Synthetic Drug Research Articles

Efficacy and Safety of Risankizumab for Active Psoriatic Arthritis: 100-Week Results from the Phase3 KEEPsAKE1 Randomized Clinical Trial.

Patients with psoriatic arthritis (PsA) require treatment providing durable long-term efficacy in different disease domains as well as safety. We present 100-week efficacy and safety results of risankizumab in patients with active PsA and previous inadequate response/intolerance to ≥ 1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR). KEEPsAKE1 (NCT03675308) is a global phase3 study, including a 24-week, double-blind, placebo-controlled and ongoing open-label extension periods. Patients were randomized 1:1 to receive risankizumab 150mg or placebo at baseline and weeks4 and 16. After week24, all patients received open-label risankizumab every 12weeks thereafter. Patients were evaluated through 100weeks. Endpoints included achieving ≥ 20% reduction in American College of Rheumatology criteria for symptoms of rheumatoid arthritis (ACR20), minimal disease activity (MDA; defined as ≥ 5/7 criteria of low disease activity and extent), and other measures. Overall, 828/964 (85.9%) patients completed week100. For patients receiving continuous risankizumab, 57.3%, 70.6%, and 64.3% achieved ACR20 at weeks24, 52, and 100, respectively. For the placebo/risankizumab cohort, 33.5% achieved ACR20 at week24 but increased after switching to active treatment at weeks52 (63.7%) and 100 (62.1%). In ACR20 responders at week52, 81.2% of both treatment cohorts maintained response at week100. MDA was achieved by 25.0%, 38.3%, and 38.2% of the continuous risankizumab cohort at weeks24, 52, and 100. In the placebo/risankizumab cohort, 10.2% achieved MDA at week24, increasing at weeks52 (28.0%) and 100 (35.2%). MDA response was maintained at week100 in week52 responders in the continuous risankizumab (75.5%) and placebo/risankizumab cohorts (78.2%). Similar trends were observed for other efficacy measures. Risankizumab was generally well tolerated through 100weeks. For patients with active PsA who are csDMARD-IR, risankizumab demonstrated durable long-term efficacy and was generally well tolerated, with a consistent long-term safety profile. ClinicalTrials.gov identifier, NCT03675308.

Efficacy and Safety of Risankizumab for Active Psoriatic Arthritis: 100-Week Results from the KEEPsAKE2 Randomized Clinical Trial.

Long-term therapeutic options providing durable response and tolerability are needed for psoriatic arthritis (PsA). The ongoing KEEPsAKE2 trial is evaluating risankizumab treatment in patients with active PsA who previously had inadequate response/intolerance to ≥ 1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR) and/or 1-2 biologic DMARDs (bDMARD-IR). Herein, we report results through 100weeks of treatment. KEEPsAKE2 is a global phase3 trial. Patients with active PsA were randomized 1:1 to double-blind subcutaneous risankizumab 150mg or placebo (weeks0, 4, and 16). At week24, all patients received open-label risankizumab every 12weeks until end of study. Efficacy endpoints included achieving ≥ 20% improvement in PsA symptoms using American College of Rheumatology criteria (ACR20), attaining minimal disease activity (MDA; meeting ≥ 5/7 criteria of low disease activity and extent), and improving in other measures. At the cutoff date, 345/443 (77.9%) patients were ongoing in thestudy. ACR20 was achieved in 57.1% and 52.5% of the continuous risankizumab and placebo/risankizumab cohorts, respectively, at week100 and in 60.0% and 55.8%, respectively, at week52. In week52 responders, maintenance of ACR20 at week100 was achieved in 74.8% (continuous risankizumab) and 78.7% (placebo/risankizumab) of patients. In the continuous risankizumab and placebo/risankizumab cohorts, respectively, MDA was achieved by 33.0% and 33.3% of patients at week100 and by 27.2% and 33.8% at week52. Among MDA responders at week52, maintenance of MDA response was achieved by 83.6% and 73.0% of the continuous risankizumab and placebo/risankizumab cohorts, respectively. Risankizumab was well tolerated through week100. Risankizumab demonstrated durable efficacy and tolerability through 100weeks; most patients who achieved ACR20 and MDA responses at week52 maintained this achievement through week100. There were no new safety signals in patients who had csDMARD-IR and bDMARD-IR. ClinicalTrials.gov NCT03671148.

