Major Drug Classes Research Articles

Survivability of patients admitted for stroke in a primary stroke center, Penang, Malaysia: a retrospective 5-year study

BackgroundStroke is one of the most common noncommunicable diseases, with significant public health implications both globally and in Malaysia. The aim of this study was to evaluate post-stroke survivability as well as the major drug classes prescribed for hospitalized stroke patients.MethodsA 5-year retrospective study was carried out on the survival of stroke patients admitted to Hospital Seberang Jaya, a main stroke center in the state of Penang, Malaysia. Patients admitted for stroke were first identified using the local stroke registry database, and their medical records were then accessed for data collection, which included demographic information, comorbid conditions, and medications prescribed during admission.ResultsThe Kaplan-Meier overall survivability analysis performed indicated 50.5% survival for the duration of 10 days (p < 0.001) post-stroke. Ten-day survivability differences (p < 0.05) were observed for the categories of type of stroke (ischemic stroke (60.9%) and hemorrhagic stroke (14.1%)); stroke episodes (first (61.1%) and recurrent (39.6%)); anti-platelets (prescribed (46.2%) and not prescribed (41.5%)); statins (prescribed (68.7%) and not prescribed (28.1%)); anti-hypertensive (prescribed (65.4%) and not prescribed (45.9%)); and anti-infectives (prescribed (42.5%) and not prescribed (59.6%)) respectively. Higher risks of mortality were observed among patients with hemorrhagic stroke (HR: 10.61, p = 0.004); with 3 or more comorbidities (HR:6.60, p = 0.020); and not prescribed with statins and anti-diabetic. Patients prescribed anti-infectives, on the other hand, had a higher risk of mortality when compared to patients who did not receive anti-infectives (HR: 13.10, p = 0.019). The major drug classes prescribed for stroke patients were antiplatelet drugs (86.7%), statins (84.4%), and protein pump inhibitors (75.6%).ConclusionThe findings of the study are intended to encourage more non-stroke hospitals in Malaysia to increase their efforts in treating stroke patients, as early treatment can help reduce the severity of the stroke. With the incorporation of evidence-based data, this study also contributes to local data for comparison and improves the implementation of regularly prescribed stroke medication.

Adherence to Guideline Directed Medical Therapy in Heart Failure Patients in a Tertiary Hospital in Southern Nigeria: A Real-World Experience

<i>Background</i>: There is an increase in the incidence of heart failure among the sub-Saharan population. The use of guideline-directed medical therapy has been shown not only to reduce disease progression but also frequent hospitalization, morbidity, and mortality from heart failure. This study was directed at identifying which of the major drug class for treatment of heart failure was incorporated by the physicians in the area. <i>Methodology</i>: The study involved collection of data from patient’s records using an observational checklist. A total of 166 heart failure patients with reduced EF were recruited between the age ranges of 33 and 95 years. The medications prescribed, date of drug initiation and progress in optimization of therapy were assessed over a 1-year period and data analyzed using SPSS version 25. A p-value of 0.05 and below was considered statistically significant. <i>Results</i>: The result showed that the most prevalent causes of heart failure were hypertensive heart disease (70.5%), followed by dilated cardiomyopathy (15.7%) and valvular heart disease (6.6%). The use of diuretics was prevalent among study cohorts at 87.4%, followed by Mineralocorticoid antagonist (MRAs) (78.3%), ARB/ACEI/ARNI (68.1%), beta blockers (40.4%), and less than a third of patients were on SGLT2 inhibitors (28.9%). The dosing of heart failure medications was noticed to be fixed without up-titration of doses at intervals for most classes of GDMT except the MRAs. Only about 2.4% of the study cohorts had dose optimization over this period and most study patients were not on optimal maximal doses of heart failure therapy. <i>Conclusion</i>: The use of guideline directed medical therapy has improved amongst HF patients however up titration of doses remains a major problem amongst patients managed in our clinic. The implementation of a multi-disciplinary HF clinic focused on improvement of outcomes of HF patient is essential in improving not only the use of Guideline- directed medical therapy (GDMT) but up-titration to optimal doses for maximal benefits.

Variation in anthelmintic responses are driven by genetic differences among diverse C. elegans wild strains.

