NEI Congress 2023

The proceedings contain 53 papers. The topics discussed include: clinical study of lurasidone combined with nutritional intervention strategy in the treatment of chronic schizophrenia;analysis of clinical medication scheme and nursing measures of acute stress disorder complicated with delirium under the COVID-19;a study on the mental state of prisoners near the end of their sentence caused by a psychological anxiety case;a clinical study on the effect of peperidone combined with cognitive behavioral therapy on symptoms of schizophrenia;the clinical effect of feedforward control nursing combined with methylphenidate sustained-release tablets on children with attention deficit hyperactivity disorder;study on the effect of community legal consciousness health management on cognitive function of senile patients;effects of special sports training on autonomic nervous regulation;a study of positive intervention of music therapy and neurofeedback on negative emotions and attention in college students;and alleviating effect of the geriatric care system integrating physical and psychological on the common mental problems of the elderly.

Ultra- sustained-release multi-particulate dosage form of Doxycycline as a platform of repurposing therapeutics in the fight against COVID 19: in-vitro and in-silico study

Purpose: Many recent studies highlighted Doxycycline beneficial multiple effects against SARS-COV2 either as a monotherapy or combination therapy. The creation of novel drug delivery systems is an attractive approach for the repurposing of drugs in a trial to fight COVID 19. In this study, ultra-sustained-release dosage forms were designed. Methods: A simple and cost-effective method was followed. Eudragit L100 (EL100), a pH sensitive water insoluble polymer, was combined with Doxycycline (DOX) in different ratios to form multi-particulate systems (MPs) with different drug release rates. Results: All the prepared MPs significantly sustained DOX release to reach a complete drug release after about 23.9, 142.57 and 165.58 h in case of MP1, MP2 and MP3, respectively compared to the pure drug which attained 100 % drug release within 30 min. The drug release was diffusion-dependent. Also, the prepared MPs showed satisfactory flow properties. The formula attaining the most extended drug release was subjected to characterization. In-silico molecular modeling study proved the high binding affinity of DOX/EL100 to S1-RBD of SARS-CoV-2. This high interaction may interfere with virus attachment to the host receptors and hence inhibit virus infection. Conclusion: This study shed the light on a possible platform to prepare ultra-long-acting dosage forms having different drug release rates by just simple, yet attractive, modifications which can offer promising therapeutic approaches.

Antiviral potential of garlic (Allium sativum) and its organosulfur compounds: A systematic update of pre-clinical and clinical data.

BACKGROUND: Garlic (Allium sativum L.) is a common herb consumed worldwide as functional food and traditional remedy for the prevention of infectious diseases since ancient time. Garlic and its active organosulfur compounds (OSCs) have been reported to alleviate a number of viral infections in pre-clinical and clinical investigations. However, so far no systematic review on its antiviral effects and the underlying molecular mechanisms exists. SCOPE AND APPROACH: The aim of this review is to systematically summarize pre-clinical and clinical investigations on antiviral effects of garlic and its OSCs as well as to further analyse recent findings on the mechanisms that underpin these antiviral actions. PubMed, Cochrane library, Google Scholar and Science Direct databases were searched and articles up to June 2020 were included in this review. KEY FINDINGS AND CONCLUSIONS: Pre-clinical data demonstrated that garlic and its OSCs have potential antiviral activity against different human, animal and plant pathogenic viruses through blocking viral entry into host cells, inhibiting viral RNA polymerase, reverse transcriptase, DNA synthesis and immediate-early gene 1(IEG1) transcription, as well as through downregulating the extracellular-signal-regulated kinase (ERK)/mitogen activated protein kinase (MAPK) signaling pathway. The alleviation of viral infection was also shown to link with immunomodulatory effects of garlic and its OSCs. Clinical studies further demonstrated a prophylactic effect of garlic in the prevention of widespread viral infections in humans through enhancing the immune response. This review highlights that garlic possesses significant antiviral activity and can be used prophylactically in the prevention of viral infections.

Sustained Release of Co-Amorphous Matrine-Type Alkaloids and Resveratrol with Anti-COVID-19 Potential.

