Rheumatoid arthritis (RA) is a chronic autoimmune disorder that has significant impact on quality of life and work capacity. Treatment of RA aims to control inflammation and alleviate pain, however achieving remission with minimal toxicity is frequently not possible with the current suite of drugs. This review aims to summarise current treatment practices and highlight the urgent need for alternative pharmacogenomic approaches to novel drug discovery. These approaches can elucidate new relationships between drugs, genes, and diseases to identify additional effective and safe therapeutic options. This review discusses how computational approaches such as connectivity mapping offers the ability to repurpose FDA approved drugs beyond their original treatment indication. This review also explores the concept of drug sensitisation, to predict co-prescribed drugs with synergistic effects that produce enhanced anti-disease efficacy by involving multiple disease pathways. Challenges of this computational approach are discussed including the availability of suitable high-quality datasets for comprehensive analysis and other data curation issues. The potential benefits include accelerated identification of novel drug combinations, and ability to trial and implement established treatments in a new index disease. This review underlines the huge opportunity to incorporate disease-related data and drug-related data to develop methods and algorithms which have strong potential to determine novel and effective treatment regimens.

Peptide mapping is an important tool to confirm the correct sequence expressed for a protein and to evaluate protein post-translational modifications (PTMs) that may arise during production, processing, or storage of protein drugs. Our new orally administered drug (Ab-1), a single-domain antibody, is highly stable and resistant to proteolysis. Analysis by the commonly used tryptic map method did not generate sufficient sequence coverage. Alternative methods were needed to study the Ab-1 drug substance (75 mg/mL) and drug product (3 mg/mL). To meet analytical needs, we developed two new peptide map methods with lysyl endopeptidase (Lys-C) digestion. These newly developed protein digestion protocols do not require desalting/buffer-exchange steps, thereby reducing sample preparation time and improving method robustness. Additionally, the protein digestion was performed under neutral pH with methionine acting as a scavenger to minimize artifacts, such as deamidation and oxidation, which are induced during sample preparation. Further, the method for low concentration samples performs comparably to the method for high concentration samples. Both methods provide 100% sequence coverage for Ab-1, and therefore, enable comprehensive characterization for its product quality attributes (PQA) assessment. Both methods can be used to study other antibody modalities.

This work deals with the synthesis of bare and curcumin (CUR)-loaded chitosan (CS)-based macroparticles by ionic gelation using sodium hydroxide (NaOH) or sodium tripolyphosphate (TPP) as cross-linking agents. The resulting spherical-shaped macroparticles were studied using various characterization techniques, Scanning Electron Microscopy (SEM), Fourier Transformed Infrared Spectroscopy (FTIR), Thermogravimetric Analysis (TGA), and Differential Scanning Calorimetry (DSC). The release of CUR from the CS-based particles with respect to time was analyzed, and the encapsulation efficiency and degree of swelling were studied. All formulations showed excellent CUR trapping efficiency, exceeding 90%. In particular, the TPP-crosslinked macrobeads released 34 wt% of the charged CUR within minutes, while the remaining 66 wt% was released slowly due to the biodegradation of CS. The results indicate that the correct choice of gelling agent and its concentration leads to spherical particles capable of encapsulating CUR and releasing it in a wide range of kinetics depending on the specific application.

Lippia javanica (Burm. f.) is a medicinal plant with multiple native uses in the treatment of colds, influenza, pneumonia, coughs, dermatitis, tuberculosis, asthma, and bronchial diseases. However, it remains underutilized in drug development. In this review, existing studies on the pharmacological activities of L. javanica, more specifically the antitumor, antiviral, and antibacterial properties as well as recent metabolites identified from the plant were appraised. Background information on the plant's ecological distribution, ethnobotanical importance, toxicity, and cytotoxicity activity was also provided. The information in the review was gathered from major scientific databases (Google scholar, BioMed Central, Scopus, PubMed, Springer, Web of Science, and Science Direct) using journals, conference proceedings, dissertations, books, and/or chapters. The review compiled 66 new metabolites from the plant while establishing the anticancer, antiviral, antibacterial, and other important pharmacological activities of the organic (most especially methanol and acetone) and aqueous extracts of various parts of the plant attributed to several secondary metabolites present in the volatile oil of the plant, which includes carvone, ipsdienone, limonene, linalool, myrcene, ocimenone, caryophyllene, piperitenone, sabinene, p-cymene, sabinene, myrcene, ipsenone, and tagetenone. While some of the metabolites of L. javanica have been linked through pharmacological studies to the various traditional uses of the plant, some others remain unexplored, emphasizing how underutilized the plant is in drug research and development. It is envisaged that the reports from this review will help to further encourage future research and guide further investigations into the pharmaceutical and medicinal uses of L. javanica.

Curcumin (CUR) is a phytochemical with potent anticancer activities as demonstrated by both preclinical and clinical studies. CUR bioformulations, including loading in biodegradable polymers, have been explored to increase CUR’s solubility and chemical stability, control its release, and improve its delivery to cancer cells. In this study, copolymers comprising poly (L-lactide)-poly (ethylene glycol)-poly (L-lactide) (PLA-PEG-PLA) and poly (ethylene glycol)-poly (L-lactide)-poly (ethylene glycol) (PEG-PLA-PEG) were designed and synthesized to assess and compare their curcumin delivery capacity and inhibitory potency on MCF-7 breast cancer cells. Molecular dynamics simulations indicated that PLA-PEG-PLA has a higher propensity to interact with the cell membrane and more negative free energy, suggesting it is the better carrier for cell membrane penetration. Our characterization indicated that the microsphere copolymers were synthesized successfully. Of the two formulations, PLA-PEG-PLA experimentally exhibited better results, with an initial burst release of 17.5%, followed by a slow, constant release of the encapsulated drug up to 80%. PLA-PEG-PLA-curcumin showed a significant increase in cell death in MCF-7 cancer cells (IC50 = 23.01 ± 0.85 µM) based on the MTT assay. These data were consistent with gene expression studies of Bax, Bcl2, and hTERT which showed that PLA-PEG-PLA-CUR induced apoptosis more efficiently in these cells. Our study integrates in vitro and in silico approaches to identify an optimal co-polymer for the delivery of CUR to cancer cells.

Kinases play an important role in regulating various intracellular signaling pathways that control cell proliferation, differentiation, survival and other cellular processes and their deregulation causes more than 400 diseases. Consequently, macrocyclization can be considered a noteworthy approach to develop new therapeutic agents for human diseases. Macrocyclization has emerged as an effective drug discovery strategy over the past decade to improve target selectivity and potency of small molecules. Small compounds with linear structures upon macrocyclization can lead to changes in their physicochemical and biological properties by firmly reducing conformational flexibility. A number of distinct protein kinases exhibit similar binding sites. Comparison of protein binding site provides crucial insights for the drug discovery and development. Binding site similarities are helpful to understand polypharmacology, identifying potential off-targets and repurposing of known drugs. In this review, we focused on comparing binding sites of those kinases for which macrocyclic inhibitors are available/studied so far. Furthermore, we calculated the volume of binding site pocket for each targeted kinase and then compared it with the binding site pocket of the kinase for which only acyclic inhibitors were designed till date. Our review and analysis of several explored kinases might be useful to target new protein kinases for macrocyclic drug discovery.

Sepsis is a life-threatening condition caused by a dysregulated host response to an invading pathogen such as multidrug-resistant bacteria. Despite recent advancements, sepsis is a leading cause of morbidity and mortality, resulting in a significant global impact and burden. This condition affects all age groups, with clinical outcomes depending mainly on timely diagnosis and appropriate early therapeutic intervention. Because of the unique features of nanosized systems, there is a growing interest in developing and designing novel solutions. Nanoscale-engineered materials allow a targeted and controlled release of bioactive agents, resulting in improved efficacy with minimal side effects. Additionally, nanoparticle-based sensors provide a quicker and more reliable alternative to conventional diagnostic methods for identifying infection and organ dysfunction. Despite recent advancements, fundamental nanotechnology principles are often presented in technical formats that presuppose advanced chemistry, physics, and engineering knowledge. Consequently, clinicians may not grasp the underlying science, hindering interdisciplinary collaborations and successful translation from bench to bedside. In this review, we abridge some of the most recent and most promising nanotechnology-based solutions for sepsis diagnosis and management using an intelligible format to stimulate a seamless collaboration between engineers, scientists, and clinicians.

Despite the recent approval of novel immunotherapies, as immunomodulatory drug, proteasome inhibitors and anti-CD38 monoclonal antibodies, Multiple Myeloma (MM) remains incurable and the acquisition of triple-refractoriness leads to really dismal outcomes, in even earlier lines of therapy. More recently, innovative therapeutic strategies targeting B cell maturation antigen (BCMA), highly expressed on the plasma cell surface, are drawing different future landscapes in terms of effectiveness and outcomes. Belantamab Mafodotin, a first-in-class anti-BCMA antibody drug conjugates, demonstrated good efficacy and safety profile in triple-refractory patients in the phase 2 DREAMM-2 trial and it was approved for the treatment of MM triple-exposed patients with >4 prior lines of therapy. Here, starting from Belantamab Mafodotin clinical trials also exploring combination studies and different schedules in order to improve its efficacy and toxicity, we focused on real life experiences all over the world, which have confirmed clinical trial data and encourage further Belantamab Mafodotin investigations

Abstract: Enfortumab vedotin (EV), an antibody-drug conjugate directed against Nectin-4, signif-icantly prolonged survival when compared with standard chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who previously received platinum-based chemo-therapy and a PD-1 or PD-L1 inhibitor. The confirmed overall response rate in the phase 3 EV301 trial leading to approval was 40.6%. However, no data have been published about the activity in brain metastases. Here, we present three patients from different centers with brain metastases receiving EV. A 58-year-old male Caucasian patient, who was heavily pretreated for urothelial carcinoma with visceral metastases and a solitary clinically active brain metastasis, started on EV 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle. The first evaluation after three cycles of EV showed a partial remission by RECIST v1.1 with a near complete response in the brain metastasis and disappear-ance of the neurological complaints. The patient is currently still receiving EV. A second, 74-year-old male patient started on the same regimen, after previous progression on platinum-based chemotherapy and maintenance avelumab. The patient achieved complete response and remained on therapy for five months. However, therapy was discontinued at the patient’s re-quest. Shortly after, he developed new leptomeningeal metastases. Upon rechallenge with EV, there was a significant reduction in the diffuse meningeal infiltration. A third, 50-year-old male Caucasian patient also received EV, after previous progression on cisplatin-gemcitabine and ate-zolizumab maintenance followed by palliative whole brain radiotherapy and two cycles of vin-flunine. The first evaluation after three cycles of EV showed a significant reduction of the brain metastases. The patient is currently still receiving EV. These are the first reports on efficacy of EV in patients with urothelial carcinoma and active brain metastases.

Liposome-mediated delivery is a possible means to overcome several shortcomings with C. elegans as a model for identifying and testing drugs that retard aging. These include interactions between drugs and the nematodes’ bacterial food source, and failure of drugs to be taken up into nematode tissues. To explore this, we have tested liposome-mediated delivery of a range of fluorescent dyes and drugs in C. elegans. Liposome encapsulation led to enhanced effects on lifespan, using smaller quantities of compound, and enhanced uptake of three dyes into the gut lumen. However, one dye (Texas red) did not cross into nematode tissues, indicating that liposomes cannot ensure uptake of any compound. Of six compounds previously reported to extend lifespan (vitamin C, N-acetylcysteine, glutathione (GSH), trimethadione, thioflavin T (ThT) and rapamycin), this effect was reproduced for the latter four in a condition-dependent manner. For GSH and ThT, antibiotics abrogated life extension, implying a bacterially-mediated effect. With GSH, this was attributable to reduced early death from pharyngeal infection, and associated with alterations of mitochondrial morphology in a manner suggesting a possible innate immune training effect. By contrast, ThT exhibited antibiotic effects. For rapamycin, significant increases in lifespan were only seen when bacterial proliferation was prevented. These results document the utility and limitations of liposome-mediated drug delivery for C. elegans. They also show how nematode-bacteria interactions can determine the effects of compounds on C. elegans lifespan in a variety of ways.

The structure of wound dressing materials presents one of the most relevant characteristics for effective skin tissue repair. Electrospinning is a common technique used to produce polymeric fibres that can mimic fibrillar disposition of skin extracellular matrix, favouring cell migration, and thus regeneration of the damaged tissue. Moreover, beads, also known as by-products of electrospinning, have potential as reservoirs for sustained drug release. Processing parameters, such as molecular weight and viscosity of the polymer solution, can affect the desirable morphologies of electrospun films. Thereby, this work had the purpose of producing and characterized electrospun polycaprolactone (PCL) mats loaded with propolis, a popular extract in traditional medicine with potential for skin repair aid. Films with different morphologies were obtained depending on the storage period of the solution prior to the lectrospinning, probably due to the PCL hydrolysis. FTIR analyses of the extract confirmed propolis composition. GPC and viscosity analyses demonstrated that the decrease in molar mass over the storage period was responsible for nanostructure diversity. Propolis acts as a lubricant agent, affecting the spun solutions' viscosity and the thermal properties and hydrophilicity of the films. All films are within the value range of the water vapour transpiration rate of the commercial products. The presence of beads did not affect the propolis release pattern. However, "in vitro" wound healing assay showed that propolis-loaded films composed by beaded fibres increased the cell migration process. Thus, it can be inferred that these films presented the potential for wound dressing application.