Treatment of parasitic nematode infections in humans and livestock relies on a limited arsenal of anthelmintic drugs that have historically reduced parasite burdens. However, anthelmintic resistance (AR) is increasing, and little is known about the molecular and genetic causes of resistance for most drugs. The free-living roundworm Caenorhabditis elegans has proven to be a tractable model to understand AR, where studies have led to the identification of molecular targets of all major anthelmintic drug classes. Here, we used genetically diverse C. elegans strains to perform dose-response analyses across 26 anthelmintic drugs that represent the three major anthelmintic drug classes (benzimidazoles, macrocyclic lactones, and nicotinic acetylcholine receptor agonists) in addition to seven other anthelmintic classes. First, we found that C. elegans strains displayed similar anthelmintic responses within drug classes and significant variation across drug classes. Next, we compared the effective concentration estimates to induce a 10% maximal response (EC10) and slope estimates of each dose-response curve of each strain to the laboratory reference strain, which enabled the identification of anthelmintics with population-wide differences to understand how genetics contribute to AR. Because genetically diverse strains displayed differential susceptibilities within and across anthelmintics, we show that C. elegans is a useful model for screening potential nematicides before applications to helminths. Third, we quantified the levels of anthelmintic response variation caused by genetic differences among individuals (heritability) to each drug and observed a significant correlation between exposure closest to the EC10 and the exposure that exhibited the most heritable responses. These results suggest drugs to prioritize in genome-wide association studies, which will enable the identification of AR genes.

MP75-14 ANTIHYPERTENSIVE CHOICES IN BLACK MEN CONTRIBUTE TO WORSENED RATES OF ED AND POOR HYPERTENSION CONTROL

You have accessJournal of UrologyCME1 Apr 2023MP75-14 ANTIHYPERTENSIVE CHOICES IN BLACK MEN CONTRIBUTE TO WORSENED RATES OF ED AND POOR HYPERTENSION CONTROL Denise Asafu-Adjei, Olivia Copelan, Cara Joyce, and Milan Patel Denise Asafu-AdjeiDenise Asafu-Adjei More articles by this author , Olivia CopelanOlivia Copelan More articles by this author , Cara JoyceCara Joyce More articles by this author , and Milan PatelMilan Patel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003349.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of death in Black men in the U.S. Erectile dysfunction (ED) serves as an indicator of CVD. CVD disproportionately affects Black men, with hypertension being the leading contributor. Several studies have cited ED side effects as a major factor in antihypertensive noncompliance in Black men, further exacerbating hypertension and ED. For decades, guidelines have recommended thiazides and calcium channel blockers as first line therapies for hypertension in Blacks, despite these options being associated with increased rates of ED. A 2022 retrospective study by Holt et al showed that race-based hypertension guidelines yielded no clear benefits in patient outcomes. We aimed to assess the clinical characteristics and treatment patterns of hypertensive men with ED at an academic medical center. METHODS: All men presenting for an initial visit for ED (primary ICD-10 code N52.9) between October 2015-July 2022 were included for analysis. The electronic health record was queried for patient demographics, provider type, comorbidities, and major drug classes of antihypertensives. Adjusted odds ratios were estimated from multivariable logistic regression (any CVD and any medications) and ordinal logistic regression (number of CVD comorbidities) analyses. RESULTS: Of 2020 men who presented for ED, the mean age was 55±14, 49.7% were White (n=987, 49.7%), 24.8% Black (n=493), and 18.9% Hispanic (n=375). The most common cardiovascular comorbidity was hypertension (n=960, 47.5%). Underlying cardiovascular disease burden was generally higher among Black men. Black men had higher odds of being prescribed an antihypertensive (aOR vs White: 1.50, 95% CI: 1.16-1.93; aOR vs Hispanic: 1.96, 95% CI: 1.45-2.67). However, Black men were prescribed beta blockers and thiazides significantly more than White and Hispanic men. White men were prescribed angiotensin receptor blockers (ARBs) significantly more than Black and Hispanic men. CONCLUSIONS: This study mirrors the effects of race-based hypertension guidelines. ARBs have typically been more favorable antihypertensives when considering sexual function. In this study, we showed that Black men were prescribed ARBs at significantly lower rates compared to White and Hispanic men. Given the significant ED side effects has on hypertension compliance, shifting traditional treatment regimens could lead to improved rates of hypertension control and erectile function. ED sits in a unique position to impact how we solve the CVD crisis. Source of Funding: none © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1085 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Denise Asafu-Adjei More articles by this author Olivia Copelan More articles by this author Cara Joyce More articles by this author Milan Patel More articles by this author Expand All Advertisement PDF downloadLoading ...

