms. Hence, there is a need to dig deeply into psychedelic neurobiology to uncover how psychedelics could best be used as scientific tools to benefit psychiatric disorders including schizophrenia.

Nano lipidic carriers for codelivery of sorafenib and ganoderic acid for enhanced synergistic antitumor efficacy against hepatocellular carcinoma.

The current study focuses on the development and evaluation of nano lipidic carriers (NLCs) for codelivery of sorafenib (SRF) and ganoderic acid (GA) therapy in order to treat hepatocellular carcinoma (HCC). The dual drug-loaded NLCs were prepared by hot microemulsion technique, where SRF and GA as the drugs, Precirol ATO5, Capmul PG8 as the lipids, while Solutol HS15 and ethanol was used as surfactant and cosolvents. The optimized drug-loaded NLCs were extensively characterized through in vitro and in vivo studies. The optimized formulation had particle size 29.28 nm, entrapment efficiency 93.1%, and loading capacity 14.21%. In vitro drug release studies revealed>64% of the drug was released in the first 6 h. The enzymatic stability analysis revealed stable nature of NLCs in various gastric pH, while accelerated stability analysis at 25◦C/60% RH indicated the insignificant effect of studied condition on particle size, entrapment efficiency, and loading capacity of NLCs. The cytotoxicity performed on HepG2 cells indicated higher cytotoxicity of SRF and GA-loaded NLCs as compared to the free drugs (p < 0.05). Furthermore, the optimized formulation suppressed the development of hepatic nodules in the Wistar rats and significantly reduced the levels of hepatic enzymes and nonhepatic elements against DEN intoxication. The SRF and GA-loaded NLCs also showed a significant effect in suppressing the tumor growth and inflammatory cytokines in the experimental study. Further, histopathology study of rats treated SRF and GA-loaded NLCs and DEN showed absence of necrosis, apoptosis, and disorganized hepatic parenchyma, etc. over other treated groups of rats. Overall, the dual drug-loaded NLCs outperformed over the plain drugs in terms of chemoprotection, implying superior therapeutic action and most significantly eliminating the hepatic toxicity induced by DEN in Wistar rat model.

An insight into the implications of estrogen deficiency and transforming growth factor ß in antiepileptic drugs-induced bone loss.

There have been a number of reports that chronic antiepileptic drug (AEDs) therapy is associated with abnormal bone and calcium metabolism, osteoporosis/osteomalacia, and increased risk of fractures. Bony adverse effects of long term antiepileptic drug therapy have been reported for more than four decades but the exact molecular mechanism is still lacking. Several mechanisms have been proposed regarding AEDs induced bone loss; Hypovitaminosis D, hyperparathyroidism, estrogen deficiency, calcitonin deficiency. Transforming growth factor-ß (TGF- ß) is abundant in bone matrix and has been shown to regulate the activity of osteoblasts and osteoclasts in vitro. All isoforms of TGF- ß are expressed in bone and intricately play role in bone homeostasis by modulating estrogen level. Ovariectomised animal have shown down regulation of TGF- ß in bone that could also be a probable target of AEDs therapy associated bone loss. One of the widely accepted hypotheses regarding the conventional drugs induced bone loss is hypovitaminosis D which is by virtue of their microsomal enzyme inducing effect. However, despite of the lack of enzyme inducing effect of certain newer antiepileptic drugs, reduced bone mineral density with these drugs have also been reported. Thus an understanding of bone biology, pathophysiology of AEDs induced bone loss at molecular level can aid in the better management of bone loss in patients on chronic AEDs therapy. This review focuses mainly on certain new molecular targets of AEDs induced bone loss.

Cationic Solid Lipid Nanoparticles of Resveratrol for Hepatocellular Carcinoma Treatment: Systematic Optimization, in vitro Characterization and Preclinical Investigation.

AIM: The present study focuses on the development and evaluation of the resveratrol (RV)-loaded cationic solid lipid nanoparticles (RV-c-SLNs) for the management of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Optimization of formulation was performed using factorial design, and further in vitro drug release, cytotoxicity, biodistribution, in vivo preclinical, and biochemical evaluation were carried out. RESULTS: The optimized formulation exhibited uniform size, homogeneous disparity, positive zeta potential, and stability over 12-week storage at 25°C/60% RH. The in vitro drug release and cytotoxicity study showed 60% drug release within the first 6 hours and comparatively higher cytotoxicity on HepG2 cell line by resveratrol-solid lipid nanoparticle (RV-SLN) as compared to the RV solution. In addition, an anticancer action and biodistribution study on a rat model of HCC showed significant reduction of tumor volume and higher accumulation in the tumor tissue from RV-c-SLN (P<0.01) over RV solution and RV-SLN. Furthermore, RV-c-SLN showed significant down-regulation in the levels of pro-inflammatory cytokines and balancing of antioxidant enzymes. Histopathological investigation showed reduced occurrence of hepatic nodules, necrosis formation, infiltration of inflammatory cells, blood vessels inflammation, and cell swelling. CONCLUSION: Overall, the obtained results construed that RV-c-SLN with improved antitumor activity as clearly evident from in vitro, in vivo, and biochemical investigations.

Nanotherapeutic systems for delivering cancer vaccines: recent advances.

With an increase in the global burden of cancer-related deaths, the quest for developing new therapeutic solutions has taken momentum. In this regard, the idea of using cancer vaccines came to existence approximately 30 years ago, where gene therapy interventions have shown significant improvement in the therapeutic outcomes against several types of cancers. Cancer vaccines usually encounter a number of challenges with limited targeting ability to the tumors. Nanocarriers have been studied as a technological innovation for tumor targeting of gene therapeutics. This article provides a critical insight into the recent progress made in nanotherapeutic strategies for genetic vaccine delivery for treatment against various types of cancers. Moreover, the article intends to provide a summary of the research work being done on this topic.