Class Of Drugs Research Articles

Bioanalytical method development and validation for the quantification of raloxifene hydrochloride from mice plasma by RP-HPLC

Raloxifene hydrochloride (RLX) belongs to the Selective estrogen receptor modulator (SERM) class of drugs, exhibiting diverse affinity to estrogen receptors. The drug is known for its anti-cancer and anti-osteoporosis activity. The current study employs a Reverse Phase High-Performance Liquid Chromatography (RP-HPLC) method that is sensitive and time-efficient for quantitative evaluation of RLX from mice plasma, using tamoxifen citrate as an internal standard (IS). The protein precipitation technique was used to extract the RLX and IS. RLX was separated using a C8 column with an isocratic elution of a mobile phase consisting of acetonitrile and Milli-Q water (pH 3) at a 1 mL/min flow rate. The ultraviolet (UV) detection of the analyte and IS were carried out at 287 nm. The linearity plot was constructed in the range of 100–3200 ng/mL with a correlation coefficient of r2 ≥ 0.9996. The inter-day and intra-day accuracy and precision were found to be within acceptable limits. Stability studies revealed that the analyte remained stable. The validated RP-HPLC method was successfully applied to quantify RLX after oral administration in mice, and the pharmacokinetic (PK) parameters were established. The present RP-HPLC method could be a beneficial tool for the fast and reliable estimation of future PK interactions, PK analysis of formulations, and therapeutic drug monitoring.

Heat-induced structural and chemical changes to a computationally designed miniprotein.

The de novo design of miniprotein inhibitors has recently emerged as a new technology to create proteins that bind with high affinity to specific therapeutic targets. Their size, ease of expression, and apparent high stability makes them excellent candidates for a new class of protein drugs. However, beyond circular dichroism melts and hydrogen/deuterium exchange experiments, little is known about their dynamics, especially at the elevated temperatures they seemingly tolerate quite well. To address that and gain insight for future designs, we have focused on identifying unintended and previously overlooked heat-induced structural and chemical changes in a particularly stable model miniprotein, EHEE_rd2_0005. Nuclear magnetic resonance (NMR) studies suggest the presence of dynamics on multiple time and temperature scales. Transiently elevating the temperature results in spontaneous chemical deamidation visible in the NMR spectra, which we validate using both capillary electrophoresis and mass spectrometry (MS) experiments. High temperatures also result in greatly accelerated intrinsic rates of hydrogen exchange and signal loss in NMR heteronuclear single quantum coherence spectra from local unfolding. These losses are in excellent agreement with both room temperature hydrogen exchange experiments and hydrogen bond disruption in replica exchange molecular dynamics simulations. Our analysis reveals important principles for future miniprotein designs and the potential for high stability to result in long-lived alternate conformational states.

Efficacy and safety of sympathetic mapping and ablation of renal nerves for the treatment of hypertension (SMART): 6-month follow-up of a randomised, controlled trial

