Broad-spectrum Drug Research Articles

Efficacy of ivermectin and its metabolites against Plasmodium falciparum liver stages in primary human hepatocytes.

Ivermectin, a broad-spectrum anti-parasitic drug, has been proposed as a novel vector control tool to reduce malaria transmission by mass drug administration. Ivermectin and some metabolites have mosquito-lethal effect, reducing Anopheles mosquito survival. Ivermectin inhibits liver stage development in a rodent malaria model, but no inhibition was observed in a primate malaria model or in a human malaria challenge trial. In the liver, cytochrome P450 3A4 and 3A5 enzymes metabolize ivermectin, which may impact drug efficacy. Thus, understanding ivermectin metabolism and assessing this impact on Plasmodium liver stage development is critical. Using primary human hepatocytes (PHHs), we characterized ivermectin metabolism and evaluated the efficacy of ivermectin and its primary metabolites M1 (3″-O-demethyl ivermectin) and M3 (4-hydroxymethyl ivermectin) against Plasmodium falciparum liver stages. Two different modes of ivermectin exposure were evaluated: prophylactic mode (days 0-3 post-infection) and curative mode (days 3-5 post-infection). We used two different PHH donors and modes to determine the inhibitory concentration (IC50) of ivermectin, M1, M3, and the known anti-malarial drug pyrimethamine, with IC50 values ranging from 1.391 to 14.44, 9.95-23.71, 4.767-8.384, and 0.9073-5.416 µM, respectively. In our PHH model, ivermectin and metabolites M1 and M3 demonstrated inhibitory activity against P. falciparum liver stages in curative treatment mode (days 3-5) and marginal activity in prophylactic treatment mode (days 0-3). Ivermectin had improved efficacy when co-administered with ketoconazole, a specific inhibitor of cytochrome P450 3A4 enzyme. Further studies should be performed to examine ivermectin liver stage efficacy when co-administered with CYP3A4 inhibitors and anti-malarial drugs to understand the pharmacokinetic and pharmacodynamic drug-drug interactions that enhance efficacy against human malaria parasites in vitro.

Joint use of population pharmacokinetics and machine learning for prediction of valproic acid plasma concentration in elderly epileptic patients

BackgroundValproic acid (VPA) is a commonly used broad-spectrum antiepileptic drug. For elderly epileptic patients, VPA plasma concentrations have a considerable variation. We aim to establish a prediction model via a combination of machine learning and population pharmacokinetics (PPK) for VPA plasma concentration. MethodsA retrospective study was performed incorporating 43 variables, including PPK parameters. Recursive Feature Elimination with Cross-Validation was used for feature selection. Multiple algorithms were employed for ensemble model, and the model was interpreted by Shapley Additive exPlanations. ResultsThe inclusion of PPK parameters significantly enhances the performance of individual algorithm model. The composition of categorical boosting, light gradient boosting machine, and random forest (7:2:1) with the highest R2 (0.74) was determined as the ensemble model. The model included 11 variables after feature selection, of which the predictive performance was comparable to the model that incorporated all variables. ConclusionsOur model was specifically tailored for elderly epileptic patients, providing an efficient and cost-effective approach to predict VPA plasma concentration. The model combined classical PPK with machine learning, and underwent optimization through feature selection and algorithm integration. Our model can serve as a fundamental tool for clinicians in determining VPA plasma concentration and individualized dosing regimens accordingly.

Three-in-one reduction and acid-ignited micelles amplify antitumor efficacy via precise synergistic delivery of paclitaxel and naringenin

Chemotherapy is the cornerstone of cancer treatment, and paclitaxel (PTX), as a first-line broad-spectrum chemotherapy drug, is widely used in the treatment of multiple tumors in the clinic. However, unsatisfactory efficacy and drug resistance of single chemotherapy have severely hampered the clinical progress of PTX. Herein, three-in-one naringenin (NAR)-loaded PTX polymer prodrug micelles were constructed for efficient and synergistic antitumor therapy. Firstly, the polymer prodrug micelles could simultaneously act as nanoreservoirs for two hydrophobic drugs, PTX and NAR. Secondly, the polymer prodrug micelles enabled dual-responsive intelligent release of PTX and NAR triggered by reduction and acid. Finally, released PTX and NAR exerted synergistic antitumor effects for reversing tumor resistance, while NAR enhanced the immune and anti-inflammatory functions of polymer prodrug micelles. Due to the cascade-enhanced chemotherapeutic augmentation, the intelligent-responsive nanoreservoir proved to be an excellent antitumor therapeutic platform. This work was of great interest for designing superior chemotherapeutic augmentation regimens.