Urease of Aspergillus fumigatus Is Required for Survival in Macrophages and Virulence.

The number of patients suffering from fungal diseases has constantly increased during the last decade. Among the fungal pathogens, the airborne filamentous fungus Aspergillus fumigatus can cause chronic and fatal invasive mold infections. So far, only three major classes of drugs (polyenes, azoles, and echinocandins) are available for the treatment of life-threatening fungal infections, and all present pharmacological drawbacks (e.g., low solubility or toxicity). Meanwhile, clinical antifungal-resistant isolates are continuously emerging. Therefore, there is a high demand for novel antifungal drugs, preferentially those that act on new targets. We studied urease and the accessory proteins in A. fumigatus to determine their biochemical roles and their influence on virulence. Urease is crucial for the growth on urea as the sole nitrogen source, and the transcript and protein levels are elevated on urea media. The urease deficient mutant displays attenuated virulence, and its spores are more susceptible to macrophage-mediated killing. We demonstrated that this observation is associated with an inability to prevent the acidification of the phagosome. Furthermore, we could show that a nickel-chelator inhibits growth on urea. The nickel chelator is also able to reverse the effects of urease on macrophage killing and phagosome acidification, thereby reducing virulence in systemic and trachea infection models. IMPORTANCE The development of antifungal drugs is an urgent task, but it has proven to be difficult due to many similarities between fungal and animal cells. Here, we characterized the urease system in A. fumigatus, which depends on nickel for activity. Notably, nickel is not a crucial element for humans. Therefore, we went further to explore the role of nickel-dependent urease in host-pathogen interactions. We were able to show that urease is important in preventing the acidification of the phagosome and therefore reduces the killing of conidia by macrophages. Furthermore, the deletion of urease shows reduced virulence in murine infection models. Taken together, we identified urease as an essential virulence factor of A. fumigatus. We were able to show that the application of the nickel-chelator dimethylglyoxime is effective in both in vitro and in vivo infection models. This suggests that nickel chelators or urease inhibitors are potential candidates for the development of novel antifungal drugs.

Drugs Prescribing Trends in Three Polyclinics in Benghazi-Libya 2020

Background: There is an efforts made to improve drug prescribing practices in developing countries. The aim of present work was to comparing prescribing indicators, patient care, and missing information on prescriptions and identifying and assessing drug use patterns in three polyclinics in Benghazi city, Libya. Methods: In this descriptive cross section study a random sample of 1522 prescriptions were selected from three polyclinics include Ras-Ebida, Khalid Ibn-Elwalid and Al-Kish, over 4 months (July-October 2020). The data was collected through predesigned questionnaire. The prescriptions were analyzed for the following indicators: prescribing indicators, patient-care indicators and drug-use indicators. Results: A total of 1522 prescriptions (average = 507.3/clinic) were collected from the three polyclinics including 2329 prescribed (average = 1.4/prescription) items. Percentage of drugs prescribed with generic name was 0.0%, the percentage of prescriptions with antibiotics was 46.3%. The average of prescriptions of injections was 0.84. The average consultation time is 3.4 min and the average dispensing time was found to be 24 seconds. Major classes of drugs prescribed included analgesics, antibiotics, drugs used in medicine &amp; derma clinics, ophthalmic drugs, minerals &amp; vitamins, anti-inflammatory drugs, antihistaminic and antifungal drugs. The most prescribed analgesic was paracetamol (94.4%) and antibiotic was Augmentin (50.3%). In regarding prescribed drug in medicine clinics was found lisinopril (32.0%) and ophthalmic drug was cusicrom (36.8%). In addition, the majorities of prescribed vitamin were vitamin C (81.0%), for GIT drug was omeprazole (59.3%), and for dermatology was Fucidin (56.3%). While most prescribed anti-inflammatory was aspirin (52.4%), antihistaminic was loratidine (97.0%), for antifungal drug was flagyl (58.0%). Conclusion: Despite the efforts being made to improve prescribing habits and to rationalize the use of drugs, the obtained results confirm the deficiencies as reported earlier and suggest that methods of intervention should be initiated to improve prescribing trends in these polyclinics.