Drug repurposing is an attractive strategy for developing new antibacterial molecules. Herein, we evaluated the in vitro antibacterial, antibiofilm, and antivirulence activities of eight FDA-approved “non-antibiotic” drugs, comparatively to tobramycin, against selected Pseudomonas aeruginosa strains from cystic fibrosis patients. MIC and MBC values were measured by broth microdilution methods. Time-kill kinetics was studied by the macro dilution method, and synergy studies were performed by checkerboard microdilution assay. The activity against preformed biofilm was measured by crystal violet and viable cell count assays. The effects on gene expression were studied by real-time quantitative PCR, while the cytotoxic potential was evaluated against IB3-1 bronchial CF cells. Ciclopirox, 5-fluorouracil, and actinomycin D showed the best activity against P. aeruginosa planktonic cells and, therefore, underwent further evaluation. Time-kill assays indicated actinomycin D and ciclopirox, contrarily to 5-fluorouracil and tobramycin, have the potential for bacterial eradication, although with strain-dependent efficacy. Ciclopirox was the most effective against the viability of the preformed biofilm. A similar activity was observed for other drugs, although they stimulate EPS production. Ribavirin showed a specific antibiofilm effect, not dependent on bacterial killing. Exposure to drugs and tobramycin generally caused hyperexpression of the virulence traits tested, except for actinomycin D, which downregulated the expression of alkaline protease and alginate polymerization. Ciclopirox and actinomycin D revealed high cytotoxic potential. Ciclopirox and ribavirin might provide chemical scaffolds for anti-P. aeruginosa drugs. Further studies are warranted to decrease ciclopirox cytotoxicity and evaluate the in vivo protective effects.

Multimodal therapy including surgery, radiation treatment and temozolomide (TMZ) is performed on glioblastoma (GBM). However, the prognosis is still poor and there is an urgent need to develop effective treatments to improve survival. Molecular biological analysis was conducted to exam-ine the signal activation patterns at GBM specimens and remains an open problem. Advanced macrolides, such as azithromycin, reduce the phosphorylation of p70 ribosomal protein S6 kinase (p70S6K), a downstream mammalian target of rapamycin (mTOR) effector, and suppress the proliferation of T-cells. We focused on its unique profile and screened for the antitumor activity of approved macrolide antibiotics. Clindamycin (CLD) reduced the viability of GBM cells in vitro. We assessed the effects of the candidate macrolide on the mTOR pathway through Western blotting. CLD attenuated p70S6K phosphorylation in a dose dependent manner. These effects of on GBM cells were enhanced by co-treatment with TMZ. Furthermore, CLD inhibited the expression of O6-methylguanine-DNA methyltransferase (MGMT) protein in cultured cells. In the mouse xenograft model, CLD and TMZ co-administration significantly suppressed the tumor growth and markedly decreased the number of Ki-67 (clone MIB-1) positive cells within the tumor. These results suggest that CLD suppresses GBM cell growth by the inhibiting mTOR signaling. Moreover, CLD and TMZ showed promising synergistic antitumor activity.

Dermatophytes are the most common cause of fungal infections worldwide, affecting millions of people annually. The emergence of resistance among dermatophytes along with the availability of antifungal susceptibility procedures suitable for testing antifungal agents against this group of fungi make the combinatorial approach particularly interesting to be investigated. Therefore, we reviewed the scientific literature concerning the antifungal combinations in dermatophytes. A literature search on the subject performed in PubMed yielded 68 publications: 37 articles referring to in vitro studies, and 31 articles referring to case reports/clinical studies. In vitro studies involved over 400 clinical isolates of dermatophytes (69% Trichophyton spp., 29% Microsporum spp., and 2% Epidermophyton floccosum). Combinations included two antifungal agents or an antifungal agent plus another chemical compound including plant extracts/essential oils, calcineurin inhibitors, peptides, disinfectant agents and others. In general, drug combinations yielded variable results spanning from synergism to indifference. Antagonism was rarely seen. In over 700 patients with documented dermatophyte infections an antifungal combination approach could be evaluated. The most frequent combination included a systemic antifungal agent administered orally (i.e.: azole [mainly itraconazole], terbinafine or griseofulvin) plus a topical medication (i.e.: azole, terbinafine, ciclopirox, amorolfine) for several weeks. Clinical results indicate that association of antifungal agents is effective, and it might be useful in accelerate the clinical and microbiological healing of a superficial infection. Antifungal combinations in dermatophytes have gained considerable scientific interest over the years and, in consideration of the interesting results available as far, it is desirable to continue the research in this field.

Choline kinase inhibitors are an important class of cytotoxic compounds useful for the treatment of different forms of cancer since aberrant choline metabolism is a feature of neoplastic cells. Here we present the characterization and the structure activity relationship of a series of non-symmetrical choline kinase inhibitors characterized by a 3-aminophenol moiety, bound to 4-(dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium cationic heads through several linkers. These derivatives were evaluated both for their inhibitory activity on the enzyme and for their antiproliferative activity in a panel of six human tumor cell lines. The compounds with the best inhibitory results were those connected to the linker by the N-atom (4a-h) and these results are supported by docking studies. The compounds with the best antiproliferative results were those connected to the linker by the O-atom (3a-h). On the other hand, as was predictable in both families, the inhibitory effect on the enzyme is greater the shorter the length of the linker, while in tumor cells, lipophilicity and choline uptake inhibition could play a decisive role. Interestingly compounds 3c and 4f, selected for both their ability to inhibit the enzyme and good antiproliferative activity, are endowed with a low toxicity in non-tumoral cells (e.g human peripheral lymphocytes) respect to cancer cells. These compounds were also able to induce to induce apoptosis in Jurkat leukemic cells without causing significative variations of cell cycle. It is worth to mention that these derivatives, beside their inhibitory effect on choline kinase, displayed a modest ability to inhibit choline uptake thus suggesting that this mechanism may also contribute to the observed cytotoxicity.

Nonsteroidal anti-inflammatory drugs (NSAIDs), which block the activity of cyclooxygenase (COX) isoenzymes and inhibit the synthesis of prostaglandin, have been used for pain relief. We have developed a method to separate a mixture of three NSAIDs, such as aspirin, paracetamol, and naproxen, using reverse-phase high-performance liquid chromatography (RP-HPLC). An isocratic mobile phase consisting of acidic water and acetonitrile was selected to run at a low flow rate, such as 0.8 mL/min. The mixture of three NSAIDs was injected at a low volume into a C18 column that was 150 mm in length and characterized using a UV detector at 230 nm. We identified three peaks in the chromatogram indicating the three compounds. The elution time of the peaks was less than 10 minutes. To identify multiple peaks on the isocratic flow using a short column, further studies are required regarding the proposed method to generate microfluidic devices for nanoLC.

Artificial Intellignece (AI) is a platform lending immense assistance in discovering and developing drugs and thus, various such approaches have been developed with the intent of simplifying and improving biomedical operations such as drug repurposing and drug discovery. In the past decade, AI-based investigation of nanomedicines, as well as non-nanomedicines has reached the clinical level. In semblance with the traditional methods of therapy, nanomedicine therapy is employed at limited doses. The study of a variety of drugs resulted in the conclusion that the effect of each drug is variable for every patient and, evaluating that perfect drug combination manually is a time-consuming as well as an inefficient treatment method. Therefore, the use of AI simplifies and reduces the time consumption in determining the perfect customized drug combination for nano-therapy. The area with the most potential for meeting this reality is to optimize the drug and dosage parameters. It is a universally known fact that cancer is dangerous and unique because of the exacting challenges it poses during treatment and, to achieve a better treatment, the therapeutic effect on each patient must be delineated even if the volume of data generated is massive. The article aims at analyzing the AI technologies that help yield results much quicker, make the analyses simple, and efficient.

Background: Convectional methods for drug delivery often faces setbacks due to systemic distribution, short half-life and degradation of therapeutics and therefore reduce concentrations of drug available to target tissue. Nanotheranostic provide a novel method for treating and diagnosing diseases Methodology: collection and review of relevant literatureResult: while nanotheranostic offer advantage of personalized medicine and often combines diagnosis and therapy using single molecular approach, nuclear medicine relies on radioactive isotopes to diagnosed and destroys cancer cells. In both cases, nanocarriers such as lipid-based, polymer-based, drug-conjugate, inorganic nanoparticles are used to deliver drugs/probes/isotopes to target site, generating images and thereafter chemotherapy/radiotherapy begins.Conclusion: Nanotheranostic plays important role in diseases diagnostic, therapy, imaging, monitoring of disease progression / response through the use of nanocarriers. This is made possible through nanoparticles/nanocarriers that delivers drug to the target tissues/cells.

Tailoring extracellular vesicles (EVs) as targeted drug delivery systems to enhance the therapeutic efficacy showed superior advantage over liposomal therapies. Herein, we developed a novel nanotool for targeting B16.F10 murine melanoma, based on EVs stabilized with Polyethylene glycol (PEG) and loaded with doxorubicin (DOX). Nanosized EVs were efficiently enriched from melanoma cells cultured under metabolic stress by ultrafiltration coupled with size exclusion chromatography (UF-SEC) and characterized by size, morphology, and proteome. To reduce their clearance in vivo, EVs were PEGylated and passively loaded with DOX (PEG-EV-DOX). Our data suggested that the low PEG coverage of EVs might still favor EV surface protein interactions with target proteins from intratumor cells, ensuring their use as “Trojan horses” to deliver DOX to the tumor tissue. Moreover, our results showed a superior antitumor activity of PEG-EV-DOX in B16.F10 murine melanoma models in vitro and in vivo compared to that exerted by clinically applied liposomal DOX in the same tumor model. The PEG-EV-DOX administration in vivo reduced NF-κB activation and increased BAX expression, suggesting better prognosis of EV-based therapy than liposomal DOX treatment. Collectively, our results highlight the promising potential of EVs as optimal tools for systemic delivery of DOX to solid tumors.

We report the treatment of a 21-year-old female Covid-19 patient by a novel combination of minocycline and a guanosine-restricted diet. Minocycline is an antibiotic with well documented broad spectrum anti-viral effects, including evidence of activity against SARS-CoV-2. Deprivation of guanosine has been documented as an effective anti-viral modality in vitro and in animal models, and specific in vitro activity against CoV-SARS-2 has been reported. The patient's symptoms resolved rapidly.

Anthelmintic drugs are the major line of defense against parasitic nematode infections, but the arsenal is limited and resistance threatens sustained efficacy of the available drugs. Discoveries of the modes of action of these drugs and mechanisms of resistance have predominantly come from studies of a related non-parasitic nematode species, Caenorhabditis elegans, and the parasitic nematode Haemonchus contortus. Here, we discuss how our understanding of anthelmintic resistance and modes of action came from the interplay of results from each of these species. We argue that this “cycle of discovery”, where results from one species inform the design of experiments in the other, can use the complementary strengths of both to understand anthelmintic modes of action and mechanisms of resistance.

The COVID-19 global pandemic has created dire consequences with an alarming rate of morbidity and mortality. There are not yet vaccine or efficacious treatment options to combat the causative SARS-CoV-2 infection. This paper describes the identification of potentially repurposable drugs for COVID-19 treatment by conducting pathway enrichment analysis on publicly available Gene Expression Omnibus datasets. We first determined SARS-CoV-2 infection-induced alterations of host gene expressions and pathways. We then identified drugs or compounds that target and counter virus-triggered cellular perturbations, suggesting their potential repurposing for COVID-19 treatment. The key findings are that SARS-CoV-2 infection in host cells induces mitochondrial dysfunction, inhibits oxidative phosphorylation, and activates several immune response and pro-inflammatory pathways. Triptolide, the major bioactive component of a traditional Chinese medicine herb, may rescue mitochondrial dysfunction by activating oxidative phosphorylation. Further in vitro and in vivo studies are necessary to verify these results prior to clinical application.

Background: This study discerns surgeons’ attitudes and practices in the determination of heart valve replacement for patients with endocarditis due to intravenous drug use (IVDU-IE). We aimed to identify factors contributing to surgeons’ decision-making process for initial and recurrent surgical heart valves, and the availability of institutional guidance. Methods: An IRB approved, anonymous mixed-methods survey instrument was designed and validated with 24 questions. Cardiothoracic surgeons in the U.S. and globally were recruited with a total of 220 enrolling in the study with 176 completing every question on the survey. Results: A cluster analysis revealed that although surgeons can be divided into sub-groups based on their previous experience with valve replacements, these groups are not perfectly homogenous, and the number of identified clusters is dependent on technique used. ANOVA analysis revealed that the variables that most clearly divided the surgeons into subgroups were, in order of importance, years of practice, number of valve replacements, and geography. Conclusions: Our analysis showed heterogeneity among cardiothoracic surgeons regarding how they make clinical decisions regarding re-operative valve replacement related to IVDU-IE Therefore, an opportunity exists for an interprofessional team to develop guidelines to decrease variability in surgical decision-making regarding valve replacement associated with IVDU-IE

Mycobacterium abscessus is a non-tuberculous mycobacteria notoriously known for causing severe, chronic infections. Treatment of these infections is challenging due to either intrinsic or acquired resistance of M. abscessus to multiple antibiotics. Despite prolonged poly-antimicrobial therapy, treatment of M. abscessus infections often fails, leading to progressive morbidity and eventual mortality. Great research efforts are invested in finding new therapeutic options for M. abscessus. Clofazimine and rifabutin are known anti-mycobacterial antibiotics, repurposed for use against M. abscessus. Novel antimicrobials active against M. abscessus include delamanid, pretomanid and PIPD1 and the recently approved beta-lactamase inhibitors avibactam, relebactam and vaborbactam. Previously unused antimicrobial combinations e.g. vancomycin-clarithromycin and dual beta-lactam therapy have been shown to have synergistic effect against M. abscessus in experimental models, suggesting their possible use in multiple-drug regimens. Finally, engineered phage therapy has been reported to be clinically successful in a severe case of disseminated M. abscessus infection. While many of these experimental therapeutics have shown activity against M. abscessus in vitro, as well as intracellular and/or animal models, most have little if any evidence of effect in humans infections. Clinical studies of M. abscesssus treatments are needed in order to reliably determine the value of their incorporation in therapeutic regimens.

