Unique Efficacy Research Articles

Tezepelumab: a promising therapy for severe uncontrolled asthma

Asthma is a complex inflammatory airway disease affecting a significant global population, spanning from childhood through adulthood. Despite advances in treatment modalities, a significant subset of patients, approximately 10%, grapple with severe asthma, characterized by increased healthcare utilization and diminished quality of life. Tezepelumab, a monoclonal antibody targeting thymic stromal lymphopoietin (TSLP), offers promising therapeutic potential. TSLP is a protein released by a variety of cells, with a predominance of epithelial cells, in reaction to plenty of stimuli, such examples as viruses, aeroallergens, and others. Its action is upstream and pertains to initiating numerous subsequent innate and adaptive immune reactions, contributing to the continuation of asthma pathophysiological processes. Tezepelumab’s unique efficacy spans diverse severe asthma phenotypes, significantly reducing exacerbation rates across eosinophilic and non-eosinophilic subtypes. Its favorable safety profile and clinically meaningful improvements in asthma control, accompanied by reductions in cytokine levels and baseline biomarkers, underscore its broad impact on asthma inflammation. Its efficacy, irrespective of type 2 (T2) endotype, reinforces the idea that TSLP blockade broadly inhibits pathways crucial to asthma pathophysiology, rather than narrowly focusing on individual downstream factors, as previous biological treatments have. This review discusses the rationale for TSLP blockade and the efficacy of tezepelumab in severe asthma using data from key trials.

Dutasteride for the Treatment of Androgenetic Alopecia: An Updated Review.

Androgenetic alopecia (AGA) is a common skin disease characterized by progressive hair loss, with negative psychological impacts on patients, especially young people. The primary pathogenesis of AGA involves the action of 5α-reductase converting testosterone to dihydrotestosterone, leading to gradual miniaturization of genetically susceptible hair follicles. Finasteride inhibits type II 5α-reductase, while dutasteride simultaneously inhibits type I and type II 5α-reductase. Currently, finasteride is approved by the Food and Drug Administration (FDA) for the treatment of AGA, but its efficacy remains poor in some patients. This article aims to review the treatment of androgenetic alopecia with dutasteride. Oral dutasteride, intradermal injection of dutasteride (mesotherapy) and other related treatment methods are included. We performed a Medical Subject Heading search in the PubMed database using "androgenetic alopecia" and "dutasteride". Compared to finasteride, oral dutasteride has better efficacy and comparable tolerability, and most adverse events are mild and reversible, making it an effective treatment option for AGA. Mesotherapy with dutasteride is a therapeutic option to reduce the systemic adverse effects of the drug, but there are no standardized treatment protocols and large-scale clinical trials. Microneedling combined with dutasteride solution also has its own unique efficacy for treating AGA. Liposomes or nanoparticles of dutasteride are still under development and may become a more optimized topical formulation in the future.

A comparison of the safety and efficacy of tapinarof and roflumilast topical therapies in the management of mild-to-moderate plaque psoriasis.

Psoriasis is an immune-mediated inflammatory skin disease. First-line topical treatments include steroids, calcineurin inhibitors, vitamin D analogs, and anthralin. Recently, novel topical therapeutics like tapinarof and roflumilast have emerged with unique anti-inflammatory mechanisms and promising efficacy profiles. This review utilized PubMed, SCOPUS, and Web of Science databases to identify recent studies on tapinarof and roflumilast. Criteria focused on efficacy, safety profiles, and therapeutic roles in psoriasis treatment. Four primary literature articles were identified for tapinarof and five for roflumilast. Both drugs demonstrated strong efficacy with minimal adverse events in treating mild-to-moderate plaque psoriasis. Tapinarof showed more frequent but mild adverse effects, while roflumilast had less frequent but more severe side effects. Tapinarof and roflumilast offer once-daily dosing and successful treatment in restricted areas, potentially enhancing patient adherence. Cost remains a limiting factor, necessitating future comparative studies to evaluate the efficacy, safety, and cost-effectiveness between the two drugs. Tapinarof and roflumilast present promising topical treatments for psoriasis, showing efficacy and manageable safety profiles. Further research is crucial to fully elucidate their comparative benefits and drawbacks in clinical practice.