Previous trials of renal denervation (RDN) have been designed to investigate reduction of blood pressure (BP) as the primary efficacy endpoint using non-selective RDN without intraoperatively verified RDN success. It is an unmet clinical need to map renal nerves, selectively denervate renal sympathetic nerves, provide readouts for the interventionalists and avoid futile RDN. We aimed to examine the safety and efficacy of renal nerve mapping/selective renal denervation (msRDN) in patients with uncontrolled hypertension (HTN) and determine whether antihypertensive drug burden is reduced while office systolic BP (OSBP) is controlled to target level (＜140mmHg). We conducted a randomized, prospective, multicenter, single-blinded, sham-controlled trial. The study combined two efficacy endpoints at 6 months as primary outcomes: The control rate of patients with OSBP ＜140mmHg (non-inferior outcome) and change in the composite index of antihypertensive drugs (Drug Index) in the treatment versus Sham group (superior outcome). This design avoids confounding from excess drug-taking in the Sham group. Antihypertensive drug burden was assessed by a composite index constructed as: Class N (number of classes of antihypertensive drugs)×(sum of doses). 15 hospitals in China participated in the study and 220 patients were enrolled in a 1:1 ratio (msRDN vs Sham). The key inclusion criteria included: age (18-65 years old), history of essential HTN (at least 6 months), heart rate (≥70 bpm), OSBP (≥150mmHg and ≤180mmHg), ambulatory BP monitoring (ABPM, 24-h SBP ≥130mmHg or daytime SBP ≥135mmHg or nighttime SBP ≥120mmHg), renal artery stenosis (＜50%) and renal function (eGFR ＞45mL/min/1.73m2). The catheter with both stimulation and ablation functions was inserted in the distal renal main artery. The RDN site (hot spot) was selected if SBP increased (≥5mmHg) by intra-renal artery (RA) electrical stimulation; an adequate RDN was confirmed by repeated electronic stimulation if no increase in BP otherwise, a 2nd ablation was performed at the same site. At sites where there was decreased SBP (≥5mmHg, cold spot) or no BP response (neutral spot) to stimulation, no ablation was performed. The mapping, ablation and confirmation procedure was repeated until the entire renal main artery had been tested then either treated or avoided. AftermsRDN, patients had to follow a predefined, vigorous drug titration regimen in order to achieve target OSBP (＜140mmHg). Drug adherence was monitored by liquid chromatography-tandem mass spectrometry analysis using urine. This study is registered with ClinicalTrials.gov (NCT02761811) and 5-year follow-up is ongoing. Between July 8, 2016 and February 23, 2022, 611 patients were consented, 220 patients were enrolled in the study who received standardized antihypertensive drug treatments (at least two drugs) for at least 28 days, presented OSBP ≥150mmHg and ≤180mmHg and metall inclusion and exclusion criteria. In left RA and right RA, mapped sites were 8.2 (3.0) and 8.0 (2.7), hot/ablated sites were 3.7 (1.4) and 4.0 (1.6), cold spots were 2.4 (2.6) and 2.0 (2.2), neutral spots were 2.0 (2.1) and 2.0 (2.1), respectively. Hot, cold and neutral spots was 48.0%, 27.5% and 24.4% of total mapped sites, respectively. At 6M, the Control Rate of OSBP was comparable between msRDN and Sham group (95.4% vs 92.8%, p=0.429), achieved non-inferiority margin-10% (2.69%; 95% CI-4.11%, 9.83%, p ＜ 0.001 for non-inferiority); the change in Drug Index was significantly lower in msRDN group compared to Sham group (4.37 (6.65) vs 7.61 (10.31), p=0.010) and superior to Sham group (-3.25; 95% CI-5.56,-0.94, p=0.003), indicating msRDN patients need significantly fewer drugs to control OSBP ＜140mmHg. 24-hour ambulatory SBP decreased from 146.8 (13.9) mmHg by 10.8 (14.1) mmHg, and from 149.8 (12.8) mmHg by 10.0 (14.0) mmHg in msRDN and Sham groups, respectively (p<0.001 from Baseline; p>0.05 between groups). Safety profiles were comparable between msRDN and Sham groups, demonstrating the safety and efficacy of renal mapping/selective RDN to treat uncontrolled HTN. The msRDN therapy achieved the goals of reducing the drug burden of HTN patients and controlling OSBP <140mmHg, with only approximately four targeted ablations per renal main artery, much lower than in previous trials. SyMap Medical (Suzhou), LTD, Suzhou, China.

Supervised and unsupervised learning models for pharmaceutical drug rating and classification using consumer generated reviews

Optimization of medication therapy depends on maximizing benefits and minimizing side effects of medications. This research showed how a joint approach using text mining, natural language processing, and machine learning can provide information for personalized and optimized medication therapy. Reviews on the benefits and side effects of prescription and over-the-counter medications were used to determine how well an integrated supervised and unsupervised learning could learn medication satisfaction. Supervised learning with naïve-Bayes, non-linear support vector machine with radial basis function kernels, and random forests with CART decision trees was measured by a micro-aggregated Matthews correlation coefficient and a macro-averaged F1 measure. Random forests outperformed support vector machines by almost 250% and naive-Bayes by 600% on the two evaluation metrics. All models did better with three rating levels, instead of five. Topic modelling and stacked cluster analysis were coupled with parts-of-speech tagging and text mining operations to establish a robust data preprocessing procedure to eliminate noisy features from the data. Unsupervised topic modelling and clustering represented an exploratory validation of how easy supervised classification would be. Well-defined latent topics were discovered including topics on “sleep quality”, “the opportunity to get back to work”, and “weight gain”. Overlapping clusters revealed that incorporating more information on social, demographic, or medical history variables could improve classifier performance. This research provided evidence that medication satisfaction can be learned with carefully designed joint supervised, unsupervised, and natural language learning techniques.

For Debate: The 2023 European Society of Hypertension guidelines - cause for concern.