Unprecedented Organogermanium Functionalized GeIV-SbIII-Templating Polyoxotungstate Nanocluster for Photothermal-Chemodynamic Cancer Therapy.

The function-oriented synthesis of polyoxometalate (POM) nanoclusters has become an increasingly important area of research. Herein, the well-known broad-spectrum anticancer drug Ge-132 which contains GeIV as potential heteroatoms and carboxyl coordination sites, is introduced to the POM system, leading to the first organogermanium functionalized GeIV-SbIII-templating POM nanocluster Na4[H2N(CH3)2]16 H18[Sm4(H2O)12W4O14Ge(CH2CH2COOH)]2[SbW9O33]4[Ge(CH2CH2COOH) SbW15O54]2·62H2O (1). An unprecedented organogermanium templating Dawson-like [Ge(CH2CH2COOH)SbW15O54]12- building block is discovered. To take advantage of the potential pharmaceutical activity of such an organogermanium-functionalized POM cluster, 1 is further composited with gold nanoparticles (NPs) to prepare 1-Au NPs, which doubles the blood circulation time of 1-based nanodrug. Efficient separation of photogenerated charges in 1-Au NPs largely boosts the photothermal conversion efficiency (PCE=55.0%), which is nearly 2.1 times that of either single 1 (PCE=26.7%) or Au NPs (PCE=26.2%), and simultaneously facilitate the generation of toxic activate reactive oxygen species in tumor microenvironment. Based on these findings, it is demonstrated that 1-Au NPs are a multifunctional and renal clearable nanomedicine with great potential in photoacoustic imaging guiding photothermal-chemodynamic therapy for breast cancer.

Multi-component Crystal Strategy for Improving Water Solubility and Antifungal Activity of Climbazole.

The primary problem with climbazole (CLB), a broad-spectrum imidazole antifungal drug, is its low water solubility. In order to increase its water solubility and antifungal activity, three new multi-component crystals were synthesized in this work, and the intermolecular interactions were systematically studied. This work helps to optimize the CLB product formulation and extend its application prospects. In this work, three novel multi-component crystals, CLB-malonic acid (CLB-MA) salt, CLB-succinic acid (CLB-SA) cocrystal and CLB-adipic acid (CLB-AA) cocrystal, were successfully synthesized. And the crystal structure, thermodynamic properties, solubility, dissolution, hygroscopicity, and antifungal activity of the three multi-component crystals were fully characterized by single-crystal X-ray diffraction (SCXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic water vapor adsorption (DVS) and powder dissolution tests, etc. The molecular interactions and molecular stacking in multi-component crystals were studied by Hirshfeld surface (HS), molecular surface electrostatic potential (MEP), interaction region indication (IRI) and atom and molecule (AIM) techniques. The results show that the three multi-component crystals have good moisture resistance stability, and their water solubility is 6-22 times that of pure CLB. Meanwhile, the measurement of the minimum inhibitory concentration (MIC) proves that the cocrystal/salt has a stronger antifungal activity than climbazole. Quantum chemistry calculations of crystal structure visualized and quantified the interactions that exist in multi-component crystals, and explored the microscopic mechanisms underlying the different performance of multi-component crystals.

Development of potent pan-coronavirus fusion inhibitors with a new design strategy.