Synthesis of paeonol hydrazone derivatives and their anti-oomycete, anti-fungal, and nematicidal activities.

The natural product paeonol is a rich and sustainable natural bioresource, and its derivatives have various unique biological efficacy. As is well known, Schiff bases are a class of organic compounds with a wide range of biological activities, including anti-fungal, insecticidal, anti-viral, and nematicidal. To discover biorational natural product-based pesticides, nine intermediates (2-10), 12 sulfonylhydrazones (11a-11c, 12a-12c, 13a-13c, and 14a-14c) and 20 benzylidene hydrazones (18a-18r, 19a, and 20a) were synthesized by structural modification of paeonol, and their structures were characterized by proton nuclear magnetic resonance (1H NMR), carbon-13 (13C) NMR, and high-resolution mass spectrometry (HRMS). The stereochemical configurations of compounds 14a, 18d, and 18r were unambiguously confirmed by single-crystal X-ray diffraction. Furthermore, bioactivities of these compounds as anti-oomycete, anti-fungal, and nematicidal agents against three serious agricultural pests, Phytophthora capsici, Fusarium graminearum, and Heterodera glycines were evaluated. Among all tested compounds: (i) compound 7 exhibited promising anti-oomycete against Phytophthora capsici, with a half maximal effective concentration (EC50) value of 15.81 mg L-1; (ii) compounds 2, 7, 10, and 19a displayed promising anti-fungal against F. graminearum, with EC50 values of 12.22, 14.72, 23.39, and 33.10 mg L-1, respectively; (iii) ten compounds (12a-12c, 14c, 18g-18j, 18m, and 19a) showed significant nematicidal activity against H. glycines, with median lethal concentration (LC50) values all less than 30.00 mg L-1. Especially for compound 18g, its LC50 value is the smallest, at 12.65 mg L-1. The research results indicate that introducing nitro groups at the C5 position of paeonol, or introducing halogens at both C5 and C3 positions, can significantly enhance its biological activity against Phytophthora capsici, F. graminearum, and H. glycines. © 2024 Society of Chemical Industry.

Treatment of bipolar depression: clinical practice vs. adherence to guidelines-data from a Bavarian drug surveillance project.

Pharmacotherapy of bipolar depression (BPD) is confronted with major clinical challenges, like limited evidence-based treatment options, regular cases of treatment resistance, and risk of treatment-emergent affective switches. Medical guidelines can support practitioners to make decisions based on current scientific evidence. The objective of this study is to evaluate to what extent recommendations of the 2019 German S3 guidelines "Diagnosis and Treatment of Bipolar Disorders" are reflected in clinical practice in inpatient treatment. We conducted a descriptive analysis of prescription numbers in 2,627 patients with BPD in a naturalistic inpatient setting analyzing data from the ongoing Bavarian multicenter drug safety project Pharmaco-Epidemiology and Vigilance (Pharmako-EpiVig) from the years 2014-2022. Of the patients, 38% were not administered any drug explicitly recommended for treatment of BPD, that is, quetiapine, lamotrigine, carbamazepine, or olanzapine. Only 6% of the patients received monotherapy with one of those drugs. Of the patients, 34% were administered ≥4 psychotropic drugs simultaneously. Patients received 912 different therapy regimens of mono or combination therapy with mood stabilizers (MS), atypical antipsychotics (AAP), and antidepressants. Of the patients, 72% received an antidepressant and 6% without concomitant prescription of an AAP or MS. Prescription rates of venlafaxine (21% to 14%) and tricyclic antidepressants (9% to 6%) decreased significantly from the first (2014-2016) to the last (2020-2022) observed time period. Of the patients, 60% received an MS. Prescription rate of valproate (22% to 14%) decreased significantly, while lithium prescription increased significantly (29% to 35%). Of the patients, 71% were administered an AAP. Quetiapine was the most prescribed drug overall (43%). Only two patients were administered a combination of olanzapine and fluoxetine. Our results demonstrate a substantial gap between guideline recommendations and current clinical practice. The remarkable heterogeneity in treatment regimens, with no discernible dominant treatment approach, is in part a reflection of the complexity of bipolar disorder but also substantiates the need of comprehensive recommendations regarding combination therapies. Increase in lithium prescription is an encouraging development due to its unique efficacy in maintenance treatment. To improve the quality of clinical practice guideline implementation, more randomized controlled trials shouldbeconducted in the future to prospectively investigate different implementation strategies.