Safety and cardiometabolic efficacy of novel antidiabetic drugs

ABSTRACT Introduction There are three major drug classes discussed in this review: dipeptidyl dipeptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAS), and sodium-glucose cotransporter-2 (SGLT2) inhibitors. A literature review of the landmark cardiovascular outcome trials from 2008 to 2021 was conducted. Areas covered The cumulative data shown in this review suggest that in patients with Type 2 Diabetes (T2D), SGLT2 inhibitors and GLP-1 RAS may reduce cardiovascular (CV) risk. Specifically, in the heart failure (HF) population, SGLT2 inhibitors have shown a reduction in hospitalizations in some randomized controlled trials (RCTs). DPP4 inhibitors have not shown a similar reduction in CV risk and even exhibited an increase in hospitalizations for HF in one RCT. It is important to note that the DPP4 inhibitors did not demonstrate an increase in major CV events, with the exception of the increase in HF hospitalizations in the SAVOR TIMI 53 trial. Expert Opinion Future avenues of research to explore include the use of novel antidiabetic agents to reduce post-myocardial infarction (MI) CV risk and arrhythmias independent of their use as diabetic agents.

Using New Peak Detection to Solve Sequence Variants Analysis Challenges in Bioprocess Development.

Recombinant therapeutic proteins have become the major class of drugs to treat various human diseases in recent years. Low levels of protein sequence variants (SVs) have been reported to be present in recombinant therapeutic proteins. The consequences of potential unwanted immune response from SVs of recombinant therapeutic proteins have increasingly drawn attention from regulatory authorities and the biopharmaceutical industry. It is highly desirable to detect low-level SVs during clone selection and early process development as part of the control strategy. Peptide mapping with LC-MS/MS analysis has been applied as a powerful tool to characterize post-translation modifications of therapeutic proteins. Despite the recent advancements in mass spectrometry hardware and software, it is still quite challenging and time-consuming to detect and identify low-level SVs. In this study, we present an optimized approach using new peak detection to detect and identify low level SVs with high confidence and high speed. The new approach makes sequence variants analysis by LC-MS/MS broadly applicable and practical in bioprocess development of therapeutic proteins.

Antifungal drug concentration impacts the spectrum of adaptive mutations in Candida albicans.

Invasive fungal infections are a leading global cause of human mortality. Only three major classes of antifungal drugs are widely used, and resistance to all three classes can arise rapidly. The most widely prescribed antifungal drug, fluconazole, disseminates rapidly and reaches a wide range of concentrations throughout the body. The impact of drug concentration on the spectrum and effect of mutations acquired during adaptation is not known for any fungal pathogen, and how the specific level of a given stress influences the distribution of beneficial mutations has been poorly explored in general. We evolved 144 lineages from three genetically distinct clinical isolates of Candida albicans to four concentrations of fluconazole (0, 1, 8, and 64 μg/ml) and performed comprehensive phenotypic and genomic comparisons of ancestral and evolved populations. Adaptation to different fluconazole concentrations resulted in distinct adaptive trajectories. In general, lineages evolved to drug concentrations close to their MIC50 (the level of drug that reduces growth by 50% in the ancestor) tended to rapidly evolve an increased MIC50 and acquired distinct segmental aneuploidies and copy number variations. By contrast, lineages evolved to drug concentrations above their ancestral MIC50 tended to acquire a different suite of mutational changes and increased in drug tolerance (the ability of a subpopulation of cells to grow slowly above their MIC50). This is the first evidence that different concentrations of drug can select for different genotypic and phenotypic outcomes in vitro and may explain observed in vivo drug response variation.

Design, synthesis, molecular docking, dynamics and in vitro evaluation of novel 2- substituted-1-hydroxyethane-1, 1-bis(phosphonic acid) derivatives as human farnesyl pyrophosphate synthase inhibitors with expected anticancer activity.