Synthesis and Crystallographic Characterization of Heteroleptic Ir(III) Complexes Containing the N-oxide Functional Group and Crystallographic Characterization of Ir(III) N-oxide Precursors

The N-oxide functional group has been exploited for synthetic strategies and drug design, and it has been utilized in imaging agents. Herein, we present rare examples of neutral heteroleptic cyclometallated Ir(III) compounds that contain an uncoordinated N-oxide functional group. These species, along with others described within, were verified by NMR, EA, HRMS, and single-crystal X-ray analysis. N-oxide-containing Ir(III) species were prepared selectively in high yields > 66% from chloro-bridged Ir(III) dimers with Acipimox, a picolinate-type ligand containing the N-oxide functional group. Non-N-oxide analogs were synthesized in a similar fashion (yields > 77%). Electrochemical comparison (cyclic voltammetry) indicates that the presence of an N-oxide functional group anodically shifts the reduction potential, suggesting that the N-oxide is acting as an electron-withdrawing group in these species. Crystallographic studies were pursued to examine the coordination behavior of these N-oxides compared to their non-oxidized congeners. The Ir(III) complexes with Acipimox indeed leave the N-oxide uncoordinated and exposed on the complexes. The uncoordinated N-oxide group is influential in directing the packing structures of these complexes directly through C-H···O and O···π interactions at the N-oxide. The crystallographic characterization of cationic Ir(III) compounds with uncoordinated nitrogen atoms is also presented. The C-H···N interactions between these complexes form a variety of dimers, finite chains, and continuous chains. Future work will focus on functionalizing the cationic Ir(III) species into their corresponding N-oxide derivatives and rigorously characterizing how the N-oxide functional group impacts the optical properties of transition metal compounds in both cationic and neutral complexes.

Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes persistent synovitis, bone damage, and progressive joint destruction. Neuroimmune modulation through electrical stimulation of the vagus nerve activates the inflammatory reflex and has been shown to inhibit the production and release of inflammatory cytokines and decrease clinical signs and symptoms in RA. The RESET-RA study was designed to determine the safety and efficacy of an active implantable device for treating RA. The RESET-RA study is a randomized, double-blind, sham-controlled, multi-center, two-stage pivotal trial that enrolled patients with moderate-to-severe RA who were incomplete responders or intolerant to at least one biologic or targeted synthetic disease-modifying anti-rheumatic drug. A neuroimmune modulation device (SetPoint Medical, Valencia, CA) was implanted on the left cervical vagus nerve within the carotid sheath in all patients. Following post-surgical clearance, patients were randomly assigned (1:1) to active stimulation or non-active (control) stimulation for 1min once per day. A predefined blinded interim analysis was performed in patients enrolled in the study's initial stage (Stage 1) that included demographics, enrollment rates, device implantation rates, and safety of the surgical procedure, device, and stimulation over 12 weeks of treatment. Sixty patients were implanted during Stage 1 of the study. All device implant procedures were completed without intraoperative complications, infections, or surgical revisions. No unanticipated adverse events were reported during the perioperative period and at the end of 12 weeks of follow-up. No study discontinuations were due to adverse events, and no serious adverse events were related to the device or stimulation. Two serious adverse events were related to the implantation procedure: vocal cord paresis and prolonged hoarseness. These were reported in two patients and are known complications of surgical implantation procedures with vagus nerve stimulation devices. The adverse event of vocal cord paresis resolved after vocal cord augmentation injections with filler and speech therapy. The prolonged hoarseness had improved with speech therapy, but mild hoarseness persists. The surgical procedures for implantation of the novel neuroimmune modulation device for the treatment of RA were safe, and the device and its use were well tolerated. NCT04539964; August 31, 2020.