As many if not most ligands at G protein-coupled receptor antagonists are inverse agonists, we have systematically reviewed inverse agonism at the nine adrenoceptor subtypes. Except for β3-adrenoceptors, inverse agonism has been reported for each of the adrenoceptor subtypes, most often for β2-adrenoceptors, including endogenously expressed receptors in human tissues. As with other receptors, detection and degree of inverse agonism depends on the cells and tissues under investigation, i.e. is greatest when the model has a high intrinsic tone/constitutive activity for the response being studied. Accordingly, it may differ between parts of a tissue, for instance atria vs. ventricles of the heart, and within a cell type between cellular responses. The basal tone of endogenously expressed receptors often is low, leading to less consistent detection and smaller extent of observed inverse agonism. The extent inverse agonism depends on specific molecular properties of a compound but clusters by chemical class. While inverse agonism is a fascinating facet in attempts to mechanistically understand observed drug effects, we are skeptical whether an a priori definition of extent of inverse agonism in the target product profile of a developmental candidate is a meaningful option in drug discovery and development.

Background and Objectives: In Libya, prescription medicines can easily be dispensed without a prescription, as self-medication with the subsequent of potential misuse and unnecessary risk for patients. This systematic review and meta-analysis explored the prevalence of self-medication among citizens in Libya. Methods: We systematically searched PubMed, ISI Web of Knowledge, EMBASE, Medline, Scopus, google scholar and ResearchGate databases for studies published in Libya reporting the prevalence of non-prescription use of medicines in community pharmacies, targeting studies published from Jan 2008 until Dec 2019. A random meta-analysis was performed to analyze pooled estimates of non-prescription usage of medicines. Results: Out of 63 articles identified, a total of 13 papers from 7 cities were met the inclusion criteria and involved a total of 4741 subjects. The overall pooled proportion of self-medication of drugs was 53.6% (95% CI: 0.93% - 1.08%), with low heterogeneity and the P-value of the whole population tasted was found to be = 1.000 (df = 12). Seven out of the 13 studies reported data on self-medication for antibiotics without prescription. The records ranged from 15.3% (95% CI 0.61–1.65) in Misurata to 76.6% (95% CI 0.80–1.25) in Tripoli. Conclusion: Self-medication use of medicines among Libyan population is a common phenomenon involving a high proportion use of antibiotics. This misuse of medications could enhance the development and spread of antibiotic resistance.

The vastness of chemical-space constrains traditional drug-discovery methods to the organic laws that are guiding the chemistry involved in filtering through candidates. Leveraging computing with machine-learning to intelligently generate compounds that meet a wide range of objectives can bring significant gains in time and effort needed to filter through a broad range of candidates. This paper details how the use of Generative-Adversarial-Networks, novel machine learning techniques to format the training dataset and the use of quantum computing offer new ways to expedite drug-discovery.

Background: Although no specific treatment for COVID 19 has been proven effective yet, some drugs with in vitro potential against SARS-CoV-2 virus have been proposed for clinical use. Hydroxychloroquine has in vitro anti-viral and immunomodulatory activity, but there is no current clinical evidence of its effectiveness on the outcome of the disease. Methods: We enrolled all 18-85 years old inpatients from Central Defense Hospital, Madrid, Spain, who were hospitalised due to COVID-19 and had a definitive outcome (either dead or discharged). We used a statistical survival analysis. Results: We analysed 220 medical records. 166 patients met the inclusion criteria. 48,8 % of patients not treated with HCQ died, versus 22% in the group of hydroxychloroquine (p=0,002). According to clinical picture at admission, hydroxychloroquine increased the mean cumulative survival in all groups from 1,4 to 1,8 times. This difference was statistically significant in the mild group. Conclusions: in a cohort of 166 patients between 18 to 85 years hospitalised with COVID-19, hydroxychloroquine treatment with an initial loading dose of 800mg improved patient survival when admitted in early stages of the disease. There was a non-statistically significant trend towards survival in all groups, which will need to be clarified in subsequent studies.

The study evaluates the toxic effects of acute and sub-acute oral administration of methanol extracts of Geophila obvallata in rats. During acute study, a dose of 1600, 2900 and 5000 mg/kg bw of extract was orally administered to rats. Rats were observed for signs of toxicity for two weeks. During sub-acute study (28 days), the extract, at doses of 100, 500 and 1000 mg/kg bw were administered orally to rats while control rats were given only tap water. At the end of the study, samples were collected for analyses. In acute toxicity studies, the extract did not induce death after single dose administration. Hence, the LD50 was estimated above 5000mg/kg. The results of sub-acute toxicity study show that no significant changes were observed in the body weights, organ weights, kidney function and organ histology. There were significant changes in hematology and biochemical indices investigated at elevated doses of 500 and 1000 mg/kg bw compared to the control. GOE may be considered non-toxic at a dose of 100 mg/kg with promising applications in drug therapy.

Background: Poisoning constitutes an important part of morbidity and mortality among environmental emergencies that can be prevented, frequent in childhood, requiring rapid diagnosis and treatment. This study aimed was to examine the epidemiological, clinical and therapeutic characteristics of drug and corrosive poisonings in terms of children. Materials and Methods: Between January 2010 and December 2018, 1678 patients between the ages of 1-16 who applied to the emergency department with drug and corrosive poisoning were included in the study. The patients were divided into three groups as 1-5, 6-11 and over 12 years of age, and the substances with known pharmacological agents were divided into 10 groups. The Zargar Classification (7) was used to determine the degree of damage caused by corrosive substances in the esophagus. Results: The mean age of the patients was 8.32 ± 3.23 years (1-15 years). The girl/boy ratio of the cases was 1.18 / 1 and 54.3% were girls. 18.9% of the cases were under five years of age, 61% were between 6-11 years and 20% were older than 12 years. 94.6% of the patients were poisoned by drugs and 5.4% of them were poisoned due to non-drug reasons. Accidental poisoning was most commonly seen in children aged 6-11 and suicides were seen in children older than 12 years. It was found that 62.2% of the poisonings were accidental and 37.8% were suicidal. The most common causes of poisoning were analgesics and paracetamol exposure as a pharmacological agent. Mortality was found to be most common in 1-5 years age group and accidental poisonings. Accidental poisoning was common in girls and suicidal poisoning was common in boys. Grade 3 damage was found endoscopically in all of the mortalities due to corrosive substances. Conclusion: It was found that accidental poisoning was observed in children under five years of age, suicides were observed in children older than 12 years and the most important cause of mortality was due to corrosive substances. Cause-specific rapid diagnosis and treatment will contribute to the reduction of morbidity and mortality.

Polymeric particles made up of biodegradable and biocompatible polymers such as poly(lactic-co-glycolic acid) (PLGA) are promising tools for several biomedical applications including drug delivery. Particular emphasis is placed on the size and surface functionality of these systems as they are regarded as the main protagonists in dictating the particle behavior in vitro and in vivo. Current methods of manufacturing polymeric drug carriers offer a wide range of achievable particle sizes, however, they are unlikely to accurately control the size while maintaining the same production method and particle uniformity, as well as final production yield. Microfluidics technology has emerged as an efficient tool to manufacture particles in a highly controllable manner. Here, we report on tuning the size of PLGA particles at diameters ranging from sub-micron to microns using a single microfluidics device, and demonstrate how particle size influences the release characteristics, cellular uptake and in vivo clearance of these particles. Highly controlled production of PLGA particles with ~100 nm, ~200 nm and >1000 nm diameter is achieved through modification of flow and formulation parameters. Efficiency of particle uptake by dendritic cells and myeloid-derived suppressor cells isolated from mice is strongly correlated with particle size and is most efficient for ~100 nm particles. Particles systemically administered to mice mainly accumulate in liver and ~100 nm particles are cleared slower. Our study shows the direct relation between the particle size varied through microfluidics and the pharmacokinetics behavior of particles, which provides a further step towards the establishment of a customizable production process to generate tailor-made nanomedicines.

(1) Background: The purpose of this study was therefore to analyze the predictive capacity of the three variables (impulsivity, sensation-seeking and drug use) in aggressors and victims of violence. (2) Methods: The design is cross-sectional quasi-experimental. A sample of 822 students aged 13 to 18 who had filled in an ad hoc questionnaire, the State Impulsivity Scale and the Sensation-Seeking Scale, was used for this. (3) Results: The results show that aggressors had high levels of gratification, automatism, attentional factor, disinhibition and susceptibility to boredom, and use alcohol and/or tobacco. The variables that could predict involvement as an aggressor in peer conflict are use of alcohol, smoking, high levels of gratification, automatism and attentional factors and a high degree of disinhibition and susceptibility to boredom. The disinhibition is the best predictor of aggressor. (4) Conclusions: Thus having available empirical evidence that facilitates detection of predictive variables for participation in violence is going to favor the design of effective education intervention for reducing risk behavior.

Diatom microalgae are the most outstanding natural source of porous silica. Diatom cell is enclosed in 3-D ordered nanopatterned silica cell wall, called frustule. The unique properties of diatoms frustule, including high specific surface area, thermal stability, biocompatibility, tailorable surface chemistry, make them really promising for biomedical applications. Moreover, diatoms are easy to cultivate in artificial environment and there is a huge availability of diatom frustules as fossil material (diatomite) in several areas of the world. For all these reasons, diatoms are an intriguing alternative to synthetic materials for the development of low-cost drug delivery systems. This review article focuses on the possible use of diatoms derived silica as drug carrier systems. The functionalization strategies of diatom micro-/nanoparticles for improving their biophysical properties, such as cellular internalization and drug loading/release kinetics, are described. In addition, the realization of hybrid diatom-based devices with advanced properties for theranostics and targeted or augmented drug delivery applications, are also discussed.

Paclitaxel is a natural, highly lipophilic anti proliferative drug widely used in medicine. We have studied the release of tritium-labeled paclitaxel (³H-PTX) from matrices destined for the coating of vascular stents and produced by the electrospinning method from the solutions of polycaprolactone (PCL) with paclitaxel (PTX) in hexafluoisoropropanol (HFIP) and/or solutions of PCL with PTX and human serum albumin (HSA) in HFIP or HIFP-dimethyl sulphoxide (DMSO) blend. The release of PTX has been shown to depend on the solvent and the composition of electrospinning solution, as well as the composition of the surrounding medium, particularly the concentration of free PTX and PTX-binding biomolecules present in human serum. It was shown that 3D matrices can completely release PTX without weight loss. Two-phase PTX release from optimized 3D matrices was obtained: ~27% of PTX was released in the first day, another 8% were released over the next 26 days. Wherein ~2.8%, ~2.3%, and ~0.25% of PTX was released on day 3, 9, and 27, respectively. Considering PTX toxicity, the rate of its diffusion through the arterial wall, and the data obtained the minimum cytostatic dose of the drug in the arterial wall will be maintained for at least three months.

Amyloids result from the aggregation of several unrelated proteins, due to either specific mutations or promoting intra- or extra-cellular conditions. Structurally, they are rich in intermolecular β-sheets and are the causative agents of several diseases, both neurodegenerative and systemic. It is believed that the most toxic species are small aggregates, referred to as oligomers, rather than the final fibrillar assemblies. Their mechanisms of toxicity are mostly mediated by aberrant interactions with the cell membranes, with resulting derangement of membrane-related functions. Much effort is being put in the search for natural antiamyloid agents, and/or in the development of synthetic molecules. Actually, it is well documented that the prevention of amyloid aggregation results in several cytoprotective effects. Here, we portray the state of the art in the field. Several natural compounds are effective antiamyloid agents, notably tetracyclines and polyphenols. They are generally non-specific, as documented by their partially overlapping mechanisms, and the capability to interfere with the aggregation of several unrelated proteins. Among rationally designed molecules, we mention the prominent examples of β-breakers peptides, whole antibodies and fragments thereof, and the special case of drugs contrasting transthyretin aggregation. In this framework, we stress the pivotal role of the computational approaches. When combined with biophysical methods, in several cases they have helped clarify in detail the protein/drug modes of interaction, which make it plausible that more effective drugs will be developed in the future.

In this study, we repositioned thiopurine drugs used for the treatment of acute leukaemia as new tyrosinase inhibitors. Tyrosinase catalyses two distinct and successive oxidations in melanin biosynthesis: the conversions of tyrosine to dihydroxyphenylalanine (DOPA) and DOPA to dopaquinone. Continuous efforts are underway to discover small molecule inhibitors of tyrosinase for therapeutic, cosmetic, and agricultural purposes. Structure-based virtual screening has predicted inhibitor candidates for mushroom tyrosinase from drugs approved by the US Food and Drug Administration (FDA). Enzyme assays have confirmed the thiopurine leukaemia drug, thioguanine, as a tyrosinase inhibitor. Two other thiopurine drugs, mercaptopurine and azathioprine, were also evaluated for their tyrosinase inhibitory activity; mercaptopurine caused stronger inhibition than thioguanine did, whereas azathioprine was a poor inhibitor. The inhibitory constants of thioguanine and mercaptopurine were calculated as 52 and 16 µM, respectively, and the value of mercaptopurine was comparable to that of the well-known inhibitor kojic acid (13 µM). The cell lysate and melanin content assay in B16F10 melanoma cells confirmed that the compounds inhibited mammalian tyrosinase. In particular, 50 µM thioguanine reduced the melanin content by 57% without cytotoxicity. Furthermore, the thiopurine drugs shared little chemical similarity with the known tyrosinase inhibitors.

Treatment of bladder cancer remains a critical unmet need and requires advanced approaches, particularly the development of local drug delivery systems. The physiology of the urinary bladder causes the main difficulties in the local treatment of bladder cancer: regular voiding prevents the maintenance of optimal concentration of the instilled drugs, while poor permeability of the urothelium limits the penetration of the drugs into the bladder wall. Therefore, much research effort is spent to overcome these hurdles, thereby improving the efficacy of available therapies. The explosive development of nanotechnology, polymer science and related fields has contributed to the emergence of a number of nanostructured vehicles (nano- and micro scale) applicable for intravesical drug delivery. Moreover, the engineering approach has facilitated the design of several macro-sized depot systems (centimeter scale) capable of remaining in the bladder for weeks and months. In this article, the main rationales and strategies for improved intravesical delivery are reviewed. Here, we focused on analysis of colloidal nano- and micro-sized drug carriers, and indwelling macro-scale devices which were evaluated for applicability in local therapy of bladder cancer in vivo.