Nitrogenous bisphosphonates (NBPs) are the major class of drugs that are used to treat osteoporosis. Recently, bisphosphonates (BPs) were reported to have an anticancer effect. These agents feature a high affinity that enables them to bind strongly to the human farnesyl pyrophosphate synthase enzyme. The correlation between this affinity and their anticancer effect was confirmed. To date, the use of an oxygen atom as an isosteric replacement for the electronegative nitrogen atom in NBPs has not been reported, and its ability to retain the linker length and bisphosphonate pharmacophore remains unknown. The main aim of this work was to design some isosteric bisphosphonate analogs with oxygen atoms and evaluation of their binding affinity and anticancer activity. The binding mode and stability of the designed compounds were achieved using human farnesyl pyrophosphate synthase (HFPPS) by docking and dynamic simulations. The compounds were synthesized, characterized, and screened for their anticancer activity against the breast cancer MCF-7 cell line and lung cancer A-549 cell line. The inhibitory activity of the tested compounds against HFPPS was evaluated. The compounds under investigation showed potential anticancer activity against the lung cell line with IC50 values of 41.7, 47.4, and 34.8 μg/ml in comparison to that of Risedronic acid (115 μg/ml). However, they do not exhibit potential activity against the breast cancer cell line. Compounds VII and VIII showed in vitro inhibition of human farnesyl pyrophosphate synthase with IC50 values of 82.2 and 98.8 μg/ml, respectively. Further optimization may be required in the future.

Differential Cardiovascular Outcomes of Each Antihypertensive Drug Class in Patients With Hypertension and Breast Cancer Undergoing Doxorubicin-Containing Chemotherapy.

The preemptive use of renin-angiotensin system (RAS) inhibitors may reduce doxorubicin (DOX)-related cardiotoxicity. Using the national insurance claims data of Korea, this study compared cardiovascular (CV) outcomes following the use of four major antihypertensive drug classes in patients with hypertension and breast cancer who underwent DOX-containing chemotherapy. A total of 4,722 patients with hypertension and breast cancer who underwent DOX-containing chemotherapy were included. The outcomes were compared between patients who used RAS inhibitors, calcium channel blockers (CCBs), beta-blockers (BBs), and thiazide and thiazide-like diuretics (TDs). The primary outcome was a composite of incident heart failure and serious ventricular arrhythmias, including ventricular tachycardia and fibrillation, ischemic heart disease, and stroke. In the propensity score-matched population, there were no significant differences in the primary outcome between RAS inhibitor and CCB users; however, patients with diabetes who used CCBs had a worse primary outcome than those who used RAS inhibitors (adjusted hazard ratio [aHR], 1.93; 95% confidence interval [CI], 1.06-3.51). BB and TD users had a worse primary outcome compared with RAS inhibitor (aHR, 1.88; 95% CI, 1.30-2.71 in BB users and aHR, 2.55; 95% CI, 1.37-4.75 in TD users) or CCB (aHR, 1.54; 95% CI, 1.09-2.16 in BB users and aHR, 2.08; 95% CI, 1.13-3.82 in TD users) users. RAS inhibitors are preferred for the treating hypertension and improving CV outcomes in patients with hypertension and breast cancer undergoing DOX-containing chemotherapy, particularly in patients with comorbid diabetes. However, CCBs are equivalent to RAS inhibitors and are more favorable than BBs and TDs in terms of improving CV outcomes.

Protein A Chromatography Purification for a Monoclonal Antibody from Process Development to Scale-up

Monoclonal antibodies have been established as a major product class of biotechnology-based drugs. The increasing demand of monoclonal antibodies has led pharmaceutical companies to adopt efficient production processes. Transferring monoclonal antibody production to the industrial manufacturing requires adequate effort in process development. The strategy to reduce development time and cost comprises high-throughput process development which is especially central for the rapid optimization of the purification process. Chromatography process is the backbone of the purification process that can deliver high purity but it requires significant resources. Combined with high-throughput process development approach, the chromatography process is easy to develop and scale-up from laboratory to manufacturing scale. Design of experiments helps high-throughput process development workflow to provide decision-support techniques. This approach ensures significantly decreased time and material needs while improving the chromatography process. Protein A affinity chromatography is one of the most important chromatographic steps because of its great performance and capabilities. Most of the working parameters can be predefined and are identical for several monoclonal antibodies. However, some parameters like elution pH, loading capacity, resin type need further optimization for each monoclonal antibody. In this study, the loading and elution parameters were screened for Protein A chromatography to identify the best purification conditions using the combination of Design of Experiments and high-throughput process development approach in micro-volume columns. Developed working parameters were used for scale-up and tested under robust process conditions. Specific chromatography conditions were applied in pilot-scale and data comparison was done with micro-volume columns, lab-column scale to validate high-throughput strategy approach