The Significance of Qin Medicine Research for The Development of Traditiongal Chinese Medicine

As the ancient capital of thirteen dynasties, Shaanxi has a long history and culture, and is also an important birthplace of traditional Chinese medicine culture and history. The Qinling Mountains, which crosses the land of Sanqin, starts from the Danjiang River in the east, ends at the Jialing River in the west, and crosses the two major water systems of the Yangtze River and Yellow River in the north and south. It provides good drug resources for doctors to cure disease and save people, thus help more patients get rid of the disease as soon as possible. Qinling Mountains, known as the reputation of natural medicine storehouse, has a very distinctive Qinling Seven Drugs, whose unique efficacy in clinical prevention and treatment has been verified for thousands of years and widely and deeply studied in the medicine community in recent years.

Efficient glycosylation and in vitro neuroprotective evaluation of abundant prenylflavonoid in hops

Structurally unique isopentenyl flavonoids are extremely low in natural plant species, and their cumbersome chemical pathways, scarcity of donors, and poor stability have severely hindered their application scenarios. Xanthohumol (XN), an isopentenyl chalcone, is a unique and abundant herbal efficacy substance in hops (Humulus upulus L.), which is an herb with a variety of clinical benefits. However, 90% of XN is left behind in the production of hop residue, resulting in a waste of natural resources. The poor water solubility and low bioavailability of XN also limit its wide application. Combined biotransformation strategies can greatly enhance the added value of resource materials and become one of the important means for the sustainable utilization of traditional Chinese medicine resources. In this study, an extreme microbial screening strategy for efficient bioconversion of phrenylflavonids is established to achieve Bacillus zanthoxyli GQ8 obtained from brewer's dregs and a non-aqueous biosynthesis system of xanthohumol glycosides (XNG, substrate concentration of 0.5 g/L, conversion rate of 73.2%) is constructed by GQ8. With HT22 cell model of H2O2-induced oxidative damage and BV2 cell model of LPS-induced neuroinflammation, XNG showed little cytotoxicity and exhibited better anti-inflammatory and antioxidant effects compared with the original compound. Our experimental results firstly provide a high-efficiency biotransformation strategy for glycosylation of XN with bacteria and provide a support that prenylflavonoid glycoside derivatives have remarkable biological activity and show better development potential.

Coumarin as an Elite Scaffold in Anti-Breast Cancer Drug Development: Design Strategies, Mechanistic Insights, and Structure-Activity Relationships.

Breast cancer is the most common cancer among women. Currently, it poses a significant threat to the healthcare system due to the emerging resistance and toxicity of available drug candidates in clinical practice, thus generating an urgent need for the development of new potent and safer anti-breast cancer drug candidates. Coumarin (chromone-2-one) is an elite ring system widely distributed among natural products and possesses a broad range of pharmacological properties. The unique distribution and pharmacological efficacy of coumarins attract natural product hunters, resulting in the identification of numerous natural coumarins from different natural sources in the last three decades, especially those with anti-breast cancer properties. Inspired by this, numerous synthetic derivatives based on coumarins have been developed by medicinal chemists all around the globe, showing promising anti-breast cancer efficacy. This review is primarily focused on the development of coumarin-inspired anti-breast cancer agents in the last three decades, especially highlighting design strategies, mechanistic insights, and their structure-activity relationship. Natural coumarins having anti-breast cancer efficacy are also briefly highlighted. This review will act as a guideline for researchers and medicinal chemists in designing optimum coumarin-based potent and safer anti-breast cancer agents.