The main regulatory factors during the adaptation of cancer cells to hypoxic stress are the hypoxia-inducible factors (HIFs), which are being increasingly recognized as an interesting and challenging target for the design of new chemotherapeutic molecules. HIF2A was found to have an large internal hydrophilic cavity within its PAS-B domain, unique to this sub-unit and is suggested to be a possible ligand-binding site. Regulation of HIF2A by cellular molecules is still greatly unknown. In This paper we have employed in-silico techniques, such as molecular docking and dynamic simulation, to design new direct inhibitors against HIF-2A subunit via targeting one of its critical domains and the final top screened molecules have been tested on hypoxic cancer cells for further validation of their inhibitory potential. we targeted the hydrophilic cavity inside the PAS-B domain of the HIF2A to identify novel molecules with a high binding capacity. Virtual Screening methodology was used for molecular docking of NSC library against the target domain inside the HIF2A PAS-B domain with the top 5% compounds with significant MolDock and Re-rank scores were selected for further analysis. The NSC 106416, NSC 217021, NSC 217026, and NSC 215639 compounds were selected based on their docking scores. NSC 215639 had the minimum polar solvation energy and also had a relative strong binding energy. NSC 217026 had the strongest binding energy among other compounds.

There are numerous approaches to model an influence of manufacturing parameters on the dissolution and disintegration of solid dosage forms. A modern approach for modelling and simulating complex and heterogeneous systems such as pharmaceutical tablets focuses on computationally-intensive finite-element or discreet element methods. Industrial challenges such as Process Analytical Technology (PAT) and Quality by Design are stimulating computer-based technologies to design, control and improve the quality of pharmaceutical compacts and their performance. In this study the disintegration and dissolution model based on the numerical solutions of the Noyes-Whitney equation and cellular automata supported disintegration model are proposed and evaluated. The results from in vitro release studies of the mefenamic acid formulations were compared to the calculated release patterns from the tablet structures obtained from microtomography experiments and the purely algorithmically created virtual tablets.

Acquired immunodeficiency syndrome (AIDS) is an enormous global health threat stemming from human immunodeficiency virus (HIV-1) infection. Up to now, the tremendous advances in combination antiretroviral therapy (cART) have shifted HIV-1 infection from a fatal illness into a manageable chronic disorder. However, the presence of latent reservoirs, multifaceted nature of HIV-1, drug resistance, severe off-target effects, poor adherence, and high cost restrict the efficacy of current cART targeting the distinct stages of the virus life cycle. Therefore, there is an unmet need for discovery of new therapeutics that not only bypass the limitations of the current therapy but also protect the body health at the same time. The main goal for complete HIV-1 eradication is purging latently infected cells from the patients’ bodies. A potential strategy called “lock-in apoptosis” targeting the budding phase of life cycle of virus leading to susceptibility to apoptosis of HIV-1 infected cells for elimination of HIV-1 reservoirs and ultimately for a complete eradication. The current work intends to present the main advantages and disadvantages of United States Food and Drug Administration (FDA) approved anti-HIV-1 drugs as well as plausible strategies for the design and development of more anti-HIV-1 compounds with better potency, favorable pharmacokinetic profiles, and improved safety issues.

Recent media reports commented about a possible antidiabetics’ misuse issue related to molecules promoted as a weight-loss treatment in non-obese people. We evaluated here available pharmacovigilance misuse/abuse signals related to semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, in comparison to other GLP-1 receptor agonists (albiglutide; dulaglutide; exenatide; liraglutide; lixisenatide; tirzepatide) and the phentermine-topiramate combination. To that aim, we analysed the Food and Drug Administration-FDA Adverse Events Reporting System (FAERS) dataset, performing a descriptive analysis of adverse event reports (AER) and calculating related pharmacovigilance measures, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR). During January 2018-December 2022, a total of 31,542 AER involving the selected molecules were submitted to FAERS; most involved dulaglutide (n=11,858; 37.6%) and semaglutide (n=8,249; 26.1%). In comparing semaglutide vs the remaining nolecules, the AER ‘drug abuse’, ‘drug withdrawal syndrome’, ‘prescription drug used without a prescription’ and ‘intentional product use issue’ respective PRR values were 4.05, 4.05, 3.60 and 1.80 (all<0.01). The same comparisons of semaglutide vs the phentermine-topiramate combination were not associated with any significant differences. To the best of our knowledge, this is the first study documenting the misusing/abusing potential of semaglutide in comparison with other GLP1 analogues and the phentermine-topiramate combination. Current findings will need to be confirmed by further empirical investigations to fully understand the safety profile of those molecules.

Recent media reports commented about a possible antidiabetics’ misuse issue related to molecules promoted as a weight-loss treatment in non-obese people. We here evaluated available pharmacovigilance misuse/abuse signals related to semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, in comparison to other GLP-1 receptor agonists (albiglutide; dulaglutide; exenatide; liraglutide; lixisenatide; tirzepatide) and the phentermine-topiramate combination. To that aim, we analysed the Food and Drug Administration-FDA Adverse Events Reporting System (FAERS) dataset, performing a descriptive analysis of adverse event reports (AER) and calculating related pharmacovigilance measures, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR). During January 2018-December 2022, a total of 31,542 AER involving the selected molecules were submitted to FAERS; most involved dulaglutide (n=11,858; 37.6%) and semaglutide (n=8,249; 26.1%). In comparing semaglutide vs the remaining antidiabetics, the AER ‘drug abuse’, ‘drug withdrawal syndrome’, ‘prescription drug used without a prescription’ and ‘intentional product use issue’ respective PRR values were 4.05, 4.05, 3.60 and 1.80 (all<0.01). The same comparisons of semaglutide vs the phentermine-topiramate combination were not associated with any significant differences. To our best, this is the first study documenting the misusing/abusing potential of semaglutide in comparison with other novel antidiabetics and the phentermine-topiramate combination. Current findings will need to be confirmed by further empirical investigations to fully understand the safety profile of those molecules.

Although various vaccines are now commercially available, they have not been able to stop the spread of COVID-19 infection completely. An excellent strategy to quickly get safe, effective, and affordable COVID-19 treatment is to repurpose drugs that are already approved for other diseases as adjuvants along with the ongoing vaccine regime. The process of developing an accurate and standardized drug repurposing dataset requires a considerable level of resources and expertise due to the commercial availability of an extensive array of drugs that could be potentially used to address the SARS-CoV-2 infection. To address this bottleneck, we created the CoviRx platform. CoviRx is a user-friendly interface that provides access to the data, which is manually curated for COVID-19 drug repurposing data. Through CoviRx, the data curated has been made open-source to help advance drug repurposing research. CoviRx also encourages users to submit their findings after thoroughly validating the data, followed by merging it by enforcing uniformity and integ-rity-preserving constraints. This article discusses the various features of CoviRx and its design principles. CoviRx has been designed so that its functionality is independent of the data it dis-plays. Thus, in the future, this platform can be extended to include any other disease X beyond COVID-19. CoviRx can be accessed at www.covirx.org.

The study explores the potential of Cell-Penetrating Peptides (CPPs) for targeted drug delivery, particularly in anticancer applications. Despite certain drawbacks, such as short duration of action and poor stability in vivo, CPPs show promise when optimized through chemical modification or clever design. Advancements in targeted drug delivery using CPPs, especially for transporting anticancer drugs and imaging reagents, highlight their evolving efficacy. Four different CPP chains (7 alpha, 7 beta, 12 alpha, and 12 beta) and four in-house anticancer lead molecules were considered for the study. The CPPs were modeled and validated for in silico interaction analysis. Targeting proteins crucial in cell growth and signaling pathways, such as ADRM1, PSMD4, CDK1, CDK2, CDK4, CDK6, P53, and EGFR, presents a significant therapeutic opportunity. The in silico molecular interaction analysis involving CPP-conjugated lead molecules and these targets indicates favorable binding affinities, particularly with beta-confirmation 12 and 7 peptide chains. Notably, CPP conjugation enhances interactions without compromising ligand potentiality. This delicate balance emphasizes the role of CPPs in augmenting protein-ligand interactions, suggesting their potential benefits in targeted drug delivery, pending further optimization and experimental validation.

Hyaluronan has been considered in recent years as a potential naturally occurring modifiable scaffold that has the capability to absorb and release drugs over an extended period of time making it suitable as a chemotherapeutic delivery agent. Considering the limited treatment options available in the treatment of glioblastoma, in this review, we discuss the novel utilization of ultra high molecular weight hyaluronan - originally identified as a mechanism for maintaining longevity in the naked mole rat, as both a protective and extracellular matrix optimising scaffold, and a means to deliver therapy in resected brain tumors. The unique properties of this unique form of hyaluronan indicate potential future use in the prevention and treatment of both proliferative based and inflammation driven disease.

Drug discovery and development is a highly complex and costly endeavor, typically requiring over a decade and substantial financial investment to bring a new drug to market. Traditional computer-aided drug design (CADD) has made significant progress in accelerating this process, but the development of quantum computing offers potential due to its unique capabilities. This paper discusses the integration of quantum computing into drug discovery and development, focusing on how quantum technologies might accelerate and enhance various stages of the drug development cycle. Specifically, we explore the application of quantum computing in addressing challenges related to drug discovery, such as molecular simulation and the prediction of drug-target interactions, as well as the optimization of clinical trial outcomes. By leveraging the inherent capabilities of quantum computing, we might be able to reduce the time and cost associated with bringing new drugs to market, ultimately benefiting public health.

Recent advancements in nanotechnology have led to the development of multifunctional iron oxide nanoparticles, presenting new opportunities in cancer therapy. This study aimed to synthesize and evaluate citric acid-coated/ folic acid conjugated nanoparticles loaded with doxorubi-cin and investigate their efficacy in experimental tumor models. For synthesis, controlled co-precipitation method was employed to produce highly dispersive, multifunctional nanofluids with a narrow size distribution of iron oxide nanoparticles. Nanoparticles were characterized using Dynamic Light Scattering (DLS) and Electrophoretic Light Scattering (ELS) for size distribution and zeta potential, X-ray Diffraction (XRD) and Transmission Electron Microscopy (TEM) for structure and morphology, Vibrating Sample Magnetometry (VSM) for magnetic properties, and UV-Visible (UV-Vis) and Fourier-Transform Infra-red (FTIR) spectroscopy for modification confirmation. In vitro experiments employed RM1 (prostate cancer) and MEC1 (Chronic lymphocytic leukemia) cell lines to assess cytotoxicity and drug delivery efficiency. Fluorescence microscopy confirmed the intracellular delivery of doxorubicin by these nanoparticles, highlighting their potential for targeted therapy. As a result, nanoparticles conjugated with folic acid showed reduced efficacy over time. This study underscores the critical role of nanoparticle modifications in optimizing therapeutic outcomes. Future research should focus on further refining nanoparticle formulations and long-term effects in vivo, for development of effective and safe agents for targeted cancer treatment.

Introduction: Peripheral neuropathies are very common and occur due to multiple causes including diabetes, tuberculosis, vasculitis, thyroid disorders, immune mediated diseases, vitamin B12 deficiency and drugs. Drug induced peripheral neuropathy (DIPN) is potentially irreversible, resulting in sensory deficits and paraesthesia. DIPN due to anti-tubercular drugs is common and can be implicated on linezolid, cycloserine and isoniazid.Case: 40-year-old female, diabetic with MDR-TB presented with severe, sharp, burning pain in her lower limbs. The patient was on all longer acting ATT drug regimen and was suspected with drug induced peripheral neuropathy. Conclusion: Linezolid, is used in treatment of tuberculosis and one of the major side effects includes peripheral neuropathy which is usually quite severe, presenting predominantly with sensory symptoms. Cessation of linezolid and neuropathic pain medications reduced the pain of patient from VCPS 8-10 to 1-2. Treatment of DIPN can be challenging as adverse drug reactions while treating tuberculosis should be kept in mind. It also warrants earliest treatment by identification of the drug in disguise and timely discontinuation of the drug.

The rapid evolution of drug resistance is one of the greatest health issues of the 21st century. There is an alarming situation to find new therapeutic strategies or candidate drugs to tackle ongoing multi-drug resistance development. The marine environment is one of the prime natural ecosystems on Earth, the majority of which is still unexplored, especially when it comes to the microbes. A wide variety of bioactive compounds have been obtained from a varied range of marine organisms, however, marine bacteria-produced bacteriocins are still undermined. Owing to the distinct environmental stresses that marine bacterial communities encounter, their bioactive compounds frequently undergo distinct adaptations that confer on them a variety of shapes and functions, setting them apart from their terrestrial counterparts. The ribosomally-synthesized and posttranslationally modified peptides (RiPPs), bacteriocins are of special interest because of their variety in structure and diverse potential biological activities. Additionally, the gut microbiome of marine creatures are largely unexplored source of new bacteriocins with promising activities. There is a huge possibility of novel bacteriocins from marine bacterial communities that might come out as efficient candidates to fight against antibiotic resistance, especially in light of the growing pressure from antibiotic-resistant diseases and industrial desire for innovative treatments. The present review summarizes known bacteriocins from marine bacteria, evolutionary aspects, challenges, and huge possibilities of unexplored bacteriocins from marine bacterial communities.