Antihypertensive activity of spray-dried nanoemulsion containing Asiatic acid-Palm oil in high salt diet-fed rats

Asiatic acid (AA) is a compound isolated from Centella asiatica, which possesses significant antihypertensive activity. Several studies have shown that its hypertensive activity can be attributed to various mechanisms, such as Angiotensin-Converting-Enzyme (ACE) inhibition in the renin-angiotensin-aldosterone system (RAAS) pathway. Meanwhile, palm oil (PO) is an antioxidant, which has proven to have synergistic effects with the compound by preventing arterial thrombosis and atherosclerosis. Despite these synergistic effects, AA dosage in antihypertensive therapy has been reported to be relatively high compared to the common synthetic drug captopril. Therefore, this study aimed to produce spray-dried powder of nanoemulsion to enhance the solubility of AA, decrease the possibility of oxidation, and increase its activity. Redispersed AA nanoparticles were also successfully obtained during the synthesis process. Several evaluations were carried out, including particle size, particle distribution, zeta potential, cell viability, and antihypertensive activity in rats to ensure the improvement of physicochemical characteristics and activity as antihypertensive agent. The results showed that AA succeeded in forming nanoemulsion with excipients. In addition, it was encapsulated in a maltodextrin carrier, exhibiting good physicochemical characteristics and safety to the Caco-2 cells. The redispersion of the spray-dried powder yielded nanoparticles with a size of 217.4 ± 10.196 nm. The spray-dried nanoemulsion of AA also had faster effect than non-formulated AA (raw powder) in lowering the blood pressure of hypertensive Sprague-Dawley (SD) rats. Graphical abstract:

Morphology and Cyto-Architecture of the Testis and Assessment of Selected Biochemical Parameters Associated with Male Fertility Following the Consumption of Tom Brown Weaning Diet in Albino Wistar Rats

Objectives/Background Natural products are preferred over synthetic drug as fertility enhancers as they are cost effective. Infertility among men of reproductive age keeps rising. Synthetic drugs ameliorate the problem but leave adverse side effects as men advance in age, hence the need for alternative medicine. Tom brown weaning diet is a processed cereal-based powdery blend which is cooked into a semi-liquid food for children from 6 months and contains good nutrient levels. This work focused on the effects of Tom brown weaning diet on testes of Wistar rats. Method Fifteen Wistar rats were divided into 3 groups namely: Control group, 50% tom brown group and 100% tom brown group. Control received only rat chow, 50% Tom brown group received tom brown diet and normal rat chows at 12 h cycle per time. This cycle was repeated till the end of the experiment. 50% Tom brown group received only tom brown diet throughout the experimental period. The testes were excised, measured, and processed for morphological and histological analysis. Results Average testicular weight and relative weight in the 50% tom brown, 100% tom brown and control groups were not significant at alpha level of P ˂ .05. This was also supported by the normal histological features seen in sections of the testes of rats in all groups as there were no shrinking and denser spermatogenic cells in the seminiferous tubules. Hormonal analysis showed a non-significant difference in the level of FSH and LH at alpha levels of P˂0.05. However, testosterone level increased significantly in 100% group compared to 50% and the control group at P˂ .05. Also, GC-MS study on the diet revealed 30 compounds in the diet. Conclusion This study revealed that Tom brown diet has no detectable damaging effect(s) on the testes but could improve the cytoarchitecture and enhance fertility.

Psychedelic Therapy: A Primer for Primary Care Clinicians-Historical Perspective and Overview.