Naphthoquinones biflorin and bis-biflorin (Capraria biflora) as possible inhibitors of the fungus Candida auris polymerase: molecular docking, molecular dynamics, MM/GBSA calculations and in silico drug-likeness study

A new worldwide concern has emerged with the recent emergence of infections caused by Candida auris. This reflects its comparative ease of transmission, substantial mortality, and the increasing level of resistance seen in the three major classes of antifungal drugs. Efforts to create a better design for structure-based drugs that described numerous modifications and the search for secondary metabolic structures derived from plant species are likely to reduce the virulence of several fungal pathogens. In this context, the present work aimed to evaluate in silico two naphthoquinones isolated from the roots of Capraria biflora, biflorin, and its dimmer, bis-biflorin, as potential inhibitors of Candida auris polymerase. Based on the simulation performed with the two naphthoquinones, biflorin and bis-biflorin, it can be stated that bis-biflorin showed the best interactions with Candida auris polymerase. Still, biflorin also demonstrated favorable coupling energy. Predictive pharmacokinetic assays suggest that biflorin has high oral bioavailability and more excellent metabolic stability compared to the bis-biflorin analogue. constituting a promising pharmacological tool. Communicated by Ramaswamy H. Sarma

Novel Dual AChE and ROCK2 Inhibitor Induces Neurogenesis via PTEN/AKT Pathway in Alzheimer’s Disease Model

Alzheimer's disease (AD) is a progressive and complex neurodegenerative disease. Acetylcholinesterase inhibitors (AChEIs) are a major class of drugs used in AD therapy. ROCK2, another promising target for AD, has been associated with the induction of neurogenesis via PTEN/AKT. This study aimed to characterize the therapeutic potential of a novel donepezil-tacrine hybrid compound (TA8Amino) to inhibit AChE and ROCK2 protein, leading to the induction of neurogenesis in SH-SY5Y cells. Experiments were carried out with undifferentiated and neuron-differentiated SH-SY5Y cells submitted to treatments with AChEIs (TA8Amino, donepezil, and tacrine) for 24 h or 7 days. TA8Amino was capable of inhibiting AChE at non-cytotoxic concentrations after 24 h. Following neuronal differentiation for 7 days, TA8Amino and donepezil increased the percentage of neurodifferentiated cells and the length of neurites, as confirmed by β-III-tubulin and MAP2 protein expression. TA8Amino was found to participate in the activation of PTEN/AKT signaling. In silico analysis showed that TA8Amino can stably bind to the active site of ROCK2, and in vitro experiments in SH-SY5Y cells demonstrate that TA8Amino significantly reduced the expression of ROCK2 protein, contrasting with donepezil and tacrine. Therefore, these results provide important information on the mechanism underlying the action of TA8Amino with regard to multi-target activities.

Hypertension and hyperhomocysteinemia as modifiable risk factors for Alzheimer's disease and dementia: New evidence, potential therapeutic strategies, and biomarkers.

This review summarizes recent evidence on how mid-life hypertension, hyperhomocysteinemia (HHcy) and blood pressure variability, as well as late-life hypotension, exacerbate Alzheimer's disease (AD) and dementia risk.Intriguingly, HHcy also increases the risk for hypertension, revealing the importance of understanding the relationship between comorbid cardiovascular risk factors. Hypertension-induced dementia presents more evidently in women, highlighting the relevance of sex differences in the impact of cardiovascular risk. We summarize each major antihypertensive drug class's effects on cognitive impairment and AD pathology, revealing how carbonic anhydrase inhibitors, diuretics modulating cerebral blood flow, have recently gained preclinical evidence as promising treatment against AD. We also report novel vascular biomarkers for AD and dementia risk, highlighting thoseassociated with hypertension and HHcy. Importantly, we propose that future studies should consider hypertension and HHcy as potential contributors to cognitive impairment, and that uncovering the underlying molecular mechanisms and biomarkers would aid in the identification ofpreventive strategies.