The medical research field has been tremendously galvanized to improve the prediction of therapy efficacy by the revolution in artificial intelligence (AI). An earnest desire to find better ways to predict the effectiveness of therapy with the use of AI has propelled the evolution of new models in which it can become more applicable in clinical settings such as breast cancer detection. However, in some instances, the U.S. Food and Drug Administration was obliged to back some previously approved inaccurate models for AI-based prognostic models because they eventually produce inaccurate prognoses for specific patients who might be at risk of heart failure. In light of instances in which the medical research community has often evolved some unrealistic expectations regarding the advances in AI and its potential use for medical purposes, implementing standard procedures for AI-based cancer models is critical. Specifically, models would have to meet some general parameters for standardization, transparency of their logistic modules, and avoidance of algorithm biases. In this review, we summarize the current knowledge about AI-based prognostic methods and describe how they may be used in the future for predicting antibody-drug conjugate efficacy in cancer patients. We also summarize findings of recent late-phase clinical trials using these conjugates for cancer therapy.

Objectives: To analyze the clinical characteristics and factors associated with adverse drug reactions (ADR) in liver cancer patients receiving oxaliplatin‐based hepatic arterial infusion chemotherapy (HAIC). Methods: A retrospective analysis was performed on the clinical data of 137 patients with liver cancer who received oxaliplatin‐based HAIC. Changes in baseline characteristics, inflammatory factors, and other laboratory indicators in the no‐ADR and ADR groups were analyzed. Results: The incidence of serious ADR (CTCAE ≥ 3) was 21.9% (30/137). There was no significant difference in the cumulative dose of oxaliplatin between the two groups [157.3 (80.3, 322.4) vs. 206.6 (139.1, 324.2), P=0.161]. The increase in NEUT and IL‐6 was greater in the group treated with ADR than in the group not treated with ADR. Changes in NEUT [4.1 (1.5, 6.2) vs. 2.5 (0.5, 4.9), P=0.045] and changes in NEUTIL‐6 [4.2 (‐0.2, 22.9) vs. 0.8 (‐3.9, 7.7), P=0.026]. TBIL, ALT, AST, ALP, WBC, NEUT, PCT, CRP, TNF, IL‐2R, IL‐6, and IL‐10 were significantly higher after treatment than before in the ADR group (P < 0.05). In contrast, ALB and AFP were decreased. Conclusions: The severe ADR (CTCAE ≥ 3) associated with oxaliplatin‐based HAIC may be closely related to increased inflammatory factors such as NEUT and IL‐6. We should be vigilant for allergic reactions to oxaliplatin and increase monitoring during treatment

Marijuana is the most used illicit drug among youths in the United States. The objectives of the study were to identify the association between marijuana use and other risk behaviors including suicidality among high school students. The 2021 Mississippi Youth Risk Behavior Survey data sets were combined for this study. Crude odds ratio (OR) and adjusted odds ratio (AOR) with a 95% confidence interval were generated using the survey packages in R to account for weights and the complex sampling design of YRBS data. Tobacco products and alcohol use were significantly associated with marijuana use. Students who responded “Yes” to questions “currently used an electronic vapor product?”, “currently smoked cigarettes or cigars?” or “currently drank alcohol?” were more likely to use marijuana compared to students who responded “No”, after adjusting for other risk factors. Marijuana use is also significantly associated with students who had sex, compared to those who never had sex. The adjusted odds ratio is nearly doubled in those who had sex with the same sex or both sexes, compared to those who had heterosexual sex only. After adjusting for other health risk factors, the association between current marijuana use and attempted suicide was not statistically significant. The impact of students’ not sleeping in their parent's or guardian's home on current marijuana use was not significant after adjusting for other risk factors. Marijuana use is evenly burdened between males and females and between all race categories among Mississippi high school students. The identified associations seem to indicate that electronic vapor, tobacco products, and alcohol use could be the forerunners for drug use and should be treated accordingly in drug use prevention programs.

The incidence of infections due to carbapenemase-producing Enterobacteriaceae (CPE) is rising worldwide. We present the case of a 48-year-old female patient, diabetic, with previous episodes of urinary tract infections that was admitted due to pyelonephritis, later identified to be caused by KPC and ESBL-producing Klebsiella pneumoniae. Both the patient and her family had no strong epidemiological link with the healthcare system, and for this reason, this case stands out in regional literature since similar reports are scarce and therefore constitutes a reason for alert in health institutions. Further studies are needed in order to ascertain the real incidence of these infections in community settings in Latin America and the Caribbean.

Background : Drug treatments for gait disorders in post-stroke patients aim to reduce muscular hyperactivity. Analysis of muscle activity is essential to help clinicians understand these disorders. The aim of this study was to quantify changes in muscle synergies before (PRE) and after (POST) rectus femoris nerve block. Methods : Gait analysis of 8 post-stroke patients before and immediately after nerve block. Muscle synergies were quantified from electromyographic signals. We have selected: the account for variance indicating the robustness of the synergies, the recruitment selectivity index indicating the degree of multiplexing of the synergies, and the recruitment consistency index indicating the variability of the synergies. Results : A decrease in VAF is observed, suggesting a reduction in gait pattern robustness. We also note that spatial and temporal primitives are slightly different (IRC, IRS) in PRE vs. POST, and that their activation is more nested in POST than in PRE. Conclusions : The motor nerve block has not created new muscle synergies of the paretic limb during gait, but indicates that there is flexibility in motor organization. This method of quanti-fication may enable clinicians to assess the motor adaptation potential of their post-stroke patient.

Microneedle technology is a novel platform technology that revolutionizes ocular drug delivery and addresses critical challenges in the treatment of ocular diseases. Routine treatment methods, such as eye drops and intravitreal injections, suffer from low bioavailability and poor patient compliance. So, novel advanced platform technologies are required to overcome these challenges. Microneedle is a minimally invasive and promising alternative technique that helps precisely control drug delivery to targeted tissues and organs. This review investigates the potential impact of microneedle technology for eye care, underscoring recent advancements, underlying mechanisms, and emerging preclinical and clinical uses. Different types of microneedles, including solid, coated, dissolvable, and hollow, have demonstrated their potential and capability to bypass several barriers in the cornea and sclera. This ensures effective drug penetration and delivery. The current innovations in material science and fabrication methods have enhanced the safety and efficacy of microneedles, reducing discomfort and the chances of infections. These microneedle technologies offer sustained and controlled drug delivery, which could improve therapeutic outcomes for various disease conditions like age-related macular degeneration, glaucoma, diabetic neuropathy, etc. In the current review, recent preclinical and clinical studies emphasize microneedle-based ocular drug delivery's feasibility and potential benefits. These include improved pharmacokinetics, reduced dosing frequency, enhanced patient adherence, and, most importantly, microneedles offer versatile platforms for delivering a wide range of small and large molecules and gene therapies. Despite the exciting progress, obstacles such as regulatory barriers, scalability, and long-term biocompatibility persist. It will be essential to tackle these challenges through interdisciplinary research and partnerships to integrate microneedle technology into standard clinical use effectively. Ultimately, microneedle drug delivery offers a revolutionary method that has the potential to significantly enhance the treatment and results of ocular diseases, marking the dawn of a new era in eye care.

Numerous study reports on chitosan hydrogels in different forms such as films, porous structures, nanoparticles, and microspheres for biomedical applications, however, this study concentrates on their modifications with different crosslinking agents and observing their effects on drug loading and releasing capacities. Linear chitosan along with crosslinked by two major cross-linkers, i.e., genipin and disulfide have been used to formulate three different hydrogel systems. The cross-linking process is heavily impacted by the temperature and the pH conditions. Three different drugs, i.e., thymoquinone, gefitinib, and erlotinib are loaded in phosphate buffer solutions and infused with three different hydrogel systems, thus, a total of nine combinations are studied and analyzed for drug loading and releasing capabilities with Ultraviolet–visible (UV-Vis) spectroscopy. This study finds thymoquinone shows the lowest loading efficacy compared to two other drugs in all three systems. Gefitinib shows stable loading and releasing regardless of crosslinking systems and genipin crosslinked system shows stable loading and releasing with all three drug molecules. These experimental results agree well with the findings of our previously published results conducted with molecular dynamics simulations.

Biomaterials are the basis for the development of medicine because they allow safe contact with a living organism. The aim of this work was to produce innovative oxide layers with a porous microstructure on the surface of commercially pure titanium Grade 4 (CpTi G4), and to characterize their properties as drug carriers. Anodization of the CpTi G4 subjected to mechanical grinding and electrochemical polishing was carried out in a solution of 1M ethylene glycol with the addition of 40 g of ammonium fluoride at a voltage of 20 V for 2, 18, 24 and 48 hours at room temperature. It was found that the longer anodization time, the greater the number of pores formed on the CpTi G4 surface as revealed by FE-SEM method, and the greater the surface roughness determined in profilometric tests. As the anodizing time increases, the amount of the drug in the form of gentamicin sulfate incorporated into the resulting pores decreases. The most favorable drug release kinetics profile determined by UV-VIS absorption spectroscopy was found for the CpTi G4 anodized for 2 h making them the best choice when it comes to the drug carrier allowing full use of the therapeutic dose of the drug.

Drug-induced liver disease represents one of the main problems in the therapeutic field. As with most pathologies, also in this case various risk factors can be recognised, such as age, sex, but also the gut microbiota. Therefore all drugs on the market can, in fact, cause hepatotoxicity of varying degrees. Drugs used in the treatment of IBD can also cause these adverse effects and even lead to DILI. In this review, the various classes of drugs used in the treatment of IBD were taken into consideration and the various adverse effects on the liver were illustrated. In particular, a major role has emerged regarding hepatotoxicity of immunosuppressants. Biological drugs, however, seem to be responsible for these complications to a much lesser extent.

Post-operative chemotherapy is still required for the treatment of glioblastoma (GBM), and nanocarrier-based drug delivery has been identified as one of the most effective methods. However, the blood-brain barrier (BBB) and non-specific delivery to non-tumor tissues can significantly limit drug accumulation in tumor tissues and cause damage to nearby normal tissues. This study describes a targeted cancer therapy approach that uses AS1411 aptamer-conjugated nanospheres, 100-300 nm in size, loaded with doxorubicin (Dox) to selectively identify tumor cells overexpressing nucleolin (NCL) proteins. The study demonstrates that the active target model, which employs aptamer-mediated drug delivery, is more effective than nonspecific enhanced permeability and maintenance (EPR)-mediated delivery and passive drug delivery in improving drug penetration and maintenance in tumor cells. Additionally, the study shows the potential for anticancer effects through 3D spheroidal and in vivo GBM xenograft models. The DNA-protein hybrid nanospheres utilized in this study offer numerous benefits, such as efficient synthesis, structural stability, high drug loading, dye labelling, biocompatibility, and biodegradability. When combined with nanospheres, the 1411 aptamer has been shown to be an effective drug delivery carrier for precisely targeting tumors. This combination has the potential to produce anti-tumor effects in active targeted therapy of GBM.

Glioblastoma, a deadly brain tumor, shows limited response to standard therapies like te-mozolomide (TMZ). Recent findings from the REGOMA trial underscore a significant survival improvement offered by regorafenib (REGO) in recurrent glioblastoma. Our study aimed to propose a 3D ex vivo drug response precision medicine approach to investigate recurrent glio-blastoma sensitivity to REGO and elucidate the underlying molecular mechanisms involved in tumor resistance or responsiveness to treatment. 3D glioblastoma organoids (GB-EXPs) obtained from 18 patients’ resected recurrent glioblastoma tumors were treated with TMZ and REGO. Drug responses were evaluated using NAD(P)H FLIM, stratifying tumors as responders (Resp) or non-responders (NR). Whole-exome sequencing was performed on 16 tissue samples, and whole-transcriptome analysis on 13 GB-EXPs treated and untreated. We found 35% (n=9) and 77% (n=20) of tumors responded to TMZ and REGO, respectively, with no instances of TMZ-Resp be-ing REGO-NR. Exome analysis revealed a unique mutational profile in REGO-Resp tumors compared to NR tumors. Transcriptome analysis identified distinct expression patterns in Resp and NR tumors, impacting Rho GTPase and NOTCH signaling, known to be involved in drug response. In conclusion, recurrent glioblastoma tumors were more responsive to REGO com-pared to TMZ treatment. Importantly, our approach enables a comprehensive longitudinal ex-ploration of the molecular changes induced by treatment, unveiling promising biomarkers in-dicative of drug response.

The persistent threat of cancer remains a significant hurdle for global health, prompting the exploration of innovative approaches in the quest for successful therapeutic interventions. Cyclin-dependent kinase 9 (CDK9), a central player in transcription regulation and cell cycle progression, has emerged as a promising target to combat cancer. Its pivotal role in oncogenic pathways and the pressing need for novel cancer treatments has propelled CDK9 into the spotlight of drug discovery efforts. This article presents a comprehensive study that connects a multidisciplinary approach, combining computational methodologies, experimental validation, and the transformative PROTAC (Proteolysis-Targeting Chimera) technology. By uniting these diverse techniques, we aim to identify, characterize, and optimize a new class of degraders targeting CDK9. We explore these compounds for kinase inhibitory properties and potential to induce targeted protein degradation, offering a novel and potentially more sustainable approach to cancer therapy. This cohesive strategy expresses the interface between computational predictions and experimental insights, with the ultimate goal of advancing the development of effective anticancer therapeutics targeting CDK9.

Background: Chronic Myeloid Leukemia (CML) is initiated in bone marrow due to chromosomal translocation t(22;9) leading to fusion oncogene BCR-ABL. Targeting BCR-ABL by tyrosine kinase inhibitors (TKI) have changed fatal CML into an almost curable disease. Despite that, TKIs lose their effectiveness due to disease progression. Unfortunately, mechanism of CML progression is poorly understood and common biomarkers for CML progression are unavailable. This study was conducted to find out novel biomarkers of CML progression by employing whole exome sequencing (WES).Materials and Methods: WES of accelerated phase (AP-) and blast crisis (BC-) CML patients was carried out, with chronic phase CML (CP-CML) patients as control. After DNA library preparation and exome enrichment, clustering and sequencing was carried out using Illumina platforms. Statistical analysis was carried out using [SAS/STAT] software version 9.4 and R package employed to find mutations shared exclusively by all AP-/BC-CML. Confirmation of mutations was carried out using Sanger sequencing and protein structure modelling using I-Tasser followed by mutant generation and visualization using PyMOL. Results: Three novel genes (ANKRD36, ANKRD36B and PRSS3) were mutated exclusively in all AP-/BC-CML patients. Only ANKRD36 gene mutations (c.1183_1184 delGC and c.1187_1185 dupTT) were confirmed by Sanger sequencing. Protein modelling studies showed that mutations induce structural changes in ANKRD36 protein. Conclusions: Our studies show that ANKRD36 is a potential common biomarker and drug target of early CML progression. ANKRD36 is yet uncharacterized in human. It has the highest expression in bone marrow, specifically myeloid cells. We recommend carrying out further studies to explore the role of ANKRD36 in biology and progression of CML.