Originally, the beta-blockers were equally ranked alongside the other antihypertensive drug classes. Things changed when two major long-term randomized controlled trials, ASCOT-BPLA and LIFE showed that the patients receiving the beta-blockers based regimes suffered 25-30% more strokes than those receiving a calcium channel blocker based regime or an angiotensin receptor blocker based regime. The inferiority of the beta-blockers at stroke prevention was not due to differences in blood pressure control during the follow-up period in both trials. The 2023 European Society of Hypertension (ESH) guidelines still argue in favour of beta-blockers that their clinical inferiority was simply to lesser blood pressure reduction rather than class effect. The analysis argues that the return of beta-blockers as a first-line option for the management of uncomplicated hypertension by the ESH is a cause for concern and should be reconsidered.

Cholinesterase Inhibitory and In Silico Toxicity Assessment of Thirty-Four Isoquinoline Alkaloids - Berberine as the Lead Compound

Cholinesterase (ChE) inhibitors used currently in clinics for the treatment of Alzheimer's disease (AD) are the most prescribed drug class with nitrogen-containing chemical formula. Galanthamine, the latest generation anti-ChE drug, contains an isoquinoline structure. The aim of the current study was to investigate the inhibitory potential of thirty-four isoquinoline alkaloids, e.g. (-)-adlumidine, β-allocryptopine, berberine, (+)-bicuculline, (-)-bicuculline, (+)-bulbocapnine, (-)-canadine, (±)-chelidimerine, corydaldine, (±)-corydalidzine, (-)-corydalmine, (+)-cularicine, dehydrocavidine, (+)-fumariline, (-)-fumarophycine, (+)-α-hydrastine, (+)-isoboldine, 13-methylcolumbamine, (-)-norjuziphine, norsanguinarine, (-)-ophiocarpine, (-)-ophiocarpine-N-oxide, oxocularine, oxosarcocapnine, palmatine, (+)-parfumine, protopine, (+)-reticuline, sanguinarine, (+)-scoulerine, (±)-sibiricine, (±)-sibiricine acetate, (-)-sinactine, and (-)-stylopine isolated from several Fumaria (fumitory) and Corydalis species towards acetyl- (AChE) and butyrylcholinesterase (BChE) by microtiter plate assays. The alkaloids with strong ChE inhibition were proceeded to molecular docking simulations as well as in silico toxicity screening for their mutagenic capacity through VEGA QSAR (AMES test) consensus model and VEGA platform as statistical approaches. The inputs were evaluated in a simplified molecular input-line entry system (SMILES). ChE inhibition assays indicated that the highest AChE inhibition was caused by berberine (IC50: 0.72 ± 0.04 µg/mL), palmatine (IC50: 6.29 ± 0.61 µg/mL), β-allocryptopine (IC50: 10.62 ± 0.45 µg/mL), (-)-sinactine (IC50: 11.94 ± 0.44 µg/mL), and dehydrocavidine (IC50: 15.01 ± 1.87 µg/mL) as compared to that of galanthamine (IC50: 0.74 ± 0.01 µg/mL), the reference drug with isoquinoline skeleton. Less number of the tested alkaloids exhibited notable BChE inhibition. Among them, berberine (IC50: 7.67 ± 0.36 µg/mL) and (-)-corydalmine (IC50: 7.78 ± 0.38 µg/mL) displayed a stronger inhibition than that of galanthamine (IC50: 12.02 ± 0.25 µg/mL). The mutagenic activity was shown for β-allocryptopine, (+)- and (-)-bicuculline, (±)-corydalidzine, (-)-corydalmine, (+)-cularicine, (-)-fumarophycine, (-)-norjuziphine, (-)-ophiocarpine-N-oxide, (+)-scoulerine, (-)-sinactine, and (-)-stylopine by means of in silico experiments. The results obtained by molecular docking simulations of berberine, palmatine, and (-)-corydalmine suggested that the estimated free ligand-binding energies of these compounds inside the binding domains of their targets are reasonable to make them capable of establishing strong polar and nonpolar bonds with the atoms of the active site amino acids. Our findings revealed that berberine, palmatin, and (-)-corydalmine stand out as the most promising isoquinoline alkaloids in terms of ChE inhibition. Among them, berberine has displayed a robust dual inhibition against both ChEs and could be evaluated further as a lead compound for AD.

The impact of expanded access programs for systemic anticancer therapy in an Irish cancer centre.