High-sensitivity and high-resolution therapeutic antibody charge variant and impurity characterization by microfluidic native capillary electrophoresis-mass spectrometry

Therapeutic antibodies are a major class of pharmaceutical drugs used to treat a wide variety of diseases. They have several advantages including the high specificity and binding affinity to their molecular targets, and generally low immunotoxicity and mild adverse effects. The characterization of therapeutic antibodies is crucial to ensure drug efficacy and safety. Charge variant analysis can be used to examine the charge variant forms of therapeutic antibodies, which may reflect modifications that impact the drug quality. Native capillary electrophoresis-mass spectrometry (nCE-MS) analysis by an integrated ZipChip CE-MS system is an alternative and complementary method to cation-exchange chromatography and imaged capillary isoelectric focusing to support the characterization of charge variants. In this study, we performed nCE-MS analysis to evaluate the charge variants and impurities in therapeutic antibodies including immunoglobin G (IgG) monoclonal antibodies (mAbs), bispecific antibodies (bsAbs), and alternative formats such as therapeutic antibodies with addition or removal of antigen-binding domain. With the ZipChip CE-MS system, high-resolution charge variant separation was achieved for different types of therapeutic antibodies. Moreover, ZipChip nCE-MS analysis enabled high-sensitivity detection and identification of species with low abundance, including proteolytic cleavage and fragmentation in mAb, monospecific mAb impurities in bsAb, and O-glycosylation in alternative formats to support biopharmaceutical development and investigations.

Back to Life Treatment of Resistant Hypertension- An Update

Resistant hypertension is characterized by severe and persistent high blood pressure that is not normalized even after administering two or more antihypertensive medications, of which one is a diuretic. Although resistant hypertension is commonly encountered in clinics, the prognosis is largely unclear. Mounting evidence indicate that resistant hypertension is a multifactorial pathology of diverse etiology. A wide variety of predisposed factors including age, ethnicity, obesity, obstructive sleep apnea, primary aldosteronism, chronic kidney disease, excessive sympathetic activation and baroreflex dysfunction may be implicated. Although a cocktail of three or four major classes of antihypertensive drugs are recommended for treatment, the benefits of pharmacological interventions is limited in many patients, so surgical denervation of the renal artery is widely practiced to improving patient outcome. Thus, surgical interventions include (i) renal sympathetic denervation, (ii) renal sympathetic innervation, and (iii) device-based carotid baroreceptor electric stimulation may be considered back-to-life options to treat resistant hypertension. Moreover, over the years, these surgical procedures have been refined and fine-tuned to optimize benefits, while minimizing adverse effects. Thus, the current surgical practice has been greatly improved from the time of inception. Therefore, this review will focus on the role of surgical interventions in the treatment and management of resistant hypertension. With the global escalation of hypertension in epidemic proportions and the huge socio-economic burden posed to patients, their families and healthcare systems, it is of utmost importance to improve treatment strategies for all forms of hypertension including resistant hypertension.

Comparative kinase and cancer cell panel profiling of kinase inhibitors approved for clinical use from 2018 to 2020.