Tongue mobility is an obstructive sleep apnoea (OSA) marker and myofunctional therapy (MFT) target. For this reason, all patients with sleep-disordered breathing should require a combined functional assessment from an ear, nose, and throat (ENT) specialist and a phonoaudiologist to confirm or rule out the presence of tongue-tie. To our knowledge, this is the first case of a 13-year-old girl diagnosed with severe OSA and a significant decrease of 94% in her apnoea index (AI), requiring frenotomy with immediate postoperative change in the tongue position. A drug-induced sleep en-doscopy (DISE) was performed before and immediately post-frenotomy, and the anatomical changes provoked by this surgery during sleep were confirmed for the first time.

In recent years, the emergence of cancer drug resistance is one of the crucial tumor hallmarks which is supported by the level of genetic heterogeneity and complexities at cellular levels. Oxidative stress, immune evasion, metabolic reprogramming, overexpression of ABC transporters and stemness are among the several key contributing molecular and cellular response mechanisms. Topo-active drugs, e.g., doxorubicin and topotecan, are clinically active and are utilized extensively against a wide variety of human tumors and often results in the development of resistance and failure to therapy. Thus, there is an urgent need for an incremental and comprehensive understanding of mechanisms of cancer drug resistance specifically in the context of topo-active drugs. This review delves into the intricate mechanistic aspects of these intracellular and extracellular topo-active drug resistance mechanisms and explores use of potential combinatorial approaches by utilizing various topo-active drugs and inhibitors of pathways involved in drug resistance. We believe that this review will help guide basic scientists, pre-clinicians, clinicians, and policymakers toward holistic and interdisciplinary strategies that transcend resistance, renewing optimism in the ongoing battle against cancer.

Breast cancer is a serious disease and the second leading cause of cancer-related death among women in the U.S. New treatments for this aggressive disease are urgently needed. Repurposing FDA-approved drugs for cancer treatment is an alternative that saves time and lowers the costs needed for drug development. In this study, we investigated the effects of proguanil, an anti-malarial drug, in breast cancer cells. Proguanil exhibited a significant cytotoxic effect on breast cancer cell lines including patient derived cell lines. Proguanil caused apoptosis through increased production of ROS and consequent decrease of mitochondrial membrane potential, mitochondrial respiration, and ATP production rates. ROS generation by proguanil was up to 3-fold higher when compared to the control. Proguanil treatment increased the expression of Bax, p-H2AX, cleaved-caspase 9, cleaved PARP, and down-regulated bcl-2 and survivin in breast cancer cell lines. The enlargement of 4T1 breast tumors in female Balb/c mice was suppressed by 55% through daily oral administration of 20mg/kg of proguanil. Western blot analyses of proguanil- treated tumors showed increased levels of p-H2AX, Bax, c-PARP, and c-caspase3 compared to control. Proguanil proved to be an efficient in vitro and in-vivo inhibitor of breast cancer cells, hence should be considered further for clinical investigation against breast cancer.

Classical Hodgkin lymphoma (cHL) is a highly curable disease (70-80%), even though long-term toxicities, drug resistance, and predicting clinical responses to therapy are major challenges in cHL treatment. To solve these problems, we characterized two cHL cell lines with acquired resistance to doxorubicin, KM-H2dx and HDLM-2dx (HRSdx), generated from KM-H2 and HDLM-2 cells, respectively. HRSdx cells developed cross-resistance to vinblastine, bendamustin, cisplatin, dacarbazine, gem-citabine, brentuximab vedotin (BV), and γ-radiation. Both HDLM-2 and HDLM-2dx cells had an intrinsic resistance to BV but not to the drug MMAE. HDLM-2dx acquired cross-resistance to caelyx. HRSdx cells had in common: decreased CD71, CD80, CD54, cyt-ROS, HLA-DR, DDR1, CD44; increased Bcl-2, CD58, COX2, CD26, CCR5, invasive capability; increased CCL5, TARC, PGE2, TGF-β, and capability to hijack monocytes. In HRSdx cells, less sensitive to DNA damage and oxidative stress, the efflux drug transporters MDR1 and MRP1 were not up-regulated, and doxorubicin accumulated in cytoplasm rather than in nucleus. Both autophagy inhibitor chloroquine and extracellular vesicles (EVs) release inhibitor GW4869 enhanced doxorubicin activity and counteracted doxorubicin resistance. In conclusion, this study identifies common modulated antigens in HRSdx cells, the associated cross-resistance patterns, and new potential therapeutic options to enhance doxorubicin activity and overcome resistance.

Biofilm-associated proteins (BAPs) are important in the development and resilience of biofilms, which are intricate populations of microbes protected by extracellular matrix. All members of the BAP family are known to possess common characteristics such as high molecular weight and a signal sequence for extracellular secretion. It has been shown that BAPs are directly linked to the pathogenicity of many bacteria. This mini review highlights several potential strategies to target BAPs for drug development.

Idiosyncratic drug induced liver injury (DILI) is an unpredictable reaction of exposed individual on a certain drug, and the drug-induced autoimmune hepatitis (DIAIH) presents a DILI phenotype that mimics idiopathic autoimmune hepatitis (AIH) when considering the clinical, biochemical, serological and histological parameters. We present a case of a 48-year-old male that was hospitalized due to severe hepatocellular liver injury two months after the self-treatment with the muscle-building dietary supplement based on arginine-alpha-ketoglutarate, L-citrulline, L tyrosine, creatine malate and beet extract. His immunology panel was positive with increased IgG levels, and the radiologic methods showed no signs of chronic liver disease. He underwent corticosteroid treatment with adequate response. After the therapy withdrawal, a clinical relapse occurred. Seven months after the initial presentation liver MR suggested the initial cirrhotic changes of the right liver lobe. Liver biopsy revealed abundant lymphoplasmacytic infiltrate with piecemeal necrosis and grade 2 fibrosis. He responded well on the corticosteroid treatment again, and was further treated with low dose prednisone without additional relapses. Several years later, further management confirmed presence of liver cirrhosis with no histological or biochemical signs of the disease activity. DIAIH is a DILI phenotype difficult to distinguish from idiopathic AIH despite a wide armamentarium of diagnostic methods. Regular patient monitoring and clinical open-mindedness with the adjustment of therapeutic approaches according to the disease course are more important than strict labelling of the disease.

Diabetic kidney disease (DKD) is one of the leading causes of end-stage renal disease worldwide and significantly increases the risk of premature death due to cardiovascular diseases. Elevated urinary albumin levels are an important clinical feature of DKD. Effective control of albuminuria not only delays glomerular filtration rate (GFR) decline but also markedly reduces cardiovascular disease risk and all-cause mortality. New drugs for treating DKD proteinuria, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), mineralocorticoid receptor antagonists (MRAs), and endothelin receptor antagonists (REAs), have shown significant efficacy. Auxiliary treatment with proprietary Chinese medicine has also yielded promising results; however, it also faces a broader scope for development. The mechanisms by which these drugs treat albuminuria in patients with DKD should be described more thoroughly. The positive effects of combination therapy with two or more drugs in reducing albuminuria and protecting the kidneys warrant further investigation. Therefore, this review explores the pathophysiological mechanism of albuminuria in patients with DKD, the value of clinical diagnosis and prognosis, new progress and mechanisms of treatment, and multidrug therapy in patients who have type 2 diabetic kidney disease (T2DKD), providing a new perspective on the clinical diagnosis and treatment of DKD.

Infectious illnesses have always posed a threat to human health, with tuberculosis (TB) being a major concern. The use of various medications and antibiotics in the fight against such illnesses has led to the emergence of drug-resistant infectious diseases, which have become increasingly dif-ficult to manage as medical and scientific research has advanced. Inadequate medical infrastruc-ture, incorrect treatment practices that exacerbate resistance patterns, and transmission within communities and healthcare facilities are the main factors contributing to the spread of drug-resistant TB. Though treating individuals with multiple drug resistance (MDR) and extreme drug resistance (XDR) strains is challenging, early identification of resistance and the imple-mentation of a well-designed treatment regimen can result in a cure. Community-based inter-ventions that address socioeconomic barriers to adherence can also enhance treatment outcomes. While there have been few studies and proposed conceptual models on how to manage and prevent various drug-resistant TB mutations and lineages, a model aimed at limiting and controlling such mutations has been developed. This paradigm seeks to bridge the gap by facilitating the exchange of knowledge among healthcare professionals (HCP) in healthcare facilities (HCF), diagnostic laboratories (DL), and research institutes (RI), particularly for underprivileged communities in the Eastern Cape. The model guide will also monitor and evaluate TB management plans

Aim was to develop a population pharmacokinetic model for methotrexate (MTX) during high-dose treatment (HDMTX) in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin’s lymphoma (NHL) and to describe the sources of variability. The study included 50 patients (1-18 years) who received 3 or 5 g/m2 of HDMTX. Nonlinear mixed effects modeling approach was applied for data analysis. Parameter estimation was performed by FOCEI, whereas stepwise covariate modeling was used to assess variability factors. The final two-compartment model incorporates the effect of body weight using allometric scaling and the influence of hemoglobin and serum creatinine on MTX clearance (CL). Population pharmacokinetic values for a typical 70 kg subject were: 11 L/h for clearance (CL), 46.5 L and 16.4 L for volume of central (V1) and peripheral compartment (V2), respectively, and 0.168 L/h for intercompartmental clearance (Q). According to the final model, MTX CL decreases with increasing serum creatinine, whereas a positive effect was captured for hemoglobin. A difference of almost 30% in MTX CL was observed among patients’ hemoglobin values reported in the study. In addition to renal function and body weight, it describes the influence of hemoglobin on CL, allowing better understanding of its contribution to HDMTX disposition.

Buckground: Although ceftazidime/avibactam (CAZ/AVI) has become important option for treating adults and children, no recommendations exist for neonates. We report a neonatal sepsis case due to CAZ/AVI-resistant KPC-2 producing-Klebsiella pneumoniae carrying blaVEB-25 and the use of a customized active surveillance program in conjunction to infection control measures. Methods: The index case was an extremely premature neonate hospitalized for 110 days that had been previously treated with multiple antibiotics. Customized molecular surveillance was implemented at hospital level and enhanced infection control measures were taken for early recognition and prevention of outbreak. Detection and identification of blaVEB-25 was performed by next-generation sequencing. Results: That was the first case of a bloodstream infection caused by KPC producing K. pneumoniae that was resistant to CAZ/AVI without the presence of a metalo-β-lactamase in the multiplex PCR platform in a neonate. All 36 additional patients tested (12 in the same NICU and 24 from other hospital departments) carried wild-type blaVEB-1 but they did not harbor blaVEB-25. Conclusion: The emergence of VEB-25 is signal for horizontal transfer of plasmids at hospital facilities and it is of greatest concern for maintaining a sharp vigilance for surveillance of novel resistance mechanisms. Molecular diagnostics can guide appropriate antimicrobial therapy and early implementation of infection control measures against antimicrobial resistance.

The current study aims to first, isolate H. pylori in cultures from gastric biopsy samples and test their susceptibility. Secondly, we aim to assess the efficacy of the standard triple therapy from patients coming of the western central region of Colombia. Patients with H. pylori positive re-ceived standard triple therapy with PPI [40 mg b.i.d.], clarithromycin [500 mg b.i.d.], amoxicillin [1g b.i.d.] for 14 days. Thereafter, antibiotic susceptibility of the isolates was assessed by E-Test. From 94 patients enrolled, 67 were positive for H. pylori by histology or culture. Resistance to metronidazole, levofloxacin, rifampicin, clarithromycin and amoxicillin was 81, 26.2, 23.9, 19 and 9.5%, respectively. No resistance was found for tetracycline. 54 patients received standard triple therapy, 48 attended follow-ups testing and of them, 30 had resistance test reports. Overall eradication rate was 81.2%, 4 patients underwent second-line management and only one patient remained H. pylori positive by urea breath test during the follow-up [six weeks]. Eradication was significantly higher in patients with clarithromycin susceptible than in resistant strains [95.6% vs. 42.8% p= 0.001]. The updated percentages of resistance to clarithromycin in this geographical area have increased, so this value must be considered when choosing the treatment regimen.

Drug delivery systems consist of cyclodextrins (CyDs) have kept constant attention for good compatibility, negligible toxicity, and improved pharmacokinetics of drugs. The unique hollow structure has endowed a lot of functions, such as inclusion of guest molecules, functional modification of active hydroxyl groups, and noncovalent interactions. Besides, the polyhydroxy structure has further extended the functions of CyDs by inter/intramolecular interactions and chemical modification. Furthermore, the versatile functions of the complex contribute to physicochemical characteristics alteration of the drugs, therapeutic talent, stimulus-responsive switch, self-assemble capability, and fiber formation. This review attempts to list the recent progress of CyDs and discuss their roles in the drug delivery system. Future perspectives of the construction of CyD-based drug delivery systems are also discussed at the end of this review, which may be the possible directions for the construction of more rational and cost-effective delivery vehicles.