Psychedelic drugs have recently emerged as plausibly effective pharmacological agents for the management of depression, anxiety, and other neuropsychiatric conditions, including those that are treatment-resistent. The latter half of the 20th century marked a revolution in the treatment of mental illnesses, exemplified by the introduction of selective serotonin reuptake inhibitors and other pharmacological agents. Nevertheless, mental illness remains a major public health crisis, affecting nearly one billion individuals worldwide. Because of the decades-long status of several psychedelics as Schedule I drugs, there have not been very many large, double-blind, randomized controlled trials of psychedelics. Owing to small sample sizes, there may be rare yet serious adverse events that have not been reported in the clinical trials thus far. Esketamine, a dissociative hallucinogen drug, was approved for the management of major depressive disorder by the Food and Drug Administration in 2019. As of January 2024, two Phase III trials of 3,4-methylenedioxymethamphetamine (MDMA), a synthetic drug that inhibits the serotonin transporter, have been completed; the results indicate that MDMA is superior to existing pharmacological treatments for post-traumatic stress disorder. A phase III trial of psilocybin, a naturally occurring serotonin receptor partial agonist, is currently underway. The following series details the current state of research in psychedelic therapeutics, including lysergic acid diethylamide (LSD), N-N-dimethyltryptamine (DMT) and ayahuasca, psilocybin, ibogaine, MDMA, and ketamine. While initial clinical trials of psychedelics for depression were very promising, trials of psilocybin with larger sample sizes (100+ participants) suggest that its remission rate is 25%-29%. This is about the same as the remission rate of antidepressants, which is roughly 30% according to the landmark STAR*D trial. Psychedelic drugs and structural derivatives offer a great deal of promise for the management of a wide range of psychiatric morbidities. It is imperative that clinicians become familiar with these novel agents and learn how to integrate psychedelic therapy with the rest of their care through open communication and referral.

Comparative effectiveness of baricitinib and alternative biological DMARDs in a Swiss cohort study of patients with RA

ObjectivesThis observational study compares the effectiveness of baricitinib (BARI), a targeted synthetic disease-modifying antirheumatic drug (tsDMARD), with alternative biological DMARDs (bDMARDs) in patients with rheumatoid arthritis (RA), from a prospective,...

Medication utilisation trends during pregnancy and factors influencing adverse pregnancy outcomes in patients with rheumatoid arthritis

ObjectivesWe aimed to investigate medication utilisation trends during pregnancy and identify factors associated with adverse pregnancy outcomes (APOs) in patients with rheumatoid arthritis (RA).MethodsFemale patients with RA aged 20–50 years...

Developments in Synthesis Strategies of Spiro-Barbiturate Compounds: A Classified Study

Abstract: Spiro compounds being multi-cyclic systems linked by a single atom, have distinct three dimensionalities, and prominently hold a position of interest in the fields of synthetic and medicinal chemistry, pharmacology, material sciences and physics. Spirobarbiturate compounds which incorporate barbituric ring derivatives into spirocyclic structures have emerged as attractive synthetic targets for drug discovery as they are known to exhibit far-ranging pharmacological applications. In this review, we aim to bring to light the extensive, contemporary research applied to the synthesis of different spirobarbiturates having varied ring sizes (3, 5, 6 and 7 membered) in a classified manner. It presents the reported methods of synthesis along with their mechanistic pathways as well as the pharmacological activities of some of these synthesized biologically significant motifs.

Lipid-Based Nanoparticles in Delivering Bioactive Compounds for Improving Therapeutic Efficacy.

In recent years, due to their distinctive and adaptable therapeutic effects, many natural bioactive compounds have been commonly used to treat diseases. Their limited solubility, low bioavailability, inadequate gastrointestinal tract stability, high metabolic rate, and shorter duration of action limited their pharmaceutical applications. However, those can be improved using nanotechnology to create various drug delivery systems, including lipid-based nanoparticles, to adjust the compounds' physicochemical properties and pharmacokinetic profile. Because of the enormous technical advancements made in the fundamental sciences and the physical and chemical manipulation of individual atoms and molecules, the subject of nanotechnology has experienced revolutionary growth. By fabricating certain functionalized particles, nanotechnology opens an innovative horizon in research and development for overcoming restrictions, including traditional medication administration systems. Nanotechnology-driven bioactive compounds are certain to have a high impact and clinical value for current and future uses. Lipid-based nanotechnologies were shown to deliver a range of naturally occurring bioactive compounds with decent entrapment potential and stability, a successfully controlled release, increased bioavailability, and intriguing therapeutic activity. This review outlines bioactive compounds such as paclitaxel, curcumin, rhodomyrtone, quercetin, kaempferol, resveratrol, epigallocatechin-3-gallate, silymarin, and oridonin, fortified within either a natural or synthetic lipid-based drug delivery system based on nanotechnology and their evaluation and clinical considerations.

