Plausible mechanism of drug resistance and side-effects of COVID-19 therapeutics: a bottleneck for its eradication.

BACKGROUND: COVID-19 pandemic has turned our world upside down by meddling with our normal lives. While there is no definitive drug against SARS-CoV-2, antiviral drugs that are already in the market, are being repurposed against it, could now complete long-term as well as all age-specific investigations, and they are successful in saving millions of lives. Nevertheless, side-effects are emergingly seen in the patients undergoing treatment, and ineffectiveness is increasingly found due to the emerging notorious variants of the virus. Many of them are also facing serious co-infections including black fungus, Zika, and H1N1 virus to name a few. OBJECTIVES: Therefore, this review highlights both drug resistance, their side-effects, and the significance for proper and long-term clinical trials of all age groups including children. METHODS: We have explored and proposed the mechanisms of drug resistance that may arise due to the misuse or overuse of drugs based on available experimental reports. RESULTS: The review provides solutions to the aforesaid issues of drug-resistance and side-effects by providing combination therapies, ancillary treatments, and other preventive strategies that can be useful in preventing drawbacks thereby curbing COVID-19 or similar future infections to maintain our normal lives. CONCLUSION: COVID-19 and its long-term effects, if any, can be eradicated with strategic and mindful use of related therapeutics in a controlled manner.

Liposomes to Cubosomes: The Evolution of Lipidic Nanocarriers and Their Cutting-Edge Biomedical Applications.

Lipidic nanoparticles have undergone extensive research toward the exploration of their diverse therapeutic applications. Although several liposomal formulations are in the clinic (e.g., DOXIL) for cancer therapy, there are many challenges associated with traditional liposomes. To address these issues, modifications in liposomal structure and further functionalization are desirable, leading to the emergence of solid lipid nanoparticles and the more recent liquid lipid nanoparticles. In this context, "cubosomes", third-generation lipidic nanocarriers, have attracted significant attention due to their numerous advantages, including their porous structure, structural adaptability, high encapsulation efficiency resulting from their extensive internal surface area, enhanced stability, and biocompatibility. Cubosomes offer the potential for both enhanced cellular uptake and controlled release of encapsulated payloads. Beyond cancer therapy, cubosomes have demonstrated effectiveness in wound healing, antibacterial treatments, and various dermatological applications. In this review, the authors provide an overview of the evolution of lipidic nanocarriers, spanning from conventional liposomes to solid lipid nanoparticles, with a special emphasis on the development and application of cubosomes. Additionally, it delves into recent applications and preclinical trials associated with cubosome formulations, which could be of significant interest to readers from backgrounds in nanomedicine and clinicians.

Enhancing Immunological Memory: Unveiling Booster Doses to Bolster Vaccine Efficacy Against Evolving SARS-CoV-2 Mutant Variants.

A growing number of re-infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in previously immunized individuals has sparked discussions about the potential need for a booster vaccine dosage to counteract declining antibody levels and new strains. The protective immunity produced by vaccinations, and past illnesses relies on immunological memory. CD4 + T cells, CD8 + T cells, B cells, and long-lasting antibody responses are all components of the adaptive immune system that can generate and maintain this immunological memory. Since novel mutant variants have emerged one after the other, the world has been hit by repeated waves. Various vaccine formulations against SARS-CoV-2 have been administered across the globe. Thus, estimating the efficacy of those vaccines against gradually developed mutant stains is the essential parameter regarding the fate of those vaccine formulations and the necessity of booster doses and their frequency. In this review, focus has also been given to how vaccination stacks up against moderate and severe acute infections in terms of the longevity of the immune cells, neutralizing antibody responses, etc. However, hybrid immunity shows a greater accuracy of re-infection of variants of concern (VOCs) of SARS-CoV-2 than infection and immunization. The review conveys knowledge of detailed information about several marketed vaccines and the status of their efficacy against specific mutant strains of SARS-CoV-2. Furthermore, this review discusses the status of immunological memory after infection, mixed infection, and vaccination.

Is Omicron the end of pandemic or start of a new innings?

In the middle of November 2021, Omicron (B.1.1.529), a novel variant of SARS-CoV-2 was identified in South Africa. Owing to continuous increasing cases with rapid transmissibility and immune evasion, the World Health Organization (WHO) has categorized this strain as a variant of concern (VOC). In total, over 60 mutations have been identified in Omicron (BA.1) and latterly, its three sub-lineages (BA.1.1, BA.2, and BA.3) have also been found with additional mutations and pathogenicity. The highly contagious Omicron causes less severe sickness than Delta, but it is still dangerous for those who have not been vaccinated. Following the unique identification of the Omicron variant, a fresh debate has erupted regarding the natural vaccines. A number of experts believe that Omicron can work as a natural vaccine, because it is similar to live attenuated vaccines in certain ways. Additionally, it was highlighted that the high rate of antibody generation in individuals cured of Omicron provide suggestive evidence in favor of those researchers who claimed Omicron acts as natural vaccine. Some disagreements also noted, as it also has tremendous health effects and high infection rate, as similar to the prior variants. This review summarizes the contradictory scenario among the scientists about Omicron variant.

