Different Mechanisms Of Action Research Articles

The Pivotal Role of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Hypertension Management and Cardiovascular and Renal Protection: A Critical Appraisal and Comparison of International Guidelines.

Arterial hypertension is the main preventable cause of premature mortality worldwide. Across Latin America, hypertension has an estimated prevalence of 25.5-52.5%, although many hypertensive patients remain untreated. Appropriate treatment, started early and continued for the remaining lifespan, significantly reduces the risk of complications and mortality. All international and most regional guidelines emphasize a central role for renin-angiotensin-aldosterone system inhibitors (RAASis) in antihypertensive treatment. The two main RAASi options are angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs). Although equivalent in terms of blood pressure reduction, ACEis are preferably recommended by some guidelines to manage other cardiovascular comorbidities, with ARBs considered as an alternative when ACEis are not tolerated. This review summarizes the differences between ACEis and ARBs and their place in the international guidelines. It provides a critical appraisal of the guidelines based on available evidence from randomized controlled trials (RCTs) and meta-analyses, especially considering that hypertensive patients in daily practice often have other comorbidities. The observed differences in cardiovascular and renal outcomes in RCTs may be attributed to the different mechanisms of action of ACEis and ARBs, including increased bradykinin levels, potentiated bradykinin response, and stimulated nitric oxide production with ACEis. It may therefore be appropriate to consider ACEis and ARBs as different antihypertensive drugs classes within the same RAASi group. Although guideline recommendations only differentiate between ACEis and ARBs in patients with cardiovascular comorbidities, clinical evidence suggests that ACEis provide benefits in many hypertensive patients, as well as those with other cardiovascular conditions.

Adhesive Capsulitis of the Ankle (Frozen Ankle): An Infrequent Syndrome.

Adhesive capsulitis, characterized by progressive fibrosis, causes a gradual, painful loss of both active and passive articular motion, leading to the final contracture of the joint capsule. The condition commonly referred to as "frozen ankle" (FA), which Goldman was the first to use, relates to the ankle joint and is challenging to both diagnose and treat. Data acquired from people who suffer from this type of damage in other joints such as the shoulder, hip, and wrist also exists. Despite the fact that a well-defined model for the medical management of FA does not exist, a wide spectrum of local treatments, both surgical and non-surgical, exist. This review gives an overview of the current scientific position of the frozen ankle in terms of evolutionary factors, etiology, the different mechanisms of action involved, current treatment options, and other possible interventions based on recent discoveries of pathophysiological mechanisms. The application of extracorporeal shockwave therapy, stretching exercises, and corticosteroid injections combined with physical therapy modalities that enhance pain management, range of motion, and functional capacity is highly advisable for the treatment of adhesive capsulitis, commonly known as "frozen joints". Furthermore, the addition of interventions both impacting and analyzing chronic hypoxia, low-grade inflammation, and sedentary life is proposed.

Herbicides for monochoria (Monochoria vaginalis) control in transplanted rice

AbstractIn Iran, monochoria is a noxious weed in fields of transplanted rice. Two field experiments were conducted to assess the efficacy of soil-applied and foliar-applied herbicides to control monochoria in transplanted rice. Prepackaged herbicides (triafamone plus ethoxysulfuron applied at 40 g ai ha−1, pyrazosulfuron-ethyl plus pretilachlor applied at 382.5 g ai ha−1, and pendimethalin plus clomazone applied at 1,200 g ai ha−1) reduced monochoria biomass by 100%, 100%, and 14%, respectively; and a single application of flucetosulfuron at 30 g ai ha−1, pendimethalin at 990 g ai ha−1, thiobencarb at 2,750 g ai ha−1, and pretilachlor at 1,000 g ai ha−1 reduced monochoria biomass by 100%, 99%, 75%, and 56%, respectively, compared with a nontreated control. Tank-mixed bensulfuron-methyl at 45 g ai ha−1 applied with pretilachlor, thiobencarb, or pendimethalin provided 100% control of monochoria. Rice height, and straw and grain yield were greater after herbicide treatments than those of the nontreated and hand-weeded controls, indicating the advantages of chemical control of monochoria over manual weeding. Full-season monochoria interference reduced rice grain yield by 32%. In the second study, the herbicides triafamone plus ethoxysulfuron, flucetosulfuron, 2,4-D at 1,080 g ai ha−1, dicamba plus 2,4-D at 928 g ai ha−1, bispyribac-sodium at 31.25 g ai ha−1, bentazon plus MCPA at 1,150 g ai ha−1, pyribenzoxim at 30 g ai ha−1, and propanil at 5,400 g ai ha−1 applied to foliage at 4- to 5-leaf seedlings of monochoria provided ≥97% control and prevented 100% of its regrowth, with the exception of propanil. This study shows that monochoria control can be achieved by using a variety of residual and foliar-applied herbicides with different mechanisms of action.