During the last two decades, kinase inhibitors have become the major drug class for targeted cancer therapy. Although the number of approved kinase inhibitors increases rapidly, comprehensive in vitro profiling and comparison of inhibitor activities is often lacking in the public domain. Here we report the extensive profiling and comparison of 21 kinase inhibitors approved by the FDA for oncology indications since June 2018 and 13 previously approved comparators on panels of 255 biochemical kinase assays and 134 cancer cell line viability assays. Comparison of the cellular inhibition profiles of the EGFR inhibitors gefitinib, dacomitinib, and osimertinib identified the uncommon EGFR p.G719S mutation as a common response marker for EGFR inhibitors. Additionally, the FGFR inhibitors erdafitinib, infigratinib, and pemigatinib potently inhibited the viability of cell lines which harbored oncogenic alterations in FGFR1-3, irrespective of the specific clinical indications of the FGFR inhibitors. These results underscore the utility of in vitro kinase inhibitor profiling in cells for identifying new potential stratification markers for patient selection. Furthermore, comparison of the in vitro inhibition profiles of the RET inhibitors pralsetinib and selpercatinib revealed they had very similar biochemical and cellular selectivity. As an exception, an NTRK3 fusion-positive cell line was potently inhibited by pralsetinib but not by selpercatinib, which could be explained by the targeting of TRK kinases in biochemical assays by pralsetinib but not selpercatinib. This illustrates that unexpected differences in cellular activities between inhibitors that act through the same primary target can be explained by subtle differences in biochemical targeting. Lastly, FLT3-mutant cell lines were responsive to both FLT3 inhibitors gilteritinib and midostaurin, and the PI3K inhibitor duvelisib. Biochemical profiling revealed that the FLT3 and PI3K inhibitors targeted distinct kinases, indicating that unique dependencies can be identified by combined biochemical and cellular profiling of kinase inhibitors. This study provides the first large scale kinase assay or cell panel profiling study for newly approved kinase inhibitors, and shows that comprehensive in vitro profiling of kinase inhibitors can provide rationales for therapy selection and indication expansion of approved kinase inhibitors.

How far are the new wave of mRNA drugs from us? mRNA product current perspective and future development.

mRNA products are therapies that are regulated from the post-transcriptional, pre-translational stage of a gene and act upstream of protein synthesis. Compared with traditional small molecule drugs and antibody drugs, mRNA drugs had the advantages of simple design, short development cycle, strong target specificity, wide therapeutic field, and long-lasting effect. mRNA drugs were now widely used in the treatment of genetic diseases, tumors, and viral infections, and are expected to become the third major class of drugs after small molecule drugs and antibody drugs. The delivery system technology was the key to ensuring the efficacy and safety of mRNA drugs, which plays an important role in protecting RNA structure, enhancing targeting ability, reducing the dose of drug delivery, and reducing toxic side effects. Lipid nanoparticles (LNP) were the most common delivery system for mRNA drugs. In recent years, mRNA drugs have seen rapid development, with the number of drugs on the market increasing each year. The success of commercializing mRNA vaccines has driven a wave of nucleic acid drug development. mRNA drugs were clinically used in genetic diseases, oncology, and infectious diseases worldwide, while domestic mRNA clinical development was focused on COVID-19 vaccines, with more scope for future indication expansion.

Allele specific PCR for a major marker of levamisole resistance in Haemonchus contortus

Haemonchus contortus is a haematophagous parasitic nematode that infects small ruminants and causes significant animal health concerns and economic losses within the livestock industry on a global scale. Treatment primarily depends on broad-spectrum anthelmintics, however, resistance is established or rapidly emerging against all major drug classes. Levamisole (LEV) remains an important treatment option for parasite control, as resistance to LEV is less prevalent than to members of other major classes of anthelmintics. LEV is an acetylcholine receptor (AChR) agonist that, when bound, results in paralysis of the worm. Numerous studies implicated the AChR sub-unit, ACR-8, in LEV sensitivity and in particular, the presence of a truncated acr-8 transcript or a deletion in the acr-8 locus in some resistant isolates. Recently, a single non-synonymous SNP in acr-8 conferring a serine-to-threonine substitution (S168T) was identified that was strongly associated with LEV resistance. Here, we investigate the role of genetic variation at the acr-8 locus in a controlled genetic cross between the LEV susceptible MHco3(ISE) and LEV resistant MHco18(UGA2004) isolates of H. contortus. Using single worm PCR assays, we found that the presence of S168T was strongly associated with LEV resistance in the parental isolates and F3 progeny of the genetic cross surviving LEV treatment. We developed and optimised an allele-specific PCR assay for the detection of S168T and validated the assay using laboratory isolates and field samples that were phenotyped for LEV resistance. In the LEV-resistant field population, a high proportion (>75%) of L3 encoded the S168T variant, whereas the variant was absent in the susceptible isolates studied. These data further support the potential role of acr-8 S168T in LEV resistance, with the allele-specific PCR providing an important step towards establishing a sensitive molecular diagnostic test for LEV resistance.