Matrine (MAR), oxymatrine (OMAR), and sophoridine (SPD) are natural alkaloids with varying biological activities; matrine was recently used for the treatment of coronavirus disease 2019 (COVID-19). However, the short half-lives and rapid elimination of these matrine-type alkaloids would lead to low oral bioavailability and serious side effects. Herein, resveratrol (RES) was selected as a co-former to prepare their co-amorphous systems to improve the therapeutic index. The formation of co-amorphous MAR-RES, OMAR-RES, and SPD-RES was established through powder X-ray diffraction and modulated temperature differential scanning calorimetry. Furthermore, Fourier transform infrared spectroscopy and NMR studies revealed the strong molecular interactions between resveratrol and these alkaloids, especially OMAR-RES. Matrine, oxymatrine, and sophoridine in the co-amorphous systems showed sustained release behaviors in the dissolution experiments, due to the recrystallization of resveratrol on the surface of co-amorphous drugs. The three co-amorphous systems exhibited excellent physicochemical stability under high relative humidity conditions. Our study not only showed that minor structural changes of active pharmaceutical ingredients may have distinct molecular interactions with the co-former, but also discovered a new type of sustained release mechanism for co-amorphous drugs. This promising co-amorphous drug approach may present a unique opportunity for repurposing these very promising drugs against COVID-19.

Sustained Delivery of SARS-CoV-2 RBD Subunit Vaccine Using a High Affinity Injectable Hydrogel Scaffold.

The receptor binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein that mediates viral entry into host cells is a good candidate immunogen for vaccine development against coronavirus disease 2019 (COVID-19). Because of its small size, most preclinical and early clinical efforts have focused on multimerizing RBD on various formats of nanoparticles to increase its immunogenicity. Using an easily administered injectable hydrogel scaffold that is rationally designed for enhanced retainment of RBD, an alternative and facile approach for boosting RBD immunogenicity in mice is demonstrated. Prolonged delivery of poly (I:C) adjuvanted RBD by the hydrogel scaffold results in sustained exposure to lymphoid tissues, which elicits serum IgG titers comparable to those induced by three bolus injections, but more long-lasting and polarized toward TH 1-mediated IgG2b. The hydrogel scaffold induces potent germinal center (GC) reactions, correlating with RBD-specific antibody generation and robust type 1 T cell responses. Besides being an enduring RBD reservoir, the hydrogel scaffold becomes a local inflammatory niche for innate immune cell activation. Collectively, the injectable hydrogel scaffold provides a simple, practical, and inexpensive means to enhance the efficacy of RBD-based subunit vaccines against COVID-19 and may be applicable to other circulating and emerging pathogens.

Dissolving microneedle patches loaded with amphotericin B microparticles for localised and sustained intradermal delivery: Potential for enhanced treatment of cutaneous fungal infections.

Fungal infections affect millions of people globally and are often unreceptive to conventional topical or oral preparations because of low drug bioavailability at the infection site, lack of sustained therapeutic effect, and the development of drug resistance. Amphotericin B (AmB) is one of the most potent antifungal agents. It is increasingly important since fungal co-infections associated with COVID-19 are frequently reported. AmB is only administered via injections (IV) and restricted to life-threatening infections due to its nephrotoxicity and administration-related side effects. In this work, we introduce, for the first time, dissolving microneedle patches (DMP) loaded with micronised particles of AmB to achieve localised and long-acting intradermal delivery of AmB for treatment of cutaneous fungal infections. AmB was pulverised with poly (vinyl alcohol) and poly (vinyl pyrrolidone) to form micronised particles-loaded gels, which were then cast into DMP moulds to form the tips. The mean particle size of AmB in AmB DMP tips after pulverisation was 1.67 ± 0.01 µm. This is an easy way to fabricate and load microparticles into DMP, as few steps are required, and no organic solvents are needed. AmB had no covalent chemical interaction with the excipients, but the crystallinity of AmB was reduced in the tips. AmB was completely released from the tips within 4 days in vitro. AmB DMP presented inhibition of Candida albicans (CA) and the killing rate of AmB DMP against CA biofilm inside porcine skin reached 100% within 24 h. AmB DMP were able to pierce excised neonatal porcine skin at an insertion depth of 301.34 ± 46.86 µm. Ex vivo dermatokinetic and drug deposition studies showed that AmB was mainly deposited in the dermis. An in vivo dermatokinetic study revealed that the area under curve (AUC0-inf) values of AmB DMP and IV (Fungizone® bolus injection 1 mg/kg) groups were 8823.0 d∙µg/g and 33.4 d∙µg/g, respectively (264-fold higher). AmB remained at high levels (219.07 ± 102.81 µg/g or more) in the skin until 7 days after the application of AmB DMP. Pharmacokinetic and biodistribution studies showed that AmB concentration in plasma, kidney, liver, and spleen in the AmB DMP group was significantly lower than that in the IV group. Accordingly, this system addressed the systemic side effects of intravenous injection of AmB and localised the drug inside the skin for a week. This work establishes a novel, easy and effective method for long-acting and localised intradermal drug delivery.