Development of potent and broad-spectrum drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains one of the top priorities, especially in the cases of the emergence of mutant viruses and inability of current vaccines to prevent viral transmission. In this study, we have generated a novel membrane fusion-inhibitory lipopeptide IPB29, which is currently under clinical trials; herein, we report its design strategy and preclinical data. First, we surprisingly found that IPB29 with a rigid linker between the peptide sequence and lipid molecule had greatly improved α-helical structure and antiviral activity. Second, IPB29 potently inhibited a large panel of SARS-CoV-2 variants including the previously and currently circulating viruses, such as Omicron XBB.5.1 and EG.5.1. Third, IPB29 could also cross-neutralize the bat- and pangolin-isolated SARS-CoV-2-related CoVs (RatG13, PCoV-GD, and PCoV-GX) and other human CoVs (SARS-CoV, MERS-CoV, HCoV-NL63, and HCoV-229E). Fourth, IPB29 administrated as an inhalation solution (IPB29-IS) in Syrian hamsters exhibited high therapeutic and preventive efficacies against SARS-CoV-2 Delta or Omicron variant. Fifth, the pharmacokinetic profiles and safety pharmacology of IPB29-IS were extensively characterized, providing data to support its evaluation in humans. In conclusion, our studies have demonstrated a novel design strategy for viral fusion inhibitors and offered an ideal drug candidate against SARS-CoV-2 and other coronaviruses.

The reality of epilepsy in primary care in Rio de Janeiro: the importance of educational projects for better patient care.

The Basic Health Unit (Unidade Básica de Saúde - UBS, in Portuguese) is the first point of contact in the public healthcare system for people with epilepsy. Primary care professionals need to appropriately diagnose, treat, and refer, if necessary, to tertiary services. To evaluate the knowledge of UBS professionals on the management of patients with epilepsy in Rio de Janeiro. Online questionnaires were performed on the topic of epilepsy before and after exposure to classes taught by epileptologists. A total of 66 doctors participated, 54.5% of whom were residents or trained in family medicine. The majority had from 1 to 3 years of practice. Insecurity prevailed in the management of pregnant women and the elderly. Around 59.1% of the participants referred patients with seizures without examinations. A total of 78% of the participants did not correctly classify seizure types, and 2/3 did not define drug-resistant epilepsy. Induction and broad-spectrum drugs were common. The therapeutic decision depended on availability in the basic health unit (UBS) (81.8%), dosage (60.6%), side effects (34.8%), and age (36.4%). Comorbidities and sex influenced 1/4 of the sample. For 23% of the participants, the type of crisis did not affect the choice. Regarding typical non-pharmacological options, 75% of the participants were aware of cannabidiol, 40.9% of surgery, 22.7% of ketogenic diet, and 22.8% of deep brain stimulation/vagus nerve stimulation (DBS/VNS). A total of 90.2% indicated the need for training. There are deficits in the knowledge of UBS professionals in the management of epilepsy. Specialized training is imperative to optimize the care offered within SUS.

Co-administration of either curcumin or resveratrol with cisplatin treatment decreases hepatotoxicity in rats via anti-inflammatory and oxidative stress-apoptotic pathways.

Cisplatin (CIS) is a broad-spectrum anticancer drug, with cytotoxic effects on either malignant or normal cells. We aimed to evaluate the hepatotoxicity in rats caused by CIS and its amelioration by the co-administration of either curcumin or resveratrol. Forty adult male rats divided into four equal groups: (control group): rats were given a saline solution (0.9%) once intraperitoneally, daily for the next 28 days; (cisplatin group): rats were given a daily oral dose of saline solution (0.9%) for 28 days after receiving a single dose of cisplatin (3.3 mg/kg) intraperitoneally for three successive days; (CIS plus curcumin/resveratrol groups): rats received the same previous dose of cisplatin (3.3 mg/kg) daily for three successive days followed by oral administration of either curcumin/resveratrol solution at a dose of (20 mg/kg) or (10 mg/kg) consequently daily for 28 days. Different laboratory tests (ALT, AST, ALP, bilirubin, oxidative stress markers) and light microscopic investigations were done. Administration of CIS resulted in hepatotoxicity in the form of increased liver enzymes, oxidative stress markers; degenerative and apoptotic changes, the co-administration of CIS with either curcumin or resveratrol improved hepatotoxicity through improved microscopic structural changes, reduction in liver enzymes activity, decreased oxidative stress markers, improved degenerative, and apoptotic changes in liver tissues. Co-administration of either curcumin or resveratrol with cisplatin treatment could ameliorate hepatotoxicity caused by cisplatin in rats via anti-inflammatory and oxidative stress-apoptotic pathways.