Expanded access programs (EAPs) allow cancer patients with unmet clinical need to obtain access to pre-authorisation treatments. There is no standardised process for implementing these programs nationally, and real-world data on their impact is lacking. This study aimed to evaluate the prevalence of such EAPs and their impact in a cancer centre. Data relating to adult cancer patients treated via EAPs from 2011 to 2021 in three Cork university hospitals was collated. Descriptive statistics were employed to get an overview of the impact these programs currently have on cancer care provision. We identified 193 patients who accessed EAPs during the study period, availing of 33 separate drugs for a total of 50 different cancer indications. The prevalence of EAP usage was shown to have been trending upwards in recent years with a total of 189 programs being accessed throughout the period. Drugs provided were from a number of different anti-cancer drug classes, particularly targeted therapies (n = 18) and immune checkpoint inhibitors (n = 17). Cancers from a wide range of both solid and liquid tumour types were treated with EAP drugs, and patients treated were from across a broad spectrum of ages (26-82, SD 11.99). EAPs have an increasing role in accessing novel cancer therapies in our community and by extension nationally. Equity of EAP access would be facilitated by a national registry of available agents which we have established. Assessment of their benefits and toxicities would be enhanced by the requirement for a real-world database as a condition of EAP approval.

MIND4OLIGOS: Determining the Monoisotopic Mass of Oligonucleotides Observed in High-Resolution Mass Spectrometry.

Oligonucleotide therapeutics have emerged as an important class of drugs offering targeted therapeutic strategies that complement traditional modalities, such as monoclonal antibodies and small molecules. Their unique ability to precisely modulate gene expression makes them vital for addressing previously undruggable targets. A critical aspect of developing these therapies is characterizing their molecular composition accurately. This includes determining the monoisotopic mass of oligonucleotides, which is essential for identifying impurities, degradants, and modifications that can affect the drug efficacy and safety. Mass spectrometry (MS) plays a pivotal role in this process, yet the accurate interpretation of complex mass spectra remains challenging, especially for large molecules, where the monoisotopic peak is often undetectable. To address this issue, we have adapted the MIND algorithm, originally developed for top-down proteomics, for use with oligonucleotide data. This adaptation allows for the prediction of monoisotopic mass from the more readily detectable, most-abundant peak mass, enhancing the ability to annotate complex spectra of oligonucleotides. Our comprehensive validation of this modified algorithm on both in silico and real-world oligonucleotide data sets has demonstrated its effectiveness and reliability. To facilitate wider adoption of this advanced analytical technique, we have encapsulated the enhanced MIND algorithm in a user-friendly Shiny application. This online platform simplifies the process of annotating complex oligonucleotide spectra, making advanced mass spectrometry analysis accessible to researchers and drug developers. The application is available at https://valkenborg-lab.shinyapps.io/mind4oligos/.

Population-based nanopore sequencing of the HIV-1 pangenome to identify drug resistance mutations.

HIV-1 drug resistance genotypic tests have primarily been performed by Sanger sequencing of gene segments encoding different drug target proteins. Since the number of targets has increased with the addition of a new class of antiretroviral drugs, a simple high-throughput system for assessing nucleotide sequences throughout the HIV-1 genome is required. Here, we developed a new solution using nanopore sequencing of viral pangenomes amplified by PCR. Benchmark tests using HIV-1 molecular clones demonstrated an accuracy of up to 99.9%. In addition, validation tests of our protocol in 106 clinical samples demonstrated high concordance of drug resistance and tropism genotypes (92.5% and 98.1%, respectively) between the nanopore sequencing-based results and archived clinical determinations made based on Sanger sequencing data. These results suggest that our new approach will be a powerful solution for the comprehensive survey of HIV-1 drug resistance mutations in clinical settings.

Microbiological and molecular studies on a multidrug-resistant Pseudomonas aeruginosa from a liver transplant patient with urinary tract infection in Egypt.