Semi-solid extrusion 3D printing of functionalized polyethylene oxide gels loaded with 1,2,3-triazolo-1,4-benzodiazepine nanofibers and valine-modified motherwort (Leonurus cardiaca L.) dry extract

Anxiety disorders are the most prevalent psychiatric disorders and are associated with a high burden of illness. Combining synthetic and native-origin compounds in treating such disorders could provide true benefits in terms of therapeutic efficacy. In the present study, we combined triazolobenzodiazepine and motherwort (Leonurus cardiaca L.) dry extract for such applications.
 The aim. The aim of this study was to develop aqueous polyethylene oxide (PEO) composite gels loaded with 1,2,3-triazolo-1,4-benzodiazepine nanofibers and a valine-modified motherwort herb dry extract for semi-solid extrusion (SSE) 3D printing. The printability of such gels and the physicochemical properties of the final 3D-printed drug preparations were investigated.
 Materials and methods. A new drug substance, 1,2,3-triazolo-1,4-benzodiazepine (MA-253) was synthesized and used to formulate oleogels and electrospun nanofibers for 3D printing. The plant-origin dry extract was prepared from a motherwort tincture and valine. The aqueous PEO gels loaded with a synthetic drug (MA-253) containing nanofibers and a valine-modified motherwort extract were prepared and subsequently used in the SSE 3D printing experiments. The homogeneity, viscosity and 3D printability of composite PEO gels were verified. The phytochemical assay of flavonoids in the 3D-printed drug preparations was conducted with the European pharmacopoeia spectrophotometric method.
 Research results. Three experimental gel formulations loaded with 1,2,3-triazolo-1,4-benzodiazepine nanofibers and a valine-modified motherwort dry extract were developed and tested for the SSE 3D printing applications. The present three gels showed good SSE 3D printability without any significant printing flaws. The SSE 3D-printed lattices prepared from the aqueous PEO gels containing 100 mg/ml of motherwort extract showed the most promising 3D printing performance. The 3D-printed drug preparations were entirely dissolved in purified water (22±2 °C) within 20 minutes, thus suggesting their applicability in oral administration.
 Conclusions. Novel aqueous PEO gel formulations loaded with nanofibrous 1,2,3-triazolo-1,4-benzodiazepine nanofibers and valine-modified motherwort herb extract are feasible for pharmaceutical SSE 3D printing. The present composite PEO gels enable the preparation of printed oral immediate-release drug delivery systems for new triazolobenzodiazepine derivatives and a drug therapy supportive plant extract

Impact of multimorbidity on the first ts/bDMARD effectiveness and retention rate after two years of follow-up in patients with rheumatoid arthritis from the BIOBADASER registry

BackgroundPatients with Rheumatoid Arthritis (RA) have a higher prevalence of comorbidities compared to the general population. However, the implications of multimorbidity on therapeutic response and treatment retention remain unexplored. Objectives: (a) To evaluate the impact of multimorbidity on the effectiveness of the first targeted synthetic or biologic disease-modifying antirheumatic drug (ts/bDMARD), in patients with RA after 2-year follow-up; (b) to investigate the influence of multimorbidity on treatment retention rate.MethodsPatients with RA from the BIOBADASER registry exposed to a first ts/bDMARDs were included. Patients were categorized based on multimorbidity status at baseline, defined as a Charlson Comorbidity index (CCI) score ≥ 3. A linear regression model, adjusted for sex and age, was employed to compare the absolute DAS28 score over time after ts/bDMARD initiation between the two groups. The Log-Rank test and Kaplan-Meier curve were used to compare the retention rates of the first ts/bDMARD between the groups.ResultsA total of 1128 patients initiating ts/bDMARD were included, with 107 (9.3%) exhibiting multimorbidity. The linear regression model showed significantly higher DAS28 (beta coefficient 0.33, 95%CI:0.07–0.58) over a two-year period in patients with multimorbidity, even after adjusting for age and sex. Finally, no differences in the ts/bDMARD retention rate were found between groups (median 6.94–6.96 years in CCI < 3 vs. 5.68–5.62 in CCI ≥ 3; p = 0.610).ConclusionsMultimorbidity in patients with RA was associated with greater DAS28 scores within the first two years after ts/bDMARD initiation, in comparison with patients without multimorbidity. A slightly shorter retention rate was found in patients with multimorbidity, although the difference was non-significant.