Anti-Microbial Drug Metronidazole Promotes Fracture Healing: Enhancement in the Bone Regenerative Efficacy of the Drug by a Biodegradable Sustained-Release In Situ Gel Formulation.

Nitroimidazoles comprise a class of broad-spectrum anti-microbial drugs with efficacy against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. Among these drugs, metronidazole (MTZ) is commonly used with other antibiotics to prevent infection in open fractures. However, the effect of MTZ on bone remains understudied. In this paper, we evaluated six nitroimidazole drugs for their impact on osteoblast differentiation and identified MTZ as having the highest osteogenic effect. MTZ enhanced bone regeneration at the femur osteotomy site in osteopenic ovariectomized (OVX) rats at the human equivalent dose. Moreover, in OVX rats, MTZ significantly improved bone mass and strength and improved microarchitecture compared to the vehicle-treated rats, which was likely achieved by an osteogenic mechanism attributed to the stimulation of the Wnt pathway in osteoblasts. To mitigate the reported neurological and genotoxic effects of MTZ, we designed an injectable sustained-release in situ gel formulation of the drug that improved fracture healing efficacy by 3.5-fold compared to oral administration. This enhanced potency was achieved through a significant increase in the circulating half-life and bioavailability of MTZ. We conclude that MTZ exhibits osteogenic effects, further accentuated by our sustained-release delivery system, which holds promise for enhancing bone regeneration in open fractures.

An immune biomarker associated with EMT serves as a predictor for prognosis and drug response in bladder cancer.

Bladder cancer (BLCA), which develops from the upper endometrial of the bladder, is the sixth most prevalent cancer across the globe. WDHD1 (WD repeat and HMG-box DNA binding protein 1 gene) directly affects signaling, the cell cycle, and the development of the cell skeleton. Uncertainty surrounds WDHD1's function in BLCA immunity and prognosis, though. Using weighed gene co-expression network analysis (WGCNA), initially, we first identified 32 risk factors in genes with differential expression for this investigation. Then, using a variety of bioinformatic techniques and experimental validation, we examined the connections between WDHD1 and BLCA expression, clinical pathological traits, WDHD1-related proteins, upper-skin-intermediate conversion (EMT), immune cell immersion, convergence factors, immune markers, and drug sensitivity. The findings demonstrated that we constructed a 32-gene risk-predicting model where WDHD1 was elevated as a representative gene expression in BLCA and related to a range of clinical traits. Furthermore, high WDHD1 expression was a standalone predictor associated with a worse survival rate. The most commonly recruited cells and their evolutionary patterns were highlighted to better comprehend WDHD1's function in cancer. High WDHD1 expression was associated with many aspects of immunology. Finally, the study found that individuals with high expression of WDHD1 were drug-sensitive to four different broad-spectrum anti-cancer drugs. These results describe dynamic changes in the tumor microenvironment in BLCA and provide evidence for the hypothesis that WDHD1 is a novel biomarker of tumor development. WDHD1 may therefore be a useful target for the detection and management of BLCA.

Pt(IV) complexes loaded hollow copper sulfide nanoparticles for tumor chemo/photothermal/photodynamic therapy

Hollow CuS nanoparticles can achieve photothermal and photodynamic therapy (PDT) in tumor treatment. However, excessive GSH in the tumor cells will consume the reactive oxygen species produced by PDT and reduce the PDT effect. Cisplatin is a broad-spectrum antineoplastic drug that can be used in a variety of tumor treatments. However, cisplatin is cytotoxic to normal cells while it kills tumor cells. Therefore, we construct Pt(IV) complexes loaded hollow CuS nanoparticles to attenuate the toxicity of cisplatin and enhance the PDT effect of the hollow CuS nanoparticles. The nanoparticles were proved to be able to accumulate around the tumor site through the enhanced permeability and retention (EPR) effect to achieve a synergistic chemo/photothermal/photodynamic therapy.