Potential alleviation of bone mineral density loss with Janus kinase inhibitors in rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by localized bone loss, general osteoporosis and increased fracture risks. Tumour necrosis factor inhibitors (TNFi), non-tumour necrosis factor inhibitors (non-TNFi) biologic, Janus kinase inhibitors (JAKi) had shown the suppression effects to osteoclast activation and improvement of bone mineral density (BMD). Anti-cyclic citrullinated peptide antibody (ACPA) is associated with osteoclast activation and the resultant bone loss. However, few studies have compared BMD changes among patients with RA treated with targeted therapies that have different mechanisms of action. This retrospective study recruited patients with RA who had undergone BMD testing twice. Changes in the BMD were compared using the generalized estimating equation (GEE) in treatment groups that received conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), TNFi, non-TNFi biologics, and JAKi. In total, 362 patients with RA were enrolled (csDMARDs, n = 153, TNFi, n = 71, non-TNFi biologics, n = 108, JAKi, n = 30). We observed greater changes in femoral BMD (left, 0.06, 95% CI 0.01-0.12, p = 0.016; right, 0.09, 95% CI 0.04-0.15, p = 0.001 by GEE) following JAKi treatment as compared with other treatments. Compared to the ACPA-negative group, patients with ACPA positivity exhibited greater improvement in the femoral BMD (left, 0.09, 95% CI 0.02-0.15, p = 0.008; right, 0.11, 95% CI 0.05-0.18, p = 0.001). Compared to other targeted therapies, JAKi might exert a more potent effect to prevent BMD loss, specifically in ACPA-positive patients with RA, and could be a potential therapeutic option to mitigate generalized bone loss. Key Points •JAKi therapy inhibits systemic bone loss in patients with RA. •ACPA-positive RA patients exhibited a greater BMD improvement than ACPA-negative RA patients. •JAKi might more potently prevent BMD decline than conventional synthetic or biological DMARDs.

Endoplasmic Reticulum Stress Inducer Dithiothreitol Affects the Morphology and Motility of Cultured Human Dermal Fibroblasts and Fibrosarcome HT1080 Cell Line

Some inducers of endoplasmic reticulum (ER) stress can affect the motility of normal and tumor cells. However, it is unknown what mechanisms mediate this effect and whether it is a consequence of ER stress. The aim of our work was to study the effect of the ER stress inducer dithiothreitol (DTT) on morphological features reflecting the locomotor properties of cells, as well as directly on the migratory properties of cultured human dermal fibroblasts and fibrosarcoma HT1080 cells. We have shown that DTT causes disruption of the organization of actin cytoskeleton in both types of cells, which is accompanied by a change in the cell surface and shape of cells, as well as a decrease in their spreading area. In addition, a decrease in the number of focal contacts was observed in dermal fibroblasts. DTT also reduced the motility of dermal fibroblasts and fibrosarcoma cells. To analyze cell motility and determine the moment of its change, we developed a method which showed that the change in the migratory properties of fibrosarcoma cells cultured with DTT began earlier than in dermal fibroblasts. Thus, activation of ER stress by DTT is accompanied by a change in the organization of the actin cytoskeleton and motility in normal and tumor human cells. Consequently, ER stress triggered by various inducers with different mechanisms of action affects the motility of normal and tumor cells, which must be taken into account when developing antitumor drugs that cause cell death through activation of ER stress.

The State of Clinical Trials in Pediatric Inflammatory Bowel Disease.