Immunogenic and reactogenic efficacy of Covaxin and Covishield: a comparative review.

SARS-CoV-2 is an RNA virus that was identified for the first time in December 2019 in Wuhan, China. The World Health Organization (WHO) labeled the novel coronavirus (COVID-19) outbreak a worldwide pandemic on March 11, 2020, due to its widespread infectivity pattern. Because of the catastrophic COVID-19 outbreak, the development of safe and efficient vaccinations has become a key priority in every health sector throughout the globe. On the 13th of January 2021, the vaccination campaign against SARS-CoV-2 was launched in India and started the administration of two types of vaccines known as Covaxin and Covishield. Covishield is an adenovirus vector-based vaccine, and Covaxin was developed by a traditional method of vaccine formulation, which is composed of adjuvanted inactivated viral particles. Each vaccine's utility or efficiency is determined by its formulation, adjuvants, and mode of action. The efficacy of the vaccination depends on numeral properties like generation antibodies, memory cells, and cell-mediated immunity. According to the third-phase experiment, Covishield showed effectiveness of nearly 90%, whereas Covaxin has an effectiveness of about 80%. Both vaccination formulations in India have so far demonstrated satisfactory efficacy against numerous mutant variants of SARS-CoV-2. The efficacy of Covishield may be diminished if the structure of spike (S) protein changes dramatically in the future. In this situation, Covaxin might be still effective for such variants owing to its ability to produce multiple antibodies against various epitopes. This study reviews the comparative immunogenic and therapeutic efficacy of Covaxin and Covishield and also discussed the probable vaccination challenges in upcoming days.

Nanosuspension: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to amphotericin B.

Present limitations in the management of ophthalmic fungal infections include the inability to provide long-term extraocular drug delivery without compromising intraocular structures and/or systemic drug exposure. In the present study, the potential of Eudragit RS 100 nanoparticles (NPs) as a new vehicle for the improvement of the delivery of drugs to the ocular mucosa was investigated. Amphotericin B (AmB) was chosen as a model compound because of its potential usefulness for the treatment of fungal diseases. A solvent displacement technique was used to produce AmB-loaded Eudragit NPs. These NPs had a mean size range of 150-290 nm and a zeta potential of +19-28 mV. Even after 6 months of stability study, results were unchanged, indicating the good potential for ocular application. In vitro release studies revealed that a maximum amount of drug was released within 24 hours (60%). The results obtained from microbial assay showed that the antifungal activity of drug-loaded NPs was equal to or slightly lower than that of free-AmB solution. In vivo experiments showed that, following topical instillation of nanosuspension to a rabbit's eye there was no irritation. From these results we can conclude that Eudragit RS 100 nanosuspension may represent an efficacious vehicle to deliver the drug into the eye. FROM THE CLINICAL EDITOR: Amphotericin B encapsulated into Eudragit, a mildly cationic nanoparticle, was shown to have 6 month stability, release 60% of its drug payload in dissolution within 24 hours, and elicited no irritation when instilled into rabbit eyes. The concept is being considered for local ophthalmologic therapy of fungal disease.

Design of Eudragit RL 100 nanoparticles by nanoprecipitation method for ocular drug delivery.

The objective of the current study was to prepare positively charged amphotericin-B-loaded nanoparticles providing a controlled release formulation. The particles were prepared by solvent displacement or nanoprecipitation method. The non-biodegradable positively charged polymer Eudragit RL 100 was used to prepare the different formulations with varying ratios of drug and polymer. The formulations were evaluated in terms of particle size, zeta potential, and differential scanning calorimetry measurements. Drug entrapment and release properties were examined also. The antimicrobial activity against Fusarium solani was determined. In vivo eye irritation study was carried out by a modified Draize test. All the formulations remained within a size range of 130 to 300 nm in fresh preparation as well as after 2 months. The zeta potential was positive (+22 to +42 mV) for all the formulations and was suitable for ophthalmic application. A prolonged drug release was shown by all the formulations. The formulation possesses a good antifungal activity against Fusarium solani when tested by disk diffusion method, and no eye irritation on in vivo testing was found. FROM THE CLINICAL EDITOR: The objective of the current study was to prepare positively charged amphotericin-B-loaded nanoparticles providing a controlled release formulation. The described formulation displayed good antifungal activity against Fusarium solani when tested by disk diffusion method, and no eye irritation on in vivo testing was found.