The repurposing of licenced drugs for use against COVID-19 is one of the most rapid ways to develop new and alternative therapeutic options to manage the ongoing pandemic. Given the approximately 8,000 licenced compounds available from Compounds Australia that can be screened, this paper demonstrates the utility of commercially-available ex vivo/3D airway and alveolar tissue models. These models are a closer representation of in vivo studies compared to in vitro models, but retain the benefits of rapid in vitro screening for drug efficacy. We demonstrate that several existing drugs appear to show anti-SARS-CoV-2 activity against both Delta and Omicron Variants of Concern in the airway model. In particular, fluvoxamine, as well as aprepitant, everolimus, and sirolimus have virus reduction efficacy comparable to the current standard of care (remdesivir, molnupiravir, nirmatrelvir). Whilst these results are encouraging, further testing and efficacy studies are required before clinical use can be considered.

Targeted delivery of drugs or other therapeutic agents through internal or external triggers has been used to control and accelerate the release from liposomal carriers in a number of studies, but relatively few utilize energy of therapeutic X-rays as a trigger. We have synthesized liposomes that are triggered by ionizing radiation (RTLs) to release their therapeutic payload. These liposomes are composed of natural egg PE, DSPC, cholesterol, and DSPE-PEG-2000, and the mean size of the RTL was in the range of 114 to 133 nm, as measured by NTA. The trigger mechanism is the organic halogen, chloral hydrate, which is known to generate free protons upon exposure to ionizing radiation. Once protons are liberated, a drop in internal pH of the liposome promotes destabilization of the lipid bilayer and escape of the liposomal contents. In proof of principle studies, we assessed RTL radiation-release of fluorescent tracers upon exposure to a low pH extracellular environment or exposure to X-ray irradiation. Biodistribution imaging before and after irradiation demonstrated a preferential uptake and release of the liposomes and their cargo at the site of local tumor irradiation. Finally, a potent metabolite of the commonly used chemotherapy irinotecan, SN-38, was loaded into RTL along with near infrared (NIR) fluorescent dyes for imaging studies and measuring tumor cell cytotoxicity alone or combined with radiation exposure, in vitro and in vivo. Fully loaded RTLs were found to increase tumor cell killing with radiation in vitro and enhance tumor growth delay in vivo after three i.v. injections combined with three, 5 Gy local tumor radiation exposures compared to either treatment modality alone.

The prediction of drug-target interactions plays a fundamental role in facilitating drug discovery, where the goal is to find prospective drug candidates. With the increase in the number of drug-protein interactions, machine learning techniques, especially deep learning methods, have become applicable for drug-target interaction discovery because they significantly reduce the required experimental workload. In this paper, we present a spontaneous formulation of the drug-target interaction prediction problem as an instance of multi-instance learning. We address the problem in three stages, first organizing given drug and target sequences into instances via a private-public mechanism, then identifying the predicted scores of all instances in the same bag, and finally combining all the predicted scores as the output prediction. A comprehensive evaluation demonstrates that the proposed method outperforms other state-of-the-art methods on three benchmark datasets.

Background: A novel virulent coronavirus is what causes Novel Corona-virus Disease 2019 (nCOVID 19). It results in severe respiratory distress syndrome and potentially fatal infectious pneumonia. On March 12, 2020, the World Health Organization first labeled it a pandemic, which was then followed on the same day by a community health emergency of global concern. Vaccines against this deadly virus are now being created. Many drugs with different uses have been repurposed and tested for the prevention and treatment of the infection. Objective: The purpose of this review is to provide an in-depth analysis of data on possible pharmacological targets and available coronavirus treatments. Methods: Following the review protocol, a literature search was conducted. Results: Chloroquine phosphate and hydroxychloroquine, Remdesivir, and Lopinavir-Ritonavir in combination with or without interferon and convalescent plasma therapy are the main treatment candidates, according to the World Health Organization. This review article has elaborated on the current evidence of prospective pharmacological targets and related ongoing research, including inflammatory chemicals, bioactive peptides, beta cells, platelets, and the Angiotensin I Converting Enzyme 2 Receptor. This information was gathered from published journals. In addition, stories of medications and biological products like interferons and vaccinations that are utilized or could be utilized have been provided. Conclusion: There are a variety of pharmacological targets and therapeutic strategies that need more study.

Here we draw insights from the latest serendipitous findings made on the opposing roles of a validated drug-target protein Keap1. We weigh up how natural reactive electrophiles and electrophilic small-molecule drugs in clinical use directly impinge on seemingly conflicting, yet both Keap1-electrophile-modification-dependent, cell-survival- vs. cell-death-promoting behaviors. In the process, we convey how understanding reactive chemical-signal regulation at a single-protein-specific level is an enabling necessity in deconstructing otherwise intricate reactive-small-molecule-responsive cellular pathways. We hope this opinion piece further spurs the broader interests of basic and pharmaceutical research communities toward better understanding of molecular mechanisms underpinning reactive small-molecule-regulated signaling subsystems.

Cryptococcus neoformans causes meningoencephalitis in immunocompromised individuals, which is treated with Fluconazole (FLC) monotherapy when resources are limited. This can lead to azole resistance, which can be mediated by overexpression of ABC transporters, a class of efflux pumps. ABC pump-mediated efflux of FLC is also augmented in 10-generation old C. neoformans cells. Here, we describe a new ABC transporter Afr3 (CNAG_06909), which is overexpressed in C. neoformans cells of advanced generational age, that accumulate during chronic infection. The delta-afr3 mutant strain showed higher FLC susceptibility by FLC E-Test strip testing and also by a killing test that measured survival after 3 h FLC exposure. Furthermore, delta-afr3 cells exhibited lower Rhodamine 6G efflux compared to the H99 wild type cells. Afr3 was expressed in the Saccharomyces cerevisiae AD-delta strain, which lacks several drug transporters, thus reducing background transport. The AD-delta + Afr3 strain demonstrated a higher efflux with both Rhodamine 6G and Nile Red, even though the FLC MICs were not changed. Characterization of the delta-afr3 mutant revealed unattenuated growth but a prolongation (22%) of the replicative life span. In addition, delta-afr3 exhibited decreased resistance to macrophage killing and attenuated virulence in the Galleria mellonella infection model. In summary, our data indicate that a novel ABC pump Afr3p, which is upregulated in C. neoformans cells of advanced age may contribute to their enhanced FLC tolerance, by promoting drug efflux. Lastly, its role in macrophage resistance may also contribute to the selection of older C. neoformans cells during chronic infection.

The most effective method of treating allergic diseases, aimed not at relieving symptoms, but at eliminating the cause of the disease, is allergen-specific immunotherapy (AIT). To reduce the risk of side effects and improve the delivery of allergens to the mucosa, various delivery systems, such as liposomes, dendrimers, nanoparticles, etc., can be used. To date, there are data on the creation of delivery systems based on glycyrrhizic acid (GA) and its derivatives, but such a delivery system has not been used for allergen-specific therapy until now. At the same time, it is known that GA has an anti-inflammatory effect, shifts the balance towards Th1, and increases the number of Treg cells, which means that in the future it can enhance the anti-allergic effect of AIT and reduce the risk of unwanted side effects. Thus, the study of the immunomodulatory effect of supramolecular complexes (micelles) of GA with extracts of allergens seems to be very promising for the development of new drugs for AIT.

Metastasis is the leading cause of cancer death and can be realized through the phenomenon of tumor cell fusion. The fusion of tumor cells with other tumor or normal cells leads to the appearance of tumor hybrid cells (THCs) exhibiting novel properties such as increased proliferation and migration, drug resistance, decreased apoptosis rate and avoiding immune surveillance. Experimental studies showed the association of THCs with a high frequency of cancer metastasis; however, the underlying mechanisms remain unclear. Many other questions also remain to be answered: the role of genetic alterations in tumor cell fusion, the molecular landscape of cells after fusion, the lifetime and fate of different THCs, and the specific markers of THCs, and their correlation with various cancers and clinicopathological parameters. In this review, we discuss the factors and potential mechanisms involved in the occurrence of THCs, the types of THCs, and their role in cancer drug resistance and metastasis, as well as potential therapeutic approaches for the prevention and targeting of tumor cell fusion. In conclusion, we emphasize the current knowledge gaps in the biology of THCs that should be addressed to develop highly effective therapeutics and strategies for metastasis suppression.

Molecular Dynamics (MD) simulations model motion of molecules in atomistic detail and aid in drug design. While simulations on large systems may require several days to complete, analysis of terabytes of data generated in the process could also be time consuming. Recent studies captured exciting and dramatic drug-receptor interactions under cell-like complex conditions. Such advances make simulations of biomolecular interactions more realistic, insightful, and informative and have potential to make drug design more realistic. However, currently available resources and techniques do not provide, in reasonable time, a comprehensive understanding of events seen in simulations. We demonstrate that big data approach results in significant speedups, and provides rapid insights into simulations performed. Advancing this improvement, we propose a scalable, self-tuning, and responsive framework based on Cloud-infrastructure to accomplish the best possible MD studies with given priorities and within available resources.

The family environment has an important role in determining children’s personality and behavior. This study examined the impact of the family environment on alcohol and drug misuse among Indonesian students. Data were obtained from the National Illicit Drug Use Survey of students in Indonesia in 2016, conducted in 18 provinces. The subjects were 35,340 students from 1284 schools and universities with an age range of 12-25 years. The survey used the self-administered modified NODC Structured Illicit Drug questionnaire. The results show that 13.7% of students ever drank alcohol and 2.1% of students misused drugs within the previous year. Among students who drank alcohol, 11% also used drugs. In the latter group, they were likely to have been victims of verbal and physical violence by their parents and never discussed any problems with their parents. Living with a family with existing risky behavior (alcohol drinking and/or drug misuse) was the strongest risk factor of alcohol drinking (aOR: 4.78; 4.27-5.37) and drug misuse (aOR: 2.32; 1.79-3.01). These results indicate that the family environment affects these risky behaviors in this target population. Making adjustments through parental support, control, and parenting style, particularly in initiating parent–child communication, may have benefits in preventing alcohol drinking and drug use in this target population.

Individual response to drugs is highly variable and largely influenced by genetic variants and gene-expression profiles. Also, it has been shown that response to drugs is strongly sex-dependent, both in terms of efficacy and toxicity. To expand current knowledge on sex differences in the expression of genes relevant for drug response, we generated a catalogue of differentially expressed human transcripts encoded by 289 genes in 41 human tissues from 838 adult individuals of the Genotype-Tissue Expression project (GTEx, v8 release) and focused our analysis on relevant transcripts implicated in drug response. We have detected significant sex-differentiated expression of 99 transcripts encoded by 59 genes in the tissues most relevant for human pharmacology (Liver, Lung, Kidney, Small intestine terminal ileum, Skin not sun-exposed, and Whole Blood). Among them, as expected, we observed significant differences in the expression of transcripts encoded by the cytochromes in the liver, CYP2B6, CYP3A7, CYP3A5, and CYP1A1. Our systematic investigation on differences between male and female in the expression of drug response related genes, reinforce the need to overcome the sex bias of clinical trials.

The multidrug efflux transporter ABCB1 is clinically important for drug absorption and distribution and can be a determinant of chemotherapy failure. Recent structure data shows that three glutamines donate hydrogen bonds to co-ordinate taxol in the drug binding pocket. This is consistent with earlier drug structure-activity relationships that implicated the importance of hydrogen bonds in drug recognition by ABCB1. By replacing the glutamines with alanines we have tested whether any or all of Q347, Q725 and Q990 are important for the transport of three different drug classes. Flow cytometric transport assays show that Q347A and Q990A act synergistically to reduce transport of Calcein-AM, BODIPY-verapamil and OREGON GREEN-taxol bisacetate but the magnitude of the effect was dependent on the test drug and no combination of mutations completely abrogated function. Surprisingly, Q725A mutants generally improved transport of Calcein-AM and BODIPY-verapamil, suggesting that engagement of the wild-type Q725 in a hydrogen bond is inhibitory for the transport mechanism. To test transport of unmodified taxol, stable expression of Q347/725A and the triple mutant was engineered and shown to confer equivalent resistance to the drug as the wild-type transporter, further indicating that none of these potential hydrogen bonds between transporter and transport substrate are critical for function of ABCB1. The implications of the data for plasticity of the drug binding pocket are discussed.

Antibiotic inefficacy in treating bacterial infections is largely studied in the context of developing resistance mechanisms. However, little attention has been paid to combined diseases mechanisms, interspecies pathogenesis and the resulting impact on antimicrobial treatment. This review will consider the co-infections of Salmonella and Schistosoma mansoni. It summarises the protective mechanisms that the pathophysiology of the two infections confer, which leads to an antibiotic protection phenomenon. This review will elucidate the functional characteristics of the gut microbiota in the context of these co-infections, the pathogenicity of these infections in infected mice, and the efficacy of the antibiotics used in treatment of these co-infections over time. Salmonella-Schistosoma interactions and the mechanism for antibiotic protection are not well established. However, antimicrobial drug inefficacy is an existing phenomenon in these co-infections. The treatment of schistosomiasis to ensure the efficacy of antibiotic therapy for bacterial infections should be considered in co-infected patients.

Enhanced permeation retention (EPR) was a significant milestone discovery by Maeda et al. paving the road for the emerging nanomedicine as a powerful tool in the fight against cancer. Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE-5) used for treatment of erectile dysfunction (ED) through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. Overexpression of PDE-5 was reported in lung, colon, metastatic breast cancers and bladder squamous carcinoma. Accordingly, there has been a growing interest in using sildenafil as monotherapy or chemoadjuvant in EPR augmentation and management of different types of cancer. Sildenafil had been reported to increase the sensitivity of tumor cells of different origins to the cytotoxic effect of chemotherapeutic agents with augmented apoptosis mediated through inducing the expression of Bad and Bax proapoptotic proteins. It was also reported that the use of sildenafil prior to the administration of Doxorubicin (DOX) increased its EPR-related concentration in breast cancer tissues by 2 folds. Further, a substantial reason of anticancer chemotherapeutic failure is due to multidrug resistance (MDR), exacerbated by the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCCs. Sildenafil has demonstrated inhibitory effects on the efflux activity of ABCC4, ABCC5, ABCB1, and ABCG2, ultimately reversing MDR caused by these transporters. In this review, we critically examine the overall potential of sildenafil in enhancing EPR-based anticancer drug delivery pointing up the outcome of the most important related preclinical and clinical studies.