Pseudomonas aeruginosa is an opportunistic pathogen responsible for complicated UTIs and exhibits high antibiotic resistance, leading to increased mortality rates, especially in cases of multidrug-resistant strains. This study aimed to investigate the antibiotic susceptibility patterns and genomic characterization of XDR strains identified in end-stage liver disease patients who underwent liver transplants. In this study, a number of 30 individuals who underwent liver transplants were registered. Ninety urine and 60 wound site swab samples were collected and processed for culturing, identification, and antimicrobial sensitivity. Extensively drug-resistant strain EMARA01 was confirmed through Sanger sequencing and was then processed for whole genome sequencing to characterize the genomic pattern. Sequencing data were processed for de novo assembly using various tools and databases, including genome annotation, serotype identification, virulence factor genes, and antimicrobial resistance gene. Pangenome analysis of randomly selected 147 reference strains and EMAR01 sequenced strain was performed using the Bacterial Pan Genome Analysis (BPGA) software. Of these total examined samples, nosocomial infection due to P. aeruginosa was detected in twelve patients' samples. AST analysis showed that P. aeruginosa strains exhibit resistance to tobramycin, erythromycin, and gentamicin, followed by piperacillin and ofloxacin, and no strains exhibit resistance to meropenem and imipenem. The CARD database identified 59 AMR genes similar to the EMAR01 strain genome and mostly belong to the family involved in the resistance-nodulation-cell division (RND) antibiotic efflux pump. Five genes; nalC, nalD, MexR, MexA, and MexB, exhibit resistance to 14 classes of antibiotics, while two AMR; CpxR, and OprM, exhibit resistance to 15 classes of drugs. Pangenome analysis revealed that the pan-genome remained open, suggesting the potential for acquiring accessory and unique genes. Notably, the genes predominantly involved in amino acid transport metabolism were identified using the KEGG database. This study provides valuable insights into the antimicrobial resistance profile, genetic features, and genomic evolution of P. aeruginosa strains causing UTIs in liver transplant patients. The findings emphasize the significance of comprehending AMR mechanisms and genetic diversity in P. aeruginosa for developing effective treatment strategies and infection control measures.

Increased Absorption of Thyroxine in a Murine Model of Hypothyroidism Using Water/CO2 Nanobubbles

Thyroxine (T4) is a drug extensively utilized for the treatment of hypothyroidism. However, the oral absorption of T4 presents certain limitations. This research investigates the efficacy of CO2 nanobubbles in water as a potential oral carrier for T4 administration to C57BL/6 hypothyroid mice. Following 18 h of fasting, the formulation was administered to the mice, demonstrating that the combination of CO2 nanobubbles and T4 enhanced the drug’s absorption in blood serum by approximately 40%. To comprehend this observation at a molecular level, we explored the interaction mechanism through which T4 engages with the CO2 nanobubbles, employing molecular simulations, semi-empirical quantum mechanics, and PMF calculations. Our simulations revealed a high affinity of T4 for the water–gas interface, driven by additive interactions between the hydrophobic region of T4 and the gas phase and electrostatic interactions of the polar groups of T4 with water at the water–gas interface. Concurrently, we observed that at the water–gas interface, the cluster of T4 formed in the water region disassembles, contributing to the drug’s bioavailability. Furthermore, we examined how the gas within the nanobubbles aids in facilitating the drug’s translocation through cell membranes. This research contributes to a deeper understanding of the role of CO2 nanobubbles in drug absorption and subsequent release into the bloodstream. The findings suggest that utilizing CO2 nanobubbles could enhance T4 bioavailability and cell permeability, leading to more efficient transport into cells. Additional research opens the possibility of employing lower concentrations of this class of drugs, thereby potentially reducing the associated side effects due to poor absorption.

A Review on the Effects of Physical Activity and Curcumin Supplementation on the Toxicity of Disease Caused by Anthracyclines with a Review of Doxorubicin

Introduction: Today, cancer is known as one of the biggest public health problems and the second cause of death in the world, and due to its high prevalence, it is considered as one of the main health problems all over the world. There are many treatment strategies, including chemotherapy, to treat cancer in patients. Chemotherapy is actually the use of antineoplastic drugs alone or in combination with other drugs. Of course, these drugs can also damage the function of healthy cells and cause many side effects. Anthracyclines are one of the most widely class of drugs used in cancer chemotherapy, doxorubicin, daunorubicin, and epirubicin are among the anthracycline drug group, the most widely used of which is doxorubicin, which causes cardiotoxicity in the patients undergoing chemotherapy, and unfortunately, there is no definite and reliable treatment for it. Various strategies have been used to reduce the toxic effects of doxorubicin on non-target tissues, including the use of medicinal plants, diet and various types of long-term exercises with the aim of increasing tissue antioxidant levels. Therefore, determining the appropriate exercise and nutrition program considering the physical conditions for cancer patients who are undergoing chemotherapy treatment is so important. Therefore, the current review study aimed to determine the effects of DOX cytotoxicity on heart tissue and the benefits of regular physical activity and curcumin supplementation were investigated and discussed. Conclusion: The use of curcumin with aerobic exercise is likely to be a potentially useful candidate to protect against the toxicity of blood cells caused by the drug doxorubicin, which is used to prevent the growth and progression of cancer cells in patients

Association of Oral Health and Periodontal Disease with Hypertension: A Cross-Sectional Study