The Activity of Nourseothricin Against Drug-Resistant Bacteria

Because nurseothricin successfully kills MDR bacteria, it may be useful in treating illnesses that are difficult to treat with traditional therapy. In contrast to highly resistant single-target antibiotics, nourseothricin, a broad-spectrum antibiotic, inhibits bacterial protein synthesis. The article also covers how nourseothricin works in conjunction with other antibiotics to destroy bacteria and minimize resistance. Antibiotic misuse has become a worldwide issue. Nursothricin, due to its unique mechanism and efficacy against drug-resistant bacteria, is an exciting potential treatment for a variety of disorders. The paper discusses the gaps in our current understanding of nourseothricin as well as the necessity for additional research into its medical potential. Resistance to nursothricin, like resistance to other antimicrobials, is a severe problem. Extensive precautionary research is required to ensure user safety and reduce the danger of injury. More research is needed to determine whether nourseothricin works against antibiotic-resistant microorganisms. Pharmacokinetic studies and clinical trials are required to investigate its therapeutic efficacy and long-term effects. The safe and effective dosage of nourseothricin is determined through such study. Nourseothricin offers new hope for the treatment of antibiotic-resistant bacterial infections. Because of its unique mechanism and synergistic effects, it can be used to combat antibiotic resistance. More research is required to maximize its potential while minimizing any potential drawbacks. Nurseothricin has the potential to improve global health if its limitations, safety, and clinical significance are addressed. Antibiotic resistance can only be avoided by creating new antimicrobials such as nourseothricin.

Polysaccharide extracted from Sarcandra glabra residue attenuate cognitive impairment by regulating gut microbiota in diabetic mice

Diabetic encephalopathy (DE), characterized by cognitive impairment, currently lacks targeted treatment. Previous studies have shown that Sarcandra glabra extracted residue polysaccharide (SERP) exhibited hypoglycemic effects either in vitro or in streptozotocin-induced diabetes mice. However, the therapeutic effect of SERP on DE was not elucidated. This study investigated the therapeutic effect of SERP on DE and its underlying mechanism. Our results revealed that SERP regulates glucose and lipid metabolism, improves cognitive function, and exhibits diminished activity post-antibiotic intervention. Importantly, we discovered a novel mechanism by which SERP modulates the gut microbiota, specifically enriching Bacteroidales S24-7, resulting in elevated levels of butyric acid in the intestine. This regulation modulates the intestinal endocrine cell lipid metabolism level, restores damaged intestinal barriers and neural epithelial circuits, thus exhibiting cure effects. Our findings suggest that SERP could become a candidate for treating DE, potentially involving the regulation mechanism of the “microbiota-gut-brain axis”. This study underscores the unique therapeutic efficacy of SERP in managing DE, offering fresh drug candidates and innovative treatment strategies for this challenging condition.

EEG Patterns Predicting Clobazam Response in Refractory Status Epilepticus in Adults