High-throughput screening technologies continues to produce large amounts of multiomics data from different populations and cell types for various diseases, such as cancer. However, analysis of such data encounters difficulties due to cancer heterogeneity, further exacerbated by human biological complexity and genomic variability. There is a need to redefine the drug discovery development pipeline, bringing an Artificial Intelligence (AI)-powered informational view that integrates relevant biological information and explores new ways to develop effective anticancer approaches. Here, we show SynPred, an interdisciplinary approach that leverages specifically designed ensembles of AI-algorithms, links omics and biophysical traits to predict synergistic anticancer drug synergy. SynPred exhibits state-of-the-art performance metrics: accuracy – 0.85, precision – 0.77, recall – 0.75, AUROC – 0.82, and F1-score - 0.76 in an independent test set. Moreover, data interpretability was achieved by deploying the most current and robust feature importance approaches. A simple web-based application available online at http://www.moreiralab.com/resources/synpred/ was constructed to predict synergistic anticancer drug combinations requiring only the upload of the two drug SMILES to be tested, allowing easy access by non-expert researchers.

The natural product elaiophylin is a macrodiolide with broad biological activities. However, no direct target of elaiophylin in eukaryotes has been described so far, which hinders a systematic explanation of its astonishing activity range. We recently showed that the related conglobatin A, a protein-protein interface inhibitor of the interaction between the N-terminus of Hsp90 and its cochaperone Cdc37, blocks cancer stem cell properties by selectively inhibiting K-Ras4B but not H-Ras. Here we elaborate that elaiophylin likewise disrupts the Hsp90/ Cdc37 interaction, without affecting the ATP-pocket of Hsp90. Similar to conglobatin A, elaiophylin decreased expression levels of the Hsp90 client HIF1⍺, a transcription factor with various downstream targets, including galectin-3. Galectin-3 is a nanocluster scaffold of K-Ras, which explains the K-Ras selectivity of Hsp90 inhibitors. In agreement with this K-Ras targeting and the potent effect on other Hsp90 clients, we observed with elaiophylin treatment a submicromolar IC50 for MDA-MB-231 3D spheroid formation. Finally, a strong inhibition of the same cells grown in the chorioallantoic membrane (CAM) microtumor model was determined. These results suggest that several other macrodiolides may have the Hsp90/ Cdc37 interface as a target site.

Cancer is one of the health concerns in modern societies. The application of nanotechnology in medical sciences has created new possibilities for the diagnosis, imaging and the treatment of tumors in humans. The present article reviews the application of marine-based gold nanoparticles in diagnosing and treating cancer. The main data were collected from research article on the application of different marine-based gold nanoparticles in detecting and imaging cancer cells as well as in drug delivery system in treatment of cancer. Chitosan is the most used marine natural compound used to fabricate gold nanocomposites and the most reported application of this type of nano-composites is related to drug delivery system. Despite the excellent anticancer potential of different marine natural products, less studies have been conducted on the use of their compositions with gold nanoparticles in cancer therapy than other materials. Moreover, most reports available in this filed are related to their application as a drug delivery system not anticancer drug. In general, there are still challenges and limitations to the use of nanoparticles in medicine, it is hoped that in the near future nanoparticles will create a dramatic revolution not only in oncology but also in medicine.

Iloperidone (ILO) is a second-generation antipsychotic drug and a first-line treatment approved by USFDA in May 2009. Iloperidone belongs to Biopharmaceutical Classification Systems (BCS) class II; thus, it is poorly water-soluble, highly permeable, and has pH-dependent solubility. Cyclodextrins and their derivatives have a wide range of applications in different formulations due to their complexation ability, which improves the solubility, stability, safety, and bioavailability of a drug. We have tried the complexation of iloperidone with sulfobutyl ether-β-cyclodextrin (SEβCD) to improve its solubility and dissolution. Complexation was done by the kneading method. The characterization of the SEβCD complexes with Iloperidone was done by FTIR, differential scanning calorimetry (DSC), saturation solubility, etc. A multimedia dissolution of the complex was carried out and compared with the plain drug. A significant improvement in drug release was found from SEβCD complexes in all media when compared with the drug alone.

Objectives: The mechanism of action of drugs that depress the central nervous system (CNS) was unknown until molecular pharmacology discovered each drug's exact role. The benefit of knowing the mechanism of action is to design a new drug that could have the same efficacy as the prototype drug but with fewer side effects. Some of the available CNS depressant drugs that were abused or illegally used could be modified to make them used medically. Methods: We reviewed various published articles in PubMed and Google Scholar that focused on CNS depressants' molecular pharmacology.Results: It was clear that at specific plasma concentrations of ethyl alcohol showed almost same mode of action of propofol by targeting the extrasynaptic GABA-A receptors, which causes tonic GABAergic inhibition. Besides, the High affinity of some benzodiazepines (e.g., midazolam) to α1 subunit of GABA-A receptor causes sedative, hypnotic, amnesic, and some antiepileptic effects; however, some other benzodiazepines (e.g., diazepam) have high affinity to α3 subunits, which causes anxiolytic, muscle relaxant, and strong antiepileptic effects. The CB1 receptor partial agonism effect of tetrahydrocannabinol has a sedative advantage over full agonism due to desensitization of CB1 receptors. Conclusion: From the molecular pharmacology prospect, it is possible to design new drugs with more specific CNS depressants effect and fewer side effects by targeting particular receptors with a precise reaction.

Antibiotic resistance (ABR) is an emerging global threat to public health. Substantial evidence has indicated that community pharmacists (CPs) can play a critical role in managing the ever-increasing threat of antibiotic resistance. The study aimed to determine the knowledge, attitude, and practices of CPs (n=180) towards antibiotics and antibiotic resistance as well as to improve the rational use of antibiotics. Two phases of mixed methods (quantitative and qualitative) online study were conducted in Pakistan from August 2019 to March 2020 by using validated questionnaires and semi-structured interview data. Different statistical methods were used to tabulate the quantitative data whereas inductive thematic analysis was conducted to categorize themes from the qualitative data and draw conclusions. Approximately 64.4% were male (mean: 29-33 years old). Overall, CPs had good knowledge of and were familiar with superbugs and their roles in ABR (65.6%, Median=1, IQR=1) although they were poor in differentiating some antibiotic groups with their respective ABR patterns (31.1%, Median=1, IQR=1). Most CPs have a positive attitude towards antibiotics with most (90.0%) having identified ABR as a critical issue in public health (Median=1, IQR=0). Overall, CPs' practices towards antibiotics were reasonable where they tend to educate patients about the rational use of antibiotics (52.8%, Median=1, IQR=1). Two main themes (antibiotics and counseling of patients) were related to self-medication with while educational interventions are the sub-theme. ABR is multifactorial where the subthemes related to budget, time constraints incompetent staff, the absence of CPs, the lack of training, enforcement of laws and regulations are the need of the hour in Pakistan. Effective antibiotic stewardship programs, patient education, and awareness campaigns about antibiotics and ABR along with training of the CPs are important factors that have to be addressed in a timely manner.

Recently, the outbreak of coronavirus disease 2019 (COVID-19) is threatening human health globally. There is a dire need to find potential therapeutic agents. Angiotensin converting enzyme 2 (ACE2), as an entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is considered as potential therapeutic target in COVID-19 pandemic. Here, our bioinformatics analysis revealed that the biological function of ACE2 was correlated with regulation of blood pressure and mediation of SARS-CoV-2 entry into host cells. Ten ACE2 cooperative proteins were identified by using STRING with a high score. ACE2 expressed highly in the small intestine, testis, and kidney. The level of ACE2 expression in tumor tissues varies in different types of cancers compared with that in normal tissues. It was worth noting that the expression level of ACE2 in the tumor has no effect on patient survival. MiRNA hsa-miR-942-5p, and three transcription factors (TFs) including Signal transducer and activator of transcription 4 (STAT4), Estrogen related receptor α (ESRRA), and Signal transducer and activator of transcription 3 (STAT3) were selected as novel ACE2 regulators. Moreover, nine potential therapeutic drugs were predicted by two online databases. Thus, our research may expand the overall view of ACE2 in COVID-19 treatment.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, has been declared by the World Health Organization (WHO) as a pandemic. Unfortunately, finding a vaccine or developing drugs from the scratch is a time-consuming luxury given the widespread and high fatality rates of the virus. In the short term, repurposing of drugs already in use seem to be the most rational step to quickly and effectively curb the virus. Several antiviral agents had been proposed as possible remedies, but the 4-aminoquinolines, Chloroquine (CHQ) and hydroxychloroquine (HCHQ) appear to be generating more interest. They are generic, cheaply available and have proven efficacy against malaria parasites in Africa. The human immunodeficiency virus (HIV), on the other hand, targets the immune system thereby reducing the patient’s ability to fight infections. Sadly, 68% of the global HIV burden occur in Africa. It is therefore anticipated that incidence of severe forms of COVID-19 could occur in Africa because of associated endemic conditions that compromise the immune system. With CHQ and HCHQ being considered for clinical use against COVID-19, there is a need to highlight their potential merits and confounding variables in the subgroup of patients with or without HIV.

While the COVID-19 pandemic advances, the scientific community struggles in the search for treatments. Several improvements have been made, including the discovery of clinical efficacy of chloroquine (CQ) in COVID-19 patients, but the effective treatment protocols are still missing. In order to find novel treatment options many scientists utilize the in silico approach to identify compounds that could interfere with the key molecules involved in entrance, replication, or dissemination of the SARS-CoV-2. However, most of the identified molecules are currently not available as pharmacological agents, and assessing their safety and efficacy could take many months. Here, we took a different approach based on the proposed pharmacodynamic model of CQ in COVID-19. The main mechanism of action responsible for the favourable outcome of COVID-19 patients treated with CQ seems to be related to pH modulation-mediated effect on the endolysosomal trafficking, a characteristic of chemical compounds often called lysosomotropic agents because of the physico-chemical properties that enable them to passively diffuse through the endosomal membrane and undergo protonation-based trapping in the lumen of the acidic vesicles. In this review, we discuss lysosomotropic and lysosome targeting drugs that are already in clinical use and are characterized by good safety profiles, low cost, and wide availability. We emphasize that some of these drugs, in particular azithromycin and other macrolide antibiotics, indomethacin and some other non-steroidal anti-inflammatory drugs, proton pump inhibitors, and fluoxetine could provide additional therapeutic benefits in addition to the potential antiviral effect that still has to be confirmed by well-controlled clinical trials. As some of these drugs, mostly antibiotics, were already empirically used in the treatment of COVID-19, we encourage our colleagues all over the world to publish patient data so potential efficacy of these agents can be evaluated in the clinical context and rapidly implemented in the therapeutic protocols if the beneficial effect on clinical outcome is observed.

Background: Diabetic foot ulcers are an increasingly common complex problem and are associated with a very considerable health care burden. Diabetic foot ulcer with Alcaligenes faecalis infection is rarely reported in the literature. We report a case series of diabetic foot ulcer with Alcaligenes faecalis infection treated at our facility. Methods: We conducted a retrospective analysis of all patients with diabetic foot ulcer with Alcaligenes faecalis infection seen from January 2014 to April 2019. We analyzed the clinical characteristics, ulcer lesion classification, comorbidities, prior intravenous antibiotic use within three months, wound culture, antibiotics sensitivity test, and clinical outcomes of these patients. Results: Eight cases of diabetic foot ulcer with Alcaligenes faecalis infection were seen in five males and three females. The mean age was 54.6 years. All patients had other comorbidities, and all ulcer lesions were of chronic duration ( more than 14 days ). All wound cultures revealed polymicrobial infection, with two cases of diabetic foot with extensive-drug resistant Alcaligenes faecalis infection found in 2019. All patients needed intravenous antibiotic therapy and surgical interventions for the chronic ulcer lesion. The wound failed to heal in three patients. Conclusions: All diabetic foot ulcers with Alcaligenes faecalis infection were of chronic duration ( more than 14 days ) and had polymicrobial infection. Extensive-drug resistant Alcaligenes faecalis emerged in 2019. Definitive antibiotic therapy is necessary for all infected wounds and should be based on both the culture results and susceptibility data. All patients will need appropriate wound care, and most will need rapid surgical intervention for an optimal outcome.

Specialized, reductionist, and linear approaches are applied in clinical research; they are based on linear logic and used towards therapeutic molecule-based targets. However, those approaches do not consider a systemic vision that describes the remote cause of the pathogenic activation. We propose new theoretical and practical methods for the next drug generation development. Self-organization, network structure, hierarchical organization, non-linearity, feedback circuits, reactions to information, and the view of drugs as information clarify the existing pharmacological methods. We suggest a perspective and hierarchical vision of the human organism based on six levels (mechanic and structural; metabolic; bodily dynamic; emotional, cognitive, spiritual). The therapy should restore the self-organization of every level using the “intelligent” modulation of the network responses. Multi-targeted drugs should act on the remote cause of the pathogenic cascade and be administered based on personal variability and networks. This approach may help the development of individualized, precise, and integrated medicine.

Antibiotic failure is one of the most worrying health problems worldwide. Nowadays we are facing an international crisis where several issues are involved: new antibiotics are not being discovered any longer, resistance mechanisms become spread in nearly every clinical isolate of bacteria and the appearance of recurrent infections caused by persistent bacteria complicates the overcoming of infections. In this context, it has been explored new anti-infectious strategies against MDR and persistent bacteria as well as the rescue of FDA-approved compounds (drug repurposing). Among the highlighted new anti-infectious strategies we find anti-microbial peptides, anti-virulence compounds, phage therapy and new molecules. On the other hand, as drugs of repurposing that have been described, we have anti-inflammatory compounds, anti-psychotics, anti-helmintic drugs, anti-cancerous and statins.