Objectives: The association of orodental and cardiovascular health has been an area of extensive research for many years. As per American Heart Association hypertension 2017 guidelines, good periodontal health is associated with better systolic blood pressure control. However, there have been conflicting results for hypertension and dental correlation in a few other studies. Moreover, there are no recognized oral manifestations, seen in patients with hypertension. Indian data on this subject are scarce. Therefore, the present study was contemplated to determine the frequency and nature of oral manifestations in hypertensive patients as compared to normotensive patients. Materials and Methods: In this observational cross-sectional study, participants were divided into two groups. Group A included 40 hypertensive subjects and group B included 40 healthy normotensive volunteers. Oral symptoms such as dry mouth, altered taste sensation, mouth odor, and bleeding from gums were noted. An oral examination was performed to check periodontal pockets, lichenoid reactions, and gingival hyperplasia. Russell’s Periodontal Index was used to estimate gingival and periodontal health. Results: The mean age of patients in the hypertensive group was higher than normotensive groups (53.8 ± 11 vs. 42.45 ± 12, P = 0.001). Oral symptoms in the form of dry mouth, halitosis, and altered taste were reported in 60%, 52.5%, and 42.5% of hypertensive patients which were significantly higher as compared to the control group. Bleeding gums, lichenoid reactions, and gingival enlargement were also significantly higher in hypertensive than normotensive groups. The mean value of Russell’s index was 1.09 ± 0.41 in group A which was significantly different from group B (0.05 ± 0.10). Gingival hyperplasia and gum bleeding were predominantly found in patients on calcium channel blockers, whereas lichenoid reactions were significantly present in patients on angiotensin receptor blockers. Hyposalivation was reported with all four classes of antihypertensive drugs, predominantly diuretics. Conclusion: The orodental involvement in hypertensive subjects has a wide spectrum from mildly symptomatic halitosis and dryness of mouth to severe bleeding gums, lichenoid lesions, irreversible bone loss, and periodontitis that may require dental visits and interventions. The documented mucosal changes can also be attributed to antihypertensive drugs. Regular dental examinations should be made part of routine screening programs of hypertensive patients to protect them from various oral complications and subsequent inflammation-mediated changes in vasculature endothelium.

The use of biologics and JAK inhibitors in the management of moderate to severe Hidradenitis Suppurativa treatment: a scoping review.

This scoping review aims to characterize the use of biologics and Janus Kinase inhibitors (JAKi) in the treatment of Hidradenitis Suppurativa (HS), which is a chronic inflammatory condition. A comprehensive literature search was conducted in PubMed/NCBI, Embase, Web of Science databases, and the Clinicaltrials.gov register. The search included interventional trials assessing the use of biologics or JAKi in HS, with no geographic or time restrictions. Secukinumab and adalimumab were identified as the only two drugs approved by the FDA for treating moderate to severe HS in adults. Several other drug classes showed promising results based on clinical studies reviewed. IL-12/23 inhibitor ustekinumab demonstrated improvements in disease severity scores and HiSCR rates in small trials. IL-17 inhibitors such as brodalumab, bimekizumab, and CJM112 showed preliminary positive responses in early-phase clinical studies and case reports. While evidence was mixed, some TNF-α inhibitors such as infliximab provided benefits according to a randomized controlled trial, though etanercept trials yielded non-significant or inconsistent findings. Larger, well-designed studies are required to further establish their efficacy and safety, but biologics and JAKis show potential as alternative treatment options for moderate to severe HS. The findings of this review contribute to the growing interest among patients and to enhancing the understanding of physician's regarding potential alternative therapeutic options for HS and provide a basis for further research in this field.

Computational Screening for the Dipeptidyl Peptidase-IV Inhibitory Peptides from Putative Hemp Seed Hydrolyzed Peptidome as a Potential Antidiabetic Agent

Dipeptidyl peptidase-IV (DPPIV) inhibitory peptides are a class of antihyperglycemic drugs used in the treatment of type 2 diabetes mellitus, a metabolic disorder resulting from reduced levels of the incretin hormone GLP-1. Given that DPPIV degrades incretin, a key regulator of blood sugar levels, various antidiabetic medications that inhibit DPPIV, such as vildagliptin, sitagliptin, and linagliptin, are employed. However, the potential side effects of these drugs remain a matter of debate. Therefore, we aimed to investigate food-derived peptides from Cannabis sativa (hemp) seeds. Our developed bioinformatics pipeline was used to identify the putative hydrolyzed peptidome of three highly abundant proteins: albumin, edestin, and vicilin. These proteins were subjected to in silico digestion by different proteases (trypsin, chymotrypsin, and pepsin) and then screened for DPPIV inhibitory peptides using IDPPIV-SCM. To assess potential adverse effects, several prediction tools, namely, TOXINpred, AllerCatPro, and HemoPred, were employed to evaluate toxicity, allergenicity, and hemolytic effects, respectively. COPID was used to determine the amino acid composition. Molecular docking was performed using GalaxyPepDock and HPEPDOCK, 3D visualizations were conducted using the UCSF Chimera program, and MD simulations were carried out with AMBER20 MD software. Based on the predictive outcomes, FNVDTE from edestin and EAQPST from vicilin emerged as promising candidates for DPPIV inhibitors. We anticipate that our findings may pave the way for the development of alternative DPPIV inhibitors.