In vitro Anti-trypanosomal Activity of Ethanolic and n-Hexane Extracts of Hymenocardia acida Stem Bark against Trypanosoma bruceibrucei and Trypanosoma congolense

Study’s Novelty/Excerpt The potential of Hymenocardia acida stem bark extracts as an anti-trypanosomal agent was assessed. The results indicate significant in vitro activity of both ethanolic and n-hexane extracts against Trypanosoma brucei brucei and Trypanosoma congolense. Hence, H. acida could be a valuable source for developing new, broad-spectrum trypanocidal drugs. Full Abstract The development of resistance by trypanosomes to existing trypanocidal drugs necessitates the need to search for safer and more effective alternative drugs with a broad spectrum of activity. Hence, this study was carried out to evaluate the in vitro anti-trypanosomal activity of ethanolic and n-hexane extracts of Hymenocardia acida stem bark against Trypanosoma congolense and Trypanosoma brucei brucei. The stem bark of H. acida was collected, identified, dried and then ground into fine powder. The powdered H. acida stem bark was extracted successively using n-hexane and ethanol to obtain n-hexane and ethanolic extracts, respectively. Phytochemical screening of the extracts was carried out using standard procedure. In vitro, anti-trypanosomal activity of different concentrations of the stem bark extracts (2.5 mg/mL to 40.0 mg/mL) were determined using motility assay with diminazeneaceturate (100 µg/mL) and phosphate buffered saline used as positive and negative controls, respectively. Results of the phytochemical screening revealed that flavonoids, alkaloids, saponins, and tannins were present in the ethanolic and n-hexane extracts. In vitro, the anti-trypanosomal activity of ethanolic and n-hexane extracts was observed against T. brucei brucei and T. congolense. Cessation of trypanosome motility was observed after 30 and 50 minutes of exposure to 2.5 mg/mL of ethanolic extract and n-hexane extract, respectively, for both T. brucei brucei and T. congolense. In conclusion, ethanolic and n-hexane extracts of H. acida exhibited anti-trypanosomal activity against Trypanosoma brucei brucei and Trypanosoma congolense. Hence, the plant could serve as a source of new trypanocidal drugs.

Frequency and Resistance Pattern of Carbapenemases (Class A & B) in E. Coli and Klebsiella Species

Abstract: Background: Carbapenems are potent and strong antibiotics that are usually reserved as last resort for bacteria possessing basic antibiotic resistance. These are broad spectrum drugs with more effective coverage against gram negative organisms. The antibiotic resistance pattern observed in bacteria possessing chromosomal group 2f β-lactamases is unique. It involves resistance to carbapenems while remaining sensitive to broadly attacking cephalosporins. Objective: This study aims to provide assessment of frequency of class A & B carbapenamase in E.coli and Klebsiella species producers and establish the resistance pattern from clinical isolates, at a tertiary care hospital in Karachi. Materials and Methods: This is a cross sectional, prospective study conducted at general hospital liyari, Karachi during Jan 2022- Jan 2023. Sample size was calculated as 400. Samples were divided into Urine samples of urinary tract infection patients (n=150), Pus sample from different sites (n=100), Respiratory tract, tracheal aspirates and sputum sample (n=100) and blood sample from suspected septicemia (n=50). SPSS-22 was used to enter and analyze the data. Chi-square test was used to analyze significance between two mean values, keeping ≤0.05 as significant p-value. Result: Distribution of microorganisms were reported as 120 (41.1%), 80 (28.5%), 2 (0.69%), 24 (8.36%), 55 (19.1%) and 6 (2%) of E. coli, Klebsiella Pneumonia, K.Oxytoca, Gram positive. Gram negative and Yeast respectively. The confirmed presence of carbapenemase (CP) was identifies in urine sample as 4/6 (26.6%) E.coli and 2/6 (13.3%) Klebsiella, while pus samples identifies 3/4 (20%) E.coli and 1/4 (6.6%) Klebsiella. Similarly samples of respiratory tract identifies 2/5 (13%) of E.coli and 3/5 (20%) of Klebsiella. The calculated p-value was insignificant with 0.834 and 0.913 for E.coli and Klebsiella respectively. Conclusion: This study concludes that E.coli is by far the most frequently reported microorganism from class B while class A organisms are in lower frequencies. CRE indicated higher resistance from non-β-lactam antibiotics, limiting treatment options. Keywords: Phenotypic, Detection, Resistance, Carbapenemases, E. coli, Klebsiella.