The gap between available biologic and small molecule therapy for inflammatory bowel disease for children and adults remains large. At present only 2 anti-TNF agents are licensed for pediatric use compared with multiple other agents with different mechanisms of action being used in adults. The reasons are many but largely revolve around the inadequate acceptance of adult efficacy data to children, and the reluctance of industry to commit to early pediatric drug development for fear of inadequate return on investment. We suggest common sense steps that need to be taken to improve this situation.

Патогенетические аспекты введения соединений с предполагаемым противоопухолевым действием в метрономном режиме (обзор)

Chemotherapy is the main treatment method for malignant neoplasms. Classical administration regimens for chemotherapeutic agents are accompanied by strong side effects. Thus, there is a need for a rational mode of administration that can increase the effectiveness of chemotherapy and reduce its side effects. Development of new antitumour drugs must involve testing their pharmacological activity at various administration regimens. At the stage of preclinical studies of new compounds with an alleged antitumour effect, determining an optimal dosage regimen is an urgent task for interdisciplinary research. This article analyses literature on the possible use and effectiveness of metronomic administration of antitumour drugs in clinical practice and in preclinical studies depending on the pathogenetic mechanism of their action. According to recent research, metronomic administration of antitumour and antimetastatic drugs is, undoubtedly, a rational way to solve the problem of severe side effects and poor drug tolerability in cancer patients. The greatest antitumour effectiveness in the metronomic regimen is achieved at combined administration of compounds with different mechanisms of action. In preclinical studies of new antitumour agents, it is important to adhere to the basic principles of developing a metronomic administration regimen: 1) at the testing stage, it is advisable to perform screening administration of low doses of new compounds along with a therapy with a known antitumour drug; 2) the minimum dose of the new compound can be calculated using its maximum tolerated dose (initial approximate series of administration in the amount of 1/10 of the maximum tolerated dose).

A Review of the Current Landscape of Hidradenitis Suppurativa Treatment Development.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by recurrent nodules and abscesses leading to subsequent scarring and tunnel formation. Despite being a fairly common disease with a significant impact on quality of life, only one drug, adalimumab, is currently US Food and Drug Administration (FDA)-approved for treating HS. However, there are many clinical trials underway to address this gap in care for patients with HS. All clinical trials related to HS as of 10/03/2022 were reviewed via clinicaltrials.gov. Studies on topical or systemic medical therapies were included and available results reported if they were ongoing or completed within 6 months prior to the search. Over 30 drugs with at least 20 different mechanisms of action are currently in development for the treatment of HS. While many of these are in phase 2 trials, several are undergoing phase 3 trials and will likely become viable treatment options in the next 5 years. Following years of limited treatment options for HS, drug development has accelerated significantly, forecasting more treatment possibilities and better disease control for many patients. J Drugs Dermatol. 2023;22(10):1021-1026  doi:10.36849/JDD.7339.

A CRITICAL APPRAISAL OF AUTISM SPECTRUM DISORDER IN TERMS OF AYURVEDA

Introduction: Autism spectrum disorders are conditions characterised by impaired social interaction communication skills and associated stereotypic, restrictive and repetitive behavioural patterns. According to a WHO report, it is estimated that worldwide, about one in 100 children has ASD. In India, according to the calculation of the Rehabilitation Council of India, the prevalence rate is 1 in 500 or 0.2%. Multimodal management approach of Ayurveda comprising herbal supplements, Ayurveda compounds, and panchakarma therapies. In Ayurvedic literature, Acharyas mention three types of chikitsa for the whole body and mind level- daivavyapashraya, yuksivyapashraya and satvavjaya chikitsa. These treatments benefit autistic children by a different mechanism of action and improve their quality of life. It concluded that Ayurveda provides safe, effective, cheap and untoward effect-free management along with enhancing the quality of life for people living with ASD and bringing back smiles on parents' faces.