Modern problems of preclinical studying feed additives for animals and ways to solve them

Resource-saving technology in agriculture is the use of stimulating additives in animal feeding rations that promote better absorption of feed. One of the measures to prevent toxicosis in industrial livestock and poultry farming is to determine the toxicity of feed. The variety of existing methods makes it possible to determine the level and class of drug toxicity at the initial stage. In the developed classification for veterinary drugs, the cumulation coefficient, therapeutic breadth index and dose level of toxic effect are used, which makes it possible to predict the nature and degree of their danger at the stage of preclinical study of feed additives. To determine the listed indicators, it is necessary to establish LD50and the cumulation coefficient. Since feed additives are introduced into the body through the digestive tract, during preclinical studies they are studied and classified according to their hepatotoxic effect. Bilirubin, albumin, and enzyme activity contained in the blood (glutamate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and the ratio of alanine aminotransferase to alkaline phosphatase) are used as markers. It is necessary to determine the de Ritis, Schmidt coefficient and the R index. This will minimize the intake of toxic feed additives into the animals’ bodies and will contribute to an increase in their productivity.

Knowledge, Attitudes, and Practices about Hyperuricemia and Gout in Community Health Workers and Patients with Diabetes

Hyperuricemia exhibits a high incidence among individuals with diabetes; however, the significance of hyperuricemia and gout is often underestimated. This study aimed to assess the knowledge, attitude, and practice of hyperuricemia and gout among community health workers and patients with diabetes. Two questionnaires were designed to investigate knowledge, attitudes, and practices of hyperuricemia and gout among community health workers and patients with diabetes in Chenghua District, Chengdu, from August 2021 to January 2022. A total of 709 community health workers were included, whose average score was 17.74/30. Approximately half of general practitioners (GPs) demonstrated knowledge regarding the target serum uric acid levels for hyperuricemia and gout. Only 11.2% of GPs were fully aware of the preferred medicine for acute gout. The majority of GPs (86.7%) demonstrated limited awareness regarding the contraindications associated with colchicine, while a significant proportion (65.1%) lacked knowledge about the specific classes of drugs that inhibit uric acid synthesis. Among the 508 patients with diabetes included in this survey, 32.3% demonstrated awareness of hyperuricemia, while 60.8% exhibited knowledge regarding gout. The average score attained by these individuals was recorded at 7.21 out of a total of 26 points. The majority of patients with diabetes (87.8%) held the mistaken belief that hyperuricemia definitely led to the development of gout. Almost 66% agreed that a massage or a hot compress could be used when acute gouty arthritis attacks. The knowledge rate of hyperuricemia and gout among community health workers was moderate, while it was low in patients with diabetes.

Prescrizione di antibiotici in Pronto Soccorso pediatrico

Background - The emergency department (ED) is an important site of care in which inappropriate antibiotic prescribing and the consequent impact of antibiotic-resistant bacteria can be reduced. Objective - The aim of this retrospective study was to investigate the pattern of antibiotic prescriptions for upper respiratory tract infections in children examined in 3 different ED located in Azienda Ospedaliera Bergamo-Est and to highlight the possibilities for a reduction and a more appropriate use of this class of drugs, overprescribed in paediatric age. Methods - A retrospective observational study was performed on children younger than 18 years of age, who were examined in a general hospital near Bergamo from January 2020 to September 2022. The proportion and type of antibiotic prescription according to demographic, clinical, laboratory and imaging data were determined. Results - 4,731 children were included in the study and 894 (18.9%) received an antibiotic prescription. The prevalence of antibiotic prescription varies with age, with a peak at 1-5 years (21.7%), and depending on the diagnosis, from 2.5 % in children with influenza to 78.4% in children with otitis. Amoxicillin/clavulanate was the most prescribed antibiotic (47% of antibiotic prescriptions), while the percentage of amoxicillin prescription was low (36%). In patients examined for pharyngotonsillitis, amoxicillin was prescribed to 43% of those treated with antibiotics. Conclusions - This study supports the need for a new comprehensive approach to ensure successful antibiotic stewardship. A guide to the use of new diagnostic tests (molecular biology, genome sequencing and immunoenzymatic assays) in a “diagnostic stewardship” perspective may be helpful; however, clinical evaluation remains of fundamental and central importance.