Activating transcription factor 6 contributes to cisplatin‑induced ototoxicity via regulating the unfolded proteins response

As a broad-spectrum anticancer drug, cisplatin is widely used in the treatment of tumors in various systems. Unfortunately, several serious side effects of cisplatin limit its clinical application, the most common of which are nephrotoxicity and ototoxicity. Studies have shown that cochlear hair cell degeneration is the main cause of cisplatin-induced hearing loss. However, the mechanism of cisplatin-induced hair cell death remains unclear. The present study aimed to explore the potential role of activating transcription factor 6 (ATF6), an endoplasmic reticulum (ER)-localized protein, on cisplatin-induced ototoxicity in vivo and in vitro. In this study, we observed that cisplatin exposure induced apoptosis of mouse auditory OC-1 cells, accompanied by a significant increase in the expression of ATF6 and C/EBP homologous protein (CHOP). In cell or cochlear culture models, treatment with an ATF6 agonist, an ER homeostasis regulator, significantly ameliorated cisplatin-induced cytotoxicity. Further, our in vivo experiments showed that subcutaneous injection of an ATF6 agonist almost completely prevented outer hair cell loss and significantly alleviated cisplatin-induced auditory brainstem response (ABR) threshold elevation in mice. Collectively, our results revealed the underlying mechanism by which activation of ATF6 significantly improved cisplatin-induced hair cell apoptosis, at least in part by inhibiting apoptosis signal-regulating kinase 1 expression, and demonstrated that pharmacological activation of ATF6-mediated unfolded protein response is a potential treatment for cisplatin-induced ototoxicity.

In Silico Comparative Analysis of Ivermectin and Nirmatrelvir Inhibitors Interacting with the SARS-CoV-2 Main Protease.

Exploring therapeutic options is crucial in the ongoing COVID-19 pandemic caused by SARS-CoV-2. Nirmatrelvir, which is a potent inhibitor that targets the SARS-CoV-2 Mpro, shows promise as an antiviral treatment. Additionally, Ivermectin, which is a broad-spectrum antiparasitic drug, has demonstrated effectiveness against the virus in laboratory settings. However, its clinical implications are still debated. Using computational methods, such as molecular docking and 100 ns molecular dynamics simulations, we investigated how Nirmatrelvir and Ivermectin interacted with SARS-CoV-2 Mpro(A). Calculations using density functional theory were instrumental in elucidating the behavior of isolated molecules, primarily by analyzing the frontier molecular orbitals. Our analysis revealed distinct binding patterns: Nirmatrelvir formed strong interactions with amino acids, like MET49, MET165, HIS41, HIS163, HIS164, PHE140, CYS145, GLU166, and ASN142, showing stable binding, with a root-mean-square deviation (RMSD) of around 2.0 Å. On the other hand, Ivermectin interacted with THR237, THR239, LEU271, LEU272, and LEU287, displaying an RMSD of 1.87 Å, indicating enduring interactions. Both ligands stabilized Mpro(A), with Ivermectin showing stability and persistent interactions despite forming fewer hydrogen bonds. These findings offer detailed insights into how Nirmatrelvir and Ivermectin bind to the SARS-CoV-2 main protease, providing valuable information for potential therapeutic strategies against COVID-19.