Summary Background Seizure resolution is often difficult to attain promptly in status epilepticus (SE). Clobazam (CLB) is structurally different from typical benzodiazepines with an affinity to the α2 subunit of GABA-A receptors, rendering unique efficacy in seizure termination. Aim To assess the response of clobazam in refractory status epilepticus (RSE) and to correlate this response with EEG patterns. Materials and Methods This was a single-center retrospective study conducted at a neurocritical care unit between January 2018 and June 2023. The study included fifty consecutive patients with RSE, out of which sixteen adult patients had continuous EEG monitoring both before and during treatment with clobazam until the resolution of RSE. Patients for whom clobazam was the last anti-seizure medication (ASM) used were included in the study. Thirty-four patients were excluded for various reasons, like lack of continuous EEG monitoring (cEEG), status post cardiac arrest, exclusion of clobazam due to medical issues or adverse events, or admission to the hospice floor. Results Out of the sixteen patients included in the study, twelve (75%) had focal nonconvulsive RSE on cEEG and four had focal convulsive RSE when clobazam was administered. Thirteen out of sixteen patients (81.25%) responded successfully to clobazam, with an average time of 23.5 hours since starting the medication. On average, three other ASMs were tried before clobazam, initiated at a mean time of 27 hours since SE onset. The study identified EEG patterns correlated with the use of clobazam :1) lateralised periodic discharges that evolved from 1–1.5 Hz to 2–3 Hz, then evolved to rhythmic theta/delta activity with embedded LPDs; 2) repetitive spikes that evolved to theta and delta frequencies (good responders to CLB), and iii) low voltage faster frequencies and evolved to theta delta frequencies (less responders to CLB). Conclusion Rapid pharmacoresistance to first-line benzodiazepines and ASM occurs as seizures persist during SE. Our study provides EEG correlates to the successful use of CLB in RSE based on its unique targeting of the GABA-A subtype receptors involved in postsynaptic phasic inhibition.

Medical Applications and Distribution of Borneol during the Joseon Period.

Borneol(yongnoe) was a fragrance and medicinal ingredient with unique efficacy. However, it could be produced only in tropical Southeast Asia and obtained only through international trade. In addition, camphor(jangnoe) with similar material properties was developed and distributed as an inexpensive replacement for borneol, although the processing method is different from that of borneol. Even in Joseon Korea, borneol and camphor were recognized as separate medicines, and efforts were made to obtain a high-quality borneol. Borneol and camphor have a unique effect of relieving inflammation, pain and heavy feeling, so it could be widely applied to symptoms in various diseases. During the Joseon period, borneol was a rare item that could only be obtained through foreign trade, and it was also used for perfumes and insect repellents, but most widely used as medicine. There are many records of actually prescribing borneol to the royal family, and many medicines containing borneol and its effective symptoms were also recorded in the medical books. Borneol was able to spread widely in Joseon society thanks to the practice of distributing 'nabyak' to court officials every year in the twelfth month of the lunar calendar. Since nabyak was used as a household medicine that was stored and used when necessary, pills containing borneol that could be applied to various symptoms were suitable for this purpose. Despite considerable medical demand, borneol was one of the important 'dangyakjae', the Chinese medicines imported to Joseon. During the Joseon period, borneol was imported through China and Japan, but genuine borneol was difficult to obtain, so it was often presented to Joseon as gifts of envoy trade. It is thought that camphor was also imported, but it is not well mentioned in official records or medical books reflecting national demand. Perhaps this is thought to be because the government prioritized securing better quality borneol rather than campher. In the early 17th century, due to the instability of the envoy's route to the Ming Dynasty, Joseon had to import borneol only through the sea. As a result, there were problems with the supply and quality of borneol, and national interest in Japanese borneol temporarily increased. However, as the relationship with the Qing Dynasty stabilized, a system was established to import national borneol demand through the annual envoy trade. Naeuiwon, the medical center for the royal family is in charge of securing and prescribing Chinese medicines, but the cost was covered by the silver paid by Hojo, the ministry of finance of Joseon Dynasty. Since the amount of Chinese medicines used in the preparation of nabyak was not small, the financial burden of importing enough medicines including borneol increased. The purveyors for government played a role in supplying Chinese medicines to the government. Their appearance shows that private merchants were actively involved in the trade of Chinese medicines including borneol. The formation of the medicinal market by private merchants' activities greatly contributed to the widespread expansion of the applications and distribution of borneol.