Requiem for Rimonabant: Therapeutic Potential for Cannabinoid CB1 Receptor Antagonists after the Fall

The endocannabinoid system is found throughout the CNS and the body where it impacts many important physiological processes. Expectations were high that targeting cannabinoid receptors would prove therapeutically beneficial; pharmaceutical companies quickly seized on the appetitive and metabolic effects of cannabinoids to develop a drug for the treatment of weight loss. Alas, the experience with first-in-class cannabinoid type-1 receptor (CB1R) antagonist rimonabant is a now-classic cautionary tale of the perils of drug development and the outcome of rimonabant’s fall from grace dealt a blow to those pursuing therapies involving CB1R antagonists. And this most commercially compelling application of rimonabant has now been partially eclipsed by drugs with different mechanisms of action and greater effect. Still, blocking CB1 receptors causes intriguing metabolic effects, some of which appear to occur outside the CNS. Moreover, recent years have seen a startling change in the legal status of cannabis, accompanied by a popular embrace of ‘all things cannabis’. These changes combined with new pharmacological strategies and diligent medicinal chemistry may yet see the field to some measure of fulfillment of its early promise. Here, we review the story of rimonabant and some of the therapeutic niches and strategies that still hold promise after the fall.

Discovery of three-dimensional bicyclo[3.3.1]nonanols as novel heat shock protein 90 inhibitors

We developed an efficient synthetic method for constructing bicyclo[3.3.1]nonane, an sp3-carbon-rich three-dimensional scaffold consisting of two fused six-membered rings. Among the bicyclo[3.3.1]nonanols synthesized, several bicyclo[3.3.1]nonane derivatives were found to inhibit gene transcription by hypoxia-inducible factor-1 (HIF-1). The structure-activity relationship study revealed that the number of hydrophobic functional groups and a carboxylic acid moiety in the bicyclo[3.3.1]nonanols are important for inhibitory activities of both gene transcription by HIF-1 and cell growth. Bicyclo[3.3.1]nonanols fluctuated the amounts of client proteins of heat shock protein (HSP) 90 without inducing a heat shock response in cells and specifically inhibited the ATPase activity of HSP90. These results indicate that bicyclo[3.3.1]nonanols are novel HSP90 inhibitors with a different mechanism of action from conventional HSP90 inhibitors.

Antitumor and antibacterial activity of metabolites of endophytic Colletotrichum siamense isolated from coffee (Coffea arabica L. cv IAPAR-59).

Endophytic fungi produce a range of known metabolites and several others, not yet explored, which present important biological activities from the pharmaceutical and industrial perspective. Several studies have reported the diversity of endophytes in Coffea arabica plants, although few have been described in organic cultures. In the current paper, we describe the chemical profile of specialized metabolites in the ethyl acetate phase in a strain of the endophytic fungus Colletotrichum siamense associated with coffee (Coffea arabica L.) (Rubiaceae) and its potential against tumor cells and bacteria of medical and food importance. Cytotoxicity assays in tumor cells MCF-7 and HepG2/C3A were performed by MTT and microdilution in broth to evaluate the antibacterial action of metabolic extract. The antiproliferative assay showed promising results after 24h of treatment, with 50% injunction concentrations for the two cell types. UHPLC-MS/MS analyses with an electrospray ionization source were used to analyze the extracts and identify compounds of species Colletotrichum siamense, which is still little explored as a source of active metabolites. Many of these compounds observed in the endophytic need to be chemically synthesized in industry, at high costs, while production by the fungus becomes a chemically and economically more viable alternative. Pyrocatechol, gentisyl alcohol, and alpha-linolenic acid, associated with different mechanisms of action against tumor cells, were detected among the main compounds. The extract of the endophytic fungus Colletotrichum siamense presented several compounds with pharmacological potential and antibacterial activity, corroborating its potential in biotechnological applications.

Precision Medicine in Inflammatory Bowel Disease.

Ulcerative colitis and Crohn's disease are traditionally defined as the two main subtypes of inflammatory bowel disease. However, a more recent view considers IBD as a spectrum of heterogeneous phenotypes with consistent differences in clinical presentation and behaviors, likely explained by differences in underlying pathogenetic mechanisms. The etiology is still elusive, and the suggested pathogenesis is a complex interplay among genetic predisposition and abnormal immune response at the mucosal intestinal level, activated by only partially identified environmental triggers leading to altered intestinal permeability and impaired handling of gut microbiota. The undeniable continuous progress of medical therapy with more frequent shifts from traditional to more advanced modalities also underlines the actual unmet needs. We are using medications with completely different mechanisms of action, with a lack of predictive factors of outcomes and response and still an unsatisfactory rate of success. In addition, we are missing still valuable and accurate markers to predict disease progression and severity in order to avoid under- or over-treatment. In such a complex scenario, it is undoubtful that the application of artificial intelligence and machine learning algorithms may improve the management and pave the way for precision and eventually personalized medicine in these patients; however, there are still several challenges that will be the focus of this review.