ПРИМЕНЕНИЕ СОВРЕМЕННЫХ ПРЕПАРАТОВ В ЛЕЧЕНИИ КОРОВ, БОЛЬНЫХ ГНОЙНО-КАТАРАЛЬНОЙ ФОРМОЙ МАСТИТА, В УСЛОВИЯХ РЕСПУБЛИКИ СЕВЕРНАЯ ОСЕТИЯ-АЛАНИЯ

Today for veterinary specialists the selection of effective treatment regimens for mastitis in cows in order to reduce treatment time with complete restoration of mammary gland function is an urgent task. For this purpose, we conducted research on the basis of the Iraf-Agro livestock complex in North Ossetia-Alania, on cows with various forms of mastitis. To determine the effectiveness of treatment regimens for mastitis in cows, we formed two groups of 12 heads each and an average weight of 350-400 kg. Nitotx and Cobactan were used as antibacterial drugs, which in a short time have a detrimental effect on both conditionally pathogenic and pathogenic microflora. Cows in the control group were administered Nitox intramuscularly at 48-hour intervals at a dose of 1 ml per 10 kg of live weight in combination with intracisternal injection of Mastifort into the affected quarter of the udder once a day for three days. The experimental group was treated with Cobactan at a dose of 2 ml per 45 kg of live weight, and Mastifort was administered to the affected quarter once and Dexofort 0.02 mg per kg of live weight was administered intramuscularly once. The therapeutic effectiveness of complex treatment of mastitis in cows of the experimental group before recovery from mild and moderate forms of mastitis averaged from 92 to 100%. While in the control this figure was 87-100%. The duration of treatment for cows in the experimental group for purulent catarrhal mastitis was on average 5 days, while for cows in the control group it was 8 days. The reduction in treatment time occurred due to the correctly selected combination of broad-spectrum antibacterial drugs in the form of complex therapy for purulent catarrhal mastitis in cows. Thus, the use of these drugs can reduce the time required to restore milk production.

Allosteric Regulation and Inhibition of Coronavirus 3CLpro Revealed by HDX-MS.

Coronavirus (CoV) infections have caused contagious and fatal respiratory diseases in humans worldwide. CoV 3-chymotrypsin-like proteases (3CLpro or Mpro) play an important role in viral maturation, and maintenance of their dimeric conformation is crucial for viral activity. Therefore, allosterically regulated dimerization of 3CLpro can be employed as a drug development target. Here, we investigated the allosteric regulatory mechanism of 3CLpro dimerization by using hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) technology. We found that the FLAG tag directly coupled to the N-finger of 3CLpro significantly increased HDX kinetics at the dimer interface, and 3CLpro transformed from a dimer to a monomer. The 3CLpro mutants of SARS-CoV-2, which are monomeric, also exhibited increased deuterium exchange. Binding of the allosteric inhibitor Gastrodenol to most betacoronavirus 3CLpros led to increased allosteric deuterium exchange, resulting in the monomeric conformation of the CoV 3CLpro upon binding. Molecular dynamics (MD) simulation analysis further indicated the molecular mechanism of action of Gastrodenol on CoV 3CLpro: binding of Gastrodenol to SARS-CoV-2 3CLpro destroyed the hydrogen bond in the dimer interface. These results suggest that Gastrodenol may be a potential broad-spectrum anti-betacoronavirus drug.

Investigation of miltefosine-model membranes interactions at the molecular level for two different PS levels modeling cancer cells

Miltefosine (MLT) is a broad-spectrum drug included in the alkylphospholipids (APL) used against leishmania and various types of cancer. The most crucial feature of APLs is that they are thought to only kill cancerous cells without harming normal cells. However, the molecular mechanism of action of APLs is not completely understood. The increase in the phosphatidylserine (PS) ratio is a marker showing the stage of cancer and even metastasis. The goal of this research was to investigate the molecular effects of miltefosine at the molecular level in different PS ratios. The effects of MLT on membrane phase transition, membrane orders, and dynamics were studied using DPPC/DPPS (3:1) and DPPC/DPPS (1:1) multilayer (MLV) vesicles mimicking DPPS ratio variation, Differential Scanning Calorimetry (DSC), and Fourier Transform Infrared spectroscopy (FTIR). Our findings indicate that miltefosine is evidence at the molecular level that it is directed towards the tumor cell and that the drug’s effect increases with the increase of anionic lipids in the membrane depending on the stage of cancer.