Bioinspired Selenium-Nitrogen Exchange (SeNEx) Click Chemistry Suitable for Nanomole-Scale Medicinal Chemistry and Bioconjugation.

Click chemistry is a powerful molecular assembly strategy for rapid functional discovery. The development of click reactions with new connecting linkage is of great importance for expanding the click chemistry toolbox. We report the first selenium-nitrogen exchange (SeNEx) click reaction between benzoselenazolones and terminal alkynes (Se-N to Se-C), which is inspired by the biochemical SeNEx between Ebselen and cysteine (Cys) residue (Se-N to Se-S). The formed selenoalkyne connection is readily elaborated, thus endowing this chemistry with multidimensional molecular diversity. Besides, this reaction is modular, predictable, and high-yielding, features fast kinetics (k2≥14.43 M-1 s-1), excellent functional group compatibility, and works well at miniaturization (nanomole-scale), opening up many interesting opportunities for organo-Se synthesis and bioconjugation, as exemplified by sequential click chemistry (coupled with ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) and sulfur-fluoride exchange (SuFEx)), selenomacrocycle synthesis, nanomole-scale synthesis of Se-containing natural product library and DNA-encoded library (DEL), late-stage peptide modification and ligation, and multiple functionalization of proteins. These results indicated that SeNEx is a useful strategy for new click chemistry developments, and the established SeNEx chemistry will serve as a transformative platform in multidisciplinary fields such as synthetic chemistry, material science, chemical biology, medical chemistry, and drug discovery.

Bioinspired Selenium‐Nitrogen Exchange (SeNEx) Click Chemistry Suitable for Nanomole‐Scale Medicinal Chemistry and Bioconjugation

AbstractClick chemistry is a powerful molecular assembly strategy for rapid functional discovery. The development of click reactions with new connecting linkage is of great importance for expanding the click chemistry toolbox. We report the first selenium‐nitrogen exchange (SeNEx) click reaction between benzoselenazolones and terminal alkynes (Se−N to Se−C), which is inspired by the biochemical SeNEx between Ebselen and cysteine (Cys) residue (Se−N to Se−S). The formed selenoalkyne connection is readily elaborated, thus endowing this chemistry with multidimensional molecular diversity. Besides, this reaction is modular, predictable, and high‐yielding, features fast kinetics (k2≥14.43 M−1 s−1), excellent functional group compatibility, and works well at miniaturization (nanomole‐scale), opening up many interesting opportunities for organo‐Se synthesis and bioconjugation, as exemplified by sequential click chemistry (coupled with ruthenium‐catalyzed azide‐alkyne cycloaddition (RuAAC) and sulfur‐fluoride exchange (SuFEx)), selenomacrocycle synthesis, nanomole‐scale synthesis of Se‐containing natural product library and DNA‐encoded library (DEL), late‐stage peptide modification and ligation, and multiple functionalization of proteins. These results indicated that SeNEx is a useful strategy for new click chemistry developments, and the established SeNEx chemistry will serve as a transformative platform in multidisciplinary fields such as synthetic chemistry, material science, chemical biology, medical chemistry, and drug discovery.