Enhancing influenza vaccine immunogenicity and efficacy through infection mimicry using silk microneedles.

Traditional bolus vaccine administration leads to rapid clearance of vaccine from lymphoid tissue. However, there is increasing evidence suggesting that the kinetics of antigen delivery can impact immune responses to vaccines, particularly when tailored to mimic natural infections. Here, we present the specific enhancements sustained release immunization confers to seasonal influenza vaccine, including the magnitude, durability, and breadth of humoral responses. To achieve sustained vaccine delivery kinetics, we have developed a microneedle array patch (MIMIX), with silk fibroin-formulated vaccine tips designed to embed in the dermis after a short application to the skin and release antigen over 1-2 weeks, mimicking the time course of a natural influenza infection. In a preclinical murine model, a single influenza vaccine administration via MIMIX led to faster seroconversion, response-equivalence to prime-boost bolus immunization, higher HAI titers against drifted influenza strains, and improved protective efficacy upon lethal influenza challenge when compared with intramuscular injection. These results highlight infection mimicry, achieved through sustained release silk microneedles, as a powerful approach to improve existing seasonal influenza vaccines, while also suggesting the broader potential of this platform technology to enable more efficacious next-generation vaccines and vaccine combinations.

Biomaterials and nanomaterials for sustained release vaccine delivery.

Vaccines are considered one of the most significant medical advancements in human history, as they have prevented hundreds of millions of deaths since their discovery; however, modern travel permits disease spread at unprecedented rates, and vaccine shortcomings like thermal sensitivity and required booster shots have been made evident by the COVID-19 pandemic. Approaches to overcoming these issues appear promising via the integration of vaccine technology with biomaterials, which offer sustained-release properties and preserve proteins, prevent conformational changes, and enable storage at room temperature. Sustained release and thermal stabilization of therapeutic biomacromolecules is an emerging area that integrates material science, chemistry, immunology, nanotechnology, and pathology to investigate different biocompatible materials. Biomaterials, including natural sugar polymers, synthetic polyesters produced from biologically derived monomers, hydrogel blends, protein-polymer blends, and metal-organic frameworks, have emerged as early players in the field. This overview will focus on significant advances of sustained release biomaterial in the context of vaccines against infectious disease and the progress made towards thermally stable "single-shot" formulations. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease.

Ethyl cellulose coated sustained release aspirin spherules for treating COVID-19: DOE led rapid optimization using arbitrary interface; applicable for emergency situations.

This work attempts to resolve one of the key issues related to the design and development of sustained-release spherule of aspirin for oral formulations, tailored to treat COVID-19. For that, in the Design of Experiments (DOE) an arbitrary interface, "coating efficiency" (CE) is introduced and scaled the cumulative percentage coating (CPC) to get predictable control over drug release (DR). Subsequently, the granules containing ASP are converted to spherules and then to Ethyl cellulose (EC) Coated spherules (CS) by a novel bed coating during the rolling (BCDR) process. Among spherules, one with 0.35 mm than 0.71 mm shows required properties. The CS has a low 1200 angle by Optical Microscopy (OM), smooth surface without cracks by scanning electron microscopy (SEM), and better flow properties (Angle of repose 29.69 ± 0.780, Carr's index 6.73 ± 2.24%, Hausner's Ratio 1.07 ± 0.03) than granules and spherules. Once certain structure-dependent control over release is attained (EC coated spherules shows 10% reduction in burst release (BR) than uncoated spherules showing a release of 80-91%) the predictability is achieved and Design of space (DOS) by DOE (CE-70.14%and CPC-200% and DR-61.54%) is established. The results of DOE to experimentally validated results were within 20% deviation. The aspirin is changing its crystal structure by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) from Form-I to Form-II showing polymorphism inside the drug reservoir with respect to the process. This CE and CPC approach in DOE can be used for delivery system design of other labile drugs similar to aspirin in emergency situations.