Hemay181: A novel SDC (sugar linked drug conjugate) for solid tumors targeting tumor microenvironment.

e15006 Background: Hemay181 is a novel broad-spectrum conjugated cytotoxic drug for treating advanced solid tumours. The drug exerts its inhibitory effect on tumour growth by releasing cytotoxic drug SN-38 in tumour tissues via β-glucuronidase (βGU) metabolism to inhibit the activity of topoisomerase I (TOP1). The water solubility of Hemay181 is increased > 5000-fold compared to SN-38. Hemay181 also binds to plasma albumin to form a macromolecular drug transporter, significantly improving the drug's pharmacokinetics. In addition, βGU has low activity in normal tissues, localised to the lysosomes, but is highly expressed in the hypoxic tumour microenvironment. Methods: In vitro and In Vivo studies showed Hemay181 inhibited growth in 29 human tumour cell lines and 16 human tumor Xenograft models, including colorectal cancer, gastric cancer, triple-negative breast cancer, head and neck cancer, pancreatic cancer, lung cancer, prostate cancer and melanoma. Results: In the absence of βGU, Hemay181 showed significantly weaker inhibitory activity than Hemay181+βGU or no significant inhibitory activity. In these In vitro studies with the addition of βGU, the activity was similar to SN-38, ranging from 3.9 nM to 159 nM. Hemay181 showed tumor selectivity with low activity against two normal human cell lines. The IC50 values of Hemay181 against Chang liver (normal liver cells) and MRC 5 (embryonic lung cells) were 318 nM and 14566 nM under non-enzymatic digestion conditions. In vivo, Hemay181 had significant inhibitory effects on the growth of human colorectal cancer, pancreatic cancer, head and neck cancer, triple-negative breast cancer, lung cancer, liver cancer, ovarian cancer and gastric cancer tumour models. The lowest effective dose of Hemay181 was 1.875mg/kg in the human colon cancer HCT116 model. Within the dose range of 3.75~60 mg/kg, the highest inhibitory rate of the above different tumour models could reach more than 90%. Hemay181 significantly reduced tumour volume compared to irinotecan, which only slowed the tumour growth rates. There was no significant decrease in the body weight of Hemay181 in these studies. In the colon cancer PDX model (CR0029) (30mg/kg), the tumour inhibition rate (TGI) was 78%. At 60mg/kg, in triple-negative breast cancer (BR1458) and non-small cell lung cancer (LU3075) PDX models, a TGI was 97% and 98%, respectively. At 60mg/kg, there was a significant tumour suppressive effect on larger tumours treated with irinotecan, with a reduction of tumour volume. In vitro , 1 μM Hemay181 is stable in CD1 mouse and SD rat plasma, with a minor degree of metabolism in beagle dog, cynomolgus monkey and human plasma. Conclusions: In summary, the novel broad-spectrum anti-tumour drug Hemay181 has the characteristics of high water solubility, tumour-targeting ability, low toxicity and side effects on normal tissues. It is under evaluation in ongoing clinical studies.

Antibacterial resistance and the cost of affecting demand: The case of UK antibiotics

Consumption of broad-spectrum antibiotics is associated with rising antimicrobial resistance (AMR) levels. The use of broad-spectrum drugs, particularly of cephalosporins, quinolones, and co-amoxiclav contributes the most to the rise in AMR. We use aggregate sales data on antibiotics from the UK to estimate structural demand models and reveal drug substitution patterns. We then simulate alternative tax schemes to evaluate the effectiveness of shifting demand from broad- to narrow-spectrum drugs. Our estimates suggest that these policies can be highly effective in demand management and come at a relatively low cost regarding changes in consumer and producer surplus.