A hierarchical approach towards identification of novel inhibitors against L, D-transpeptidase YcbB as an anti-bacterial therapeutic target

The bacterial cell wall, being a vital component for cell viability, is regarded as a promising drug target. The L, D-Transpeptidase YcbB enzyme has been implicated for a significant role in cell wall polymers cross linking during typhoid toxin release, β-lactam resistance and outer membrane defect rescue. These observations have been recorded in different bacterial pathogens such as Salmonella Typhimurium, Citrobacter rodentium, and Salmonella typhi. In this work, we have shown structure based virtual screening of diverse natural and synthetic drug libraries against the enzyme and revealed three compounds as LAS_32135590, LAS_34036730 and LAS-51380924. These compounds showed highly stable energies and the findings are very competitive with the control molecule ((1RG or (4 R,5S)-3-({(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]pyrrolidin-3-yl}sulfanyl)-5-[(1S,2R)-1-formyl-2-hydroxypropyl]-4-methyl-4,5-dihydro-1H-pyrrole-2-carboxylic acid or ertapenem)) used. Compared to control (which has binding energy score of −11.63 kcal/mol), the compounds showed better binding energy. The binding energy score of LAS_32135590, LAS_34036730 and LAS-51380924 is −12.63 kcal/mol, −12.22 kcal/mol and −12.10 kcal/mol, respectively. Further, the docked snapshot of the lead compounds and control were investigated for stability under time dependent dynamics environment. All the three leads complex and control system showed significant equilibrium (mean RMSD < 3 Å) both in term of intermolecular docked conformation and binding interactions network. Further validation on the complex’s stability was acquired from the end-state MMPB/GBSA analysis that observed greater contribution from van der Waals forces and electrostatic energy while less contribution was noticed from solvation part. The compounds were also showed good drug-likeness and are non-toxic and non-mutagenic. In short, the compounds can be used in experimental testing’s and might be subjected to structure modification to get better results. Communicated by Ramaswamy H. Sarma

A Platform for Determining Medicinal Plants with Targeted 17β-Hydroxysteroid Dehydrogenase Modulation for Possible Hair Loss Prevention

Although hair loss plays a vital physiological function in present society, their impact on shaping self-esteem is undeniable. Even though there are numerous synthetic drugs available, these days, there are issues with safety, efficiency, and unclear time settings for required outcomes with the current synthetic drug remedies available; therefore, there is growing attention to discovering alternative methods to fight hair loss, primarily through plant-derived formulations. While earlier reports mostly focused on screening compounds or plant extracts affecting 5α-reductase, our research takes a unique direction. We employed a biochemical and molecular biological approach by delving into the complicated biosynthetic pathways involving 17β-hydroxysteroid dehydrogenase (17β-HSD) and 3β-hydroxysteroid dehydrogenase (3β-HSD) in producing testosterone derived from cholesterol. This process conceded requiring experimental results, posing insights into the control of the testosterone/dihydrotestosterone (DHT) production pathway. Our study confirms a discovery platform for finding potential candidates as hair loss inhibitors, highlighting exploring various biochemical mechanisms involving 17β-HSD and 3β-HSD in combination with medicinal plant extracts.

Disease activity-guided dose optimisation including discontinuation of TNF-inhibitors in rheumatoid arthritis is effective for up to 10 years: an observational follow-up of the DRESS study.