Acaricidal activity of a 2-methoxy-clovan-9-ol rich fraction from Eugenia copacabanensis (Myrtaceae) extract on Rhipicephalus microplus (Acari: Ixodidae)

Rhipicephalus microplus (Ixodidae, canestrini, 1888) is an invasive ectoparasite of cattle which causes high economic losses in emerging countries such as Brazil. Phytochemical compounds have been tested as an alternative to synthetic acaricides due to potentially lower mammalian toxicity. This study evaluated the acaricidal activity against R. microplus of the 2-methoxy-clovan-9-ol rich fraction obtained from Eugenia copacabanensis Kiaersk.leaves, a little known Myrtaceae species from the Brazilian Atlantic Forest. This fraction was obtained by maceration with methanol, partition with n-hexane and purification by normal-phase column chromatography. GC-MS, 1H and 13C NMR and IR analysis contributed to the identification of a major compound as the sesquiterpene 2-methoxy-clovan-9-ol, reported for the first time for the Myrtaceae family. The fraction was tested against R. microplus unfed larvae and engorged females and a 93% larval mortality was observed at the concentration of 50 mg mL−1. Lower concentrations of the solution tested demonstrated a significant difference in egg mass weight, hatching and control percentage. Experiments with 50.0 mg mL−1 showed significative results, with lower concentration and maximum efficacy for both assays. The IC50 values for unfed larvae and engorged females were 21.76 and 11.13 mg mL−1, respectively. These results were similar to those obtained in other studies with isolated botanical compounds and essential oils. The lower IC50 for engorged females than for unfed R. microplus larvae had also been described for other plant materials, including plants from the same Myrtaceae family. The present result suggested different mechanisms of action of the compound on the reproductive biology of engorged females, improving its effect against egg viability. These results are important for tick control, suggesting that 2-methoxy-clovan-9-ol could be a potential natural acaricidal product against both R. microplus unfed larvae and engorged females.

Cell cycle and enzymatic activity alterations induced by ROS production in human neuroblastoma cells SH-SY5Y exposed to Fumonisin B1, Ochratoxin A and their combination

The presence of mycotoxins such as Fumonisin B1(FB1) and Ochratoxin A (OTA) in food and feed has become a threat to human and animal health since they can produce several afflictions. Different mechanisms of action by which they exercise their cytotoxic activity have been attributed to them, including the production of reactive oxygen species (ROS). For this reason, a measurement of the production of ROS species, and an evaluation of the intrinsic cell enzymatic antioxidant activity, including glutathione peroxidase (GPx), glutathione transferase (GTS), and catalase (CAT) together with a cytotoxicity and cell cycle assay have been performed in undifferentiated SH-SY5Y cells exposed to FB1, OTA and [FB1 + OTA] after 24 h and 48 h. FB1 and OTA. Monitoring of intracellular ROS production was carried out by the H2-DCFDA probe; while spectrometry analysis of absorbances was used for measuring GPx, GST and CAT activity. Finally, cell proliferation and cell cycle distribution were studied by flow cytometry. When cells were treated with OTA, an increase in GPx and GST activity was observed compared to FB1 and [FB1 + OTA]; conversely, a decrease in CAT activity was observed when cells were exposed to OTA coinciding with the results observed for ROS measurement. Regarding the cell cycle, when cells were exposed to OTA, a decrease in G0/G1 was detected, revealing an arrest of cell division for SH-SY5Y cells at the concentrations studied.