Alzheimer’s disease and its treatment–yesterday, today, and tomorrow

Alois Alzheimer described the first patient with Alzheimer’s disease (AD) in 1907 and today AD is the most frequently diagnosed of dementias. AD is a multi-factorial neurodegenerative disorder with familial, life style and comorbidity influences impacting a global population of more than 47 million with a projected escalation by 2050 to exceed 130 million. In the USA the AD demographic encompasses approximately six million individuals, expected to increase to surpass 13 million by 2050, and the antecedent phase of AD, recognized as mild cognitive impairment (MCI), involves nearly 12 million individuals. The economic outlay for the management of AD and AD-related cognitive decline is estimated at approximately 355 billion USD. In addition, the intensifying prevalence of AD cases in countries with modest to intermediate income countries further enhances the urgency for more therapeutically and cost-effective treatments and for improving the quality of life for patients and their families. This narrative review evaluates the pathophysiological basis of AD with an initial focus on the therapeutic efficacy and limitations of the existing drugs that provide symptomatic relief: acetylcholinesterase inhibitors (AChEI) donepezil, galantamine, rivastigmine, and the N-methyl-D-aspartate receptor (NMDA) receptor allosteric modulator, memantine. The hypothesis that amyloid-β (Aβ) and tau are appropriate targets for drugs and have the potential to halt the progress of AD is critically analyzed with a particular focus on clinical trial data with anti-Aβ monoclonal antibodies (MABs), namely, aducanumab, lecanemab and donanemab. This review challenges the dogma that targeting Aβ will benefit the majority of subjects with AD that the anti-Aβ MABs are unlikely to be the “magic bullet”. A comparison of the benefits and disadvantages of the different classes of drugs forms the basis for determining new directions for research and alternative drug targets that are undergoing pre-clinical and clinical assessments. In addition, we discuss and stress the importance of the treatment of the co-morbidities, including hypertension, diabetes, obesity and depression that are known to increase the risk of developing AD.

Lipopolysaccharide-induced alterations in the liver metabolome of St. Croix and Suffolk sheep

The development of resistance in parasites due to overuse of anthelmintics has resulted in a marked decrease in the efficacy of these drug classes. Recent research efforts have focused on exploring alternatives such as selection for parasite-resistant breeds with the implication that immunocompetence may align with parasite resistance. Two breeds that are often investigated are the St. Croix (STC), a resistant hair breed, and Suffolk (SUF), a susceptible wool breed sheep. The liver plays a vital role in metabolism in the body and metabolizes lipopolysaccharide (LPS), which triggers whole body response through the production of appropriate metabolites, cytokines and immune cells. The objective of this study was to investigate the breed differences in liver metabolome of sheep, with divergent resistance to parasites, in response to LPS. Both STC and SUF sheep (n = 9/breed) were challenged with LPS intravenously. Rectal temperatures and sheep grimace score (SGS) were recorded hourly, for each animal, and averaged across the study for both breeds. The average rectal temperature throughout the study was similar for STC and SUF sheep (40.4°C and 40.2°C respectively), but the pattern of response was different. STC had an average SGS of 0.8 while SUF had an average of 3.3. Liver biopsies were collected from 3 sheep that were not challenged with LPS (HR0; n = 3/breed), two hours post-challenge (HR2; n = 3/breed), and six hours post-challenge (HR6; n = 3/breed). Liver tissue samples were subjected to quantitative untargeted metabolome analysis using chemical isotope labeling/liquid chromatography-mass spectrometry. Pathway analysis of the HR0 metabolome data revealed that 8 pathways (and their associated metabolites) including beta-alanine metabolism, arginine and proline metabolism and glutathione metabolism were altered (false discovery rate-adjusted P-value (FDR) ≤ 0.05) between STC and SUF sheep. At HR2, 10 altered pathways such as folate biosynthesis, taurine and hypotaurine metabolism, and glutathione metabolism. At HR6, only 2 pathways (glycerophospholipid metabolism and purine metabolism) were altered (FDR ≤ 0.05) between STC and SUF sheep. Results highlight the differences in hepatic metabolome and physiological response to LPS challenge that exist between SUF and STC. These findings suggest breed-specific differences in metabolic response to immune challenge, potentially influencing the divergent resistance of the two breeds to parasitic infections.