To investigate safety and effectiveness of disease activity-guided dose optimisation of TNF-inhibitors in rheumatoid arthritis over 10 years. Observational long-term extension of a randomised study of participants who completed the 3-year extension of the DRESS-study. After the randomised phase (month 0-18), disease activity-guided dose optimisation was allowed for all. Main outcomes were mean time-weighted DAS28-CRP; biological and targeted synthetic anti-rheumatic drug (b/tsDMARD) use per year as proportion of daily defined dose; proportion of patients reaching discontinuation; durability, effectiveness of subsequent dose reduction attempts; and radiographic progression between 3 and 10 years using the Sharp-van der Heijde score. 170 patients were included of whom 127 completed 10-year follow-up. The mean disease activity remained low (DAS28-CRP 2.13, 95% confidence interval 2.10-2.16), whilst the b/tsDMARD dose reduced from 97% at baseline (95%CI 96% to 99%, n = 170)% to56% at year 10 (49% to 63%, n = 127). 119 of 161 participants (74%) with an optimisation attempt reached discontinuation, with a median duration of 7 months (interquartile range 3-33 months), and 25 participants never had to restart their b/tsDMARD (21%, 14% to 29%). The mean dose reduction after dose optimisation was 48% (n = 159) for the first optimisation attempt and 33% for subsequent attempt (n = 86). 48% (41/86) of participants had radiographic progression exceeding the smallest detectable change (5.7 units), and progression was associated with disease activity, not b/tsDMARD use. Long-term disease activity-guided dose optimisation of TNF-inhibitors in rheumatoid arthritis, including discontinuation and multiple tapering attempts, remains safe and effective.

Novel 2,5-Diketopiperazines with In Vitro Activities against Protozoan Parasites of Tropical Diseases.

Malaria, Chagas disease, and leishmaniasis are tropical diseases caused by protozoan parasites of the genera Plasmodium, Trypanosoma and Leishmania, respectively. These diseases constitute a major burden on public health in several regions worldwide, mainly affecting low-income populations in economically poor countries. Severe side effects of currently available drug treatments and the emergence of resistant parasites need to be addressed by the development of novel drug candidates. Natural 2,5-Diketopiperazines (2,5-DKPs) constitute N-heterocyclic secondary metabolites with a wide range of biological activities of medicinal interest. Its structural and physicochemical properties make the 2,5-DKP ring a versatile, peptide-like, and stable pharmacophore attractive for synthetic drug design. In the present work, twenty-three novel synthetic 2,5-DKPs, previously synthesized through the versatile Ugi multicomponent reaction, were assayed for their anti-protozoal activities against P. falciparum, T. cruzi, and L. infantum. Some of the 2,5-DKPs have shown promising activities against the target protozoans, with inhibitory concentrations (IC50) ranging from 5.4 to 9.5 µg/mL. The most active compounds also show low cytotoxicity (CC50), affording selectivity indices ≥ 15. Results allowed for observing a clear relationship between the substitution pattern at the aromatic rings of the 2,5-DKPs and their corresponding anti-Plasmodium activity. Finally, calculated drug-like properties of the compounds revealed points for further structure optimization of promising drug candidates.

Role of Allicin in Combination with Fluoxetine for the Treatment of Major Depressive Disorder in Rodents: Pharmacokinetic and Pharmacodynamic Study

Background: Depression is one of the most common neurological disorders for which only symptomatic treatment is available with synthetic drugs with serious side effects. Allicin [S-(2-propenyl)-2-propene-1-sulfinothioate] is a bioactive component derived from Allium sativum L. (Garlic). It has the property to penetrate the blood-brain barrier, which reveals its neuroprotective property. A synthetic drug named fluoxetine (selective serotonin re-uptake inhibitor) was introduced for the clinical treatment of depression. It is a selective serotonin re-uptake inhibitor that is well absorbed after oral administration. Aims and Objectives: This study aimed to evaluate the anti-depressant effect of fluoxetine alone and in combination with allicin. Methods: A pharmacokinetic study of allicin alone as well as in combination with fluoxetine was conducted to evaluate peak concentration, peak concentration time, and area under the curve in blood plasma. Furthermore, the biochemical analysis of neurotrophin levels of brain-derived neurotrophic factor (BDNF), serotonin, and dopamine was also performed to determine the anti-depressant activity with synergism effect of allicin and fluoxetine. Results: The results of a pharmacokinetic study for co-administration of fluoxetine with allicin and enhanced neurotrophins and monoamines levels confirmed their effectiveness against depression. They may also be effective in suicidal risk associated with anti-depressant drugs. Conclusion: A combination of synthetic drugs with herbal compounds may be an alternate and effective therapy to overcome harmful effects.