Addition of Neostigmine and Atropine to Conventional Management of Postdural Puncture Headache after Cesarean Section: A Randomized Controlled Study

Abstract Background Post dural puncture headache (PDPH) is a known side effect following spinal anesthesia occurring in 2.5-40% of patients, it typically starts after 2 days but may be delayed up to 2 weeks and almost resolves spontaneously within a few days. Classic symptoms of PDPH consist of photophobia, nausea, vomiting, neck stiffness, tinnitus, diplopia and dizziness. Objective The aim of the study is to know if the neostigmine and atropine can improve PDPH treatment when added to conventional management after cesarean sections. Patients and Methods After obtaining approval from research ethics committee of Faculty of Medicine, Ain Shams University and after obtaining informed written consents from the patients. The study was conducted in the operating theaters of Ain Shams University Hospitals. The study period was 6 months after approval of the protocol, computer generated simple randomization. Patients with PDPH and a VAS < 5 were randomly allocated to receive either: Group 1: Slow intravenous injection with 20 µg/Kg neostigmine and 10 µg/Kg atropine in 20 ml 0.9% Saline given over 5 minutes every 8 hours up to 72 hours, Group 2: 20 ml of 0.9% saline intravenous every 8 hours. Results In this study, we compared the efficacy of neostigmine versus placebo (Both groups received the conventional management) in treating the PDPH, All of the 2 groups (neostigmine and Placebo) were effective in lowering VAS scores at 24, 48 and 72 h after headache's onset but neostigmine alleviated the pain more effectively and with rapid onset. The mean VAS score was significantly lower in neostigmine group compared with other group 6, 12, 24, 36, 48 and 72 h after start of medications (p < 0.001 for all of them) Placebo group 6, 12, 24, 36, 48, and 72 h (p < 0.001 for all of them). This may cause the drug to be one of the potential new drug therapies for such distressing condition, especially with its different mechanism of action that differs from other drugs. Conclusion Neostigmine/atropine was effective in treating PDPH after only 2 doses. Neostigmine can pass the choroid plexus but not the blood–brain barrier. The central effects of both drugs influence both cerebrospinal fluid secretion and cerebral vascular tone, which are the primary pathophysiological changes in PDPH. The results are consistent with previous studies and clinical reports of neostigmine activity.

Efficacy and safety of flurbiprofen‑axetil combined with nalbuphine pretreatment on remifentanil‑induced postoperative hyperalgesia: A randomized clinical trial.

Remifentanil-induced hyperalgesia (RIH) is a common and complicated issue in patients undergoing laparoscopic cholecystectomy (LC), which significantly reduces patient satisfaction. The present trial was designed to clarify the individual and combined effects of flurbiprofen-axetil and nalbuphine on remifentanil-induced hyperalgesia. This randomized double-blind clinical trial included 120 adult patients who underwent LC at The Second People's Hospital of Wuhu. The individuals were randomized into a flurbiprofen-axetil group (F group), nalbuphine group (N group), flurbiprofen-axetil combined with nalbuphine group (FN group) and saline group (S group). The four groups were given flurbiprofen-axetil (50 mg, iv.), nalbuphine (0.1 mg/kg, iv.), flurbiprofen-axetil (50 mg, iv.) combined with nalbuphine (0.1 mg/kg, iv.) or normal saline respectively prior to skin incision. The primary outcome was the postoperative mechanical pain thresholds at the inner forearm and peri-incisional area. The secondary outcomes were the visual analog scale (VAS) and Ramsay sedation scale at 0.5, 1, 4 and 24 h after surgery, and any other adverse events. The pain threshold of the medial forearm in the FN group did not differ from that in the F and N groups at 24 h after surgery (P=0.310 and P=0.910, respectively). However, the pain threshold around the incision in FN group was significantly lower than that in F and N groups 24 h after surgery (P=0.001). The VAS of the F group, N group and FN group were all significantly lower than that in the S group at 0.5, 1 and 24 h after surgery (P<0.001). No significant differences were observed in the incidence of adverse events between the four groups. Single flurbiprofen-axetil and single nalbuphine effectively prevented RIH 24 h after surgery in LC. The combination of the two analgesic drugs, with different mechanisms of action, was not superior to single therapy. The present study was registered with the Chinese Clinical Trial Registry (registration no. ChiCTR2100045347).

High-content screening of drug combinations of an mPGES-1 inhibitor in multicellular tumor spheroids leads to mechanistic insights into neuroblastoma chemoresistance.

High-throughput drug screening enables the discovery of new anticancer drugs. Although monolayer cell cultures are commonly used for screening, their limited complexity and translational efficiency require alternative models. Three-dimensional cell cultures, such as multicellular tumor spheroids (MCTS), mimic tumor architecture and offer promising opportunities for drug discovery. In this study, we developed a neuroblastoma MCTS model for high-content drug screening. We also aimed to decipher the mechanisms underlying synergistic drug combinations in this disease model. Several agents from different therapeutic categories and with different mechanisms of action were tested alone or in combination with selective inhibition of prostaglandin E2 by pharmacological inhibition of microsomal prostaglandin E synthase-1 (mPGES-1). After a systematic investigation of the sensitivity of individual agents and the effects of pairwise combinations, GFP-transfected MCTS were used in a confirmatory screen to validate the hits. Finally, inhibitory effects on multidrug resistance proteins were examined. In summary, we demonstrate how MCTS-based high-throughput drug screening has the potential to uncover effective drug combinations and provide insights into the mechanism of synergy between an mPGES-1 inhibitor and chemotherapeutic agents.

Glycyrrhiza glabra L. Extracts and Other Therapeutics against SARS-CoV-2 in Central Eurasia: Available but Overlooked.

In Central Eurasia, the availability of drugs that are inhibitors of the SARS-CoV-2 virus and have proven clinical efficacy is still limited. The aim of this study was to evaluate the activity of drugs that were available in Kazakhstan during the acute phase of the epidemic against SARS-CoV-2. Antiviral activity is reported for Favipiravir, Tilorone, and Cridanimod, which are registered drugs used for the treatment of respiratory viral infections in Kazakhstan. A licorice (Glycyrrhiza glabra) extract was also incorporated into this study because it offered an opportunity to develop plant-derived antivirals. The Favipiravir drug, which had been advertised in local markets as an anti-COVID cure, showed no activity against SARS-CoV-2 in cell cultures. On the contrary, Cridanimod showed impressive high activity (median inhibitory concentration 66 μg/mL) against SARS-CoV-2, justifying further studies of Cridanimod in clinical trials. Tilorone, despite being in the same pharmacological group as Cridanimod, stimulated SARS-CoV-2 replication in cultures. The licorice extract inhibited SARS-CoV-2 replication in cultures, with a high median effective concentration of 16.86 mg/mL. Conclusions: The synthetic, low-molecular-weight compound Cridanimod suppresses SARS-CoV-2 replication at notably low concentrations, and this drug is not toxic to cells at therapeutic concentrations. In contrast to its role as an inducer of interferons, Cridanimod is active in cells that have a genetic defect in interferon production, suggesting a different mechanism of action. Cridanimod is an attractive drug for inclusion in clinical trials against SARS-CoV-2 and, presumably, other coronaviruses. The extract from licorice shows low activity against SARS-CoV-2. At the same time, high doses of 2 g/kg of this plant extract show little or no acute toxicity in animal studies; for this reason, licorice products can still be considered for further development as a safe, orally administered adjunctive therapy.

Levodropropizine: A promising peripherally acting antitussive agent

Cough is one of the most frequent symptom for patients to seek medical attention. Cough can be associated with many disease processes and the ultimate treatment depends on determining the etiology and diagnosis. Antitussive agents with different mechanisms of action have been developed in the past, but there are still very few medications that seem to be effective without any side effects especially related to central nervous system (CNS). Levodropropizine is an antitussive agent which acts peripherally and is a non-opioid cough medication that is in use since many years as a symptomatic therapy for cough. Levodropropizine has potent antitussive activity mainly due to peripheral effects by inhibiting the activation of vagal C-fibers. In fact, levodropropizine has been proven effective in controlling cough and is devoid of the central depressant effect. Levodropropizine oral suspension (30mg/5ml) is approved by drug approval body of India, Drug Controller General of India (DCGI) for the management non-productive cough in adults. Levodropropizine is approved in some of the European countries and in Asian countries. It is widely used in Republic of Korea for the symptomatic treatment of cough in both adults and children above 2 years of age. Levodropropizine has the utmost level of benefit in comparison with central antitussive agents namely codeine and dextromethorphan for the patients with cough due to acute and chronic bronchitis.