Life‐giving Flesh: Deity, Humanity, and the Efficacy of the Atonement – Part Two

AbstractThe life‐giving power of Christ's flesh and the unique efficacy of his atoning death is grounded in the fact that the flesh belongs to a divine person, the eternal Word. The previous article critiqued an attempt to explain the life‐giving power of Christ's flesh by way of a divine suffering on the cross and instead sought to ground the efficacy of Christ's atoning death in the proper and instrumental power of Christ's humanity. This second article argues that the efficacy of Christ's atoning death is grounded also in the infinite worth of the ransom that he pays on the cross. The claim that the infinite worth of Christ's ransom is derived from his deity, which itself does not suffer or die, will be articulated in dialogue with several patristic, medieval, and early modern theologians.

Clinical evidence and potential mechanisms of traditional Chinese medicine for refractory heart failure: a literature review and perspectives.

Refractory heart failure (RHF), or end-stage heart failure, has a poor prognosis and high case fatality rate, making it one of the therapeutic difficulties in the cardiovascular field. Despite the continuous abundance of methods and means for treating RHF in modern medicine, it still cannot meet the clinical needs of patients with RHF. How to further reduce the mortality rate and readmission rate of patients with RHF and improve their quality of life is still a difficult point in current research. In China, traditional Chinese medicine (TCM) has been widely used and has accumulated rich experience in the treatment of RHF due to its unique efficacy and safety advantages. Based on this, we comprehensively summarized and analyzed the clinical evidence and mechanism of action of TCM in the treatment of RHF and proposed urgent scientific issues and future research strategies for the treatment of RHF with TCM, to provide reference for the treatment of RHF.

Life‐giving Flesh: Deity, Humanity, and the Efficacy of the Atonement – Part One

AbstractThe life‐giving power of Christ's flesh and the unique efficacy of his atoning death are grounded in the fact that the flesh belongs to a divine person, the eternal Word. Though some theologians have argued that this should be explained by a divine sort of suffering taking place on the cross, this essay briefly critiques the idea of divine suffering in the atonement and proceeds to offer constructive discussion of other ways in which the life‐giving power of Christ's flesh and the efficacy of his atoning death are grounded in his deity. This first requires a consideration of the way in which Christ's humanity is empowered and supported by his deity in his suffering and atoning death, which will be articulated in dialogue with several patristic, medieval, and early modern theologians. A second essay will then elaborate further on the relationship between the efficacy of the atonement and the deity of Christ by discussing the way in which the ransom that Christ pays on the cross derives its infinite worth from his deity.

Gallic acid mitigates intestinal inflammation and loss of tight junction protein expression using a 2D-Caco-2 and RAW 264.7 co-culture model

A 2D-intestinal epithelial Caco-2/RAW 264.7 macrophage co-culture model was developed to demonstrate the relative efficacy of different phenolic acids to mitigate changes in Caco-2 epithelial cell redox state initiated both directly by autoxidation products, H2O2, and indirectly through cell communication events originating from cytokine stimulated macrophage. An inducer cocktail (lipopolysaccharide + interferon gamma) was used to activate RAW 264.7 cells in the 2D- Caco-2/RAW co-culture and intracellular changes in Caco-2 cell redox signaling occurred in response to positive changes (p < 0.05) in inflammatory biomarkers derived in macrophage that included IL-6, TNF-α, nitric oxide and peroxynitrite, respectively. Phenolic acids varied in relative capacity to reduce NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) in cocktail inflamed induced macrophage. This response in addition to the relative predisposition of gallic acid (GA) to undergo autoxidation to generate H2O2 activity (p < 0.05), culminated in downstream cell signaling in Caco-2 nuclear factor erythroid 2-related factor (Nrf2) activity (increase 26.9 %), altered monolayer integrity (increase 33.7 %), and release of interleukin 8 (IL-8) (decrease 80.5 %) (p < 0.05). It can be concluded that the co-culture model described herein was useful to assess the importance of communication between cytokine stimulated macrophage and intestinal cells. Moreover, the relative unique efficacy of GA, compared to other phenolic acids tested to protect against activated macrophage induced changes related to intestinal dysfunction were particularly relevant to epithelial redox signaling, intestinal permeability and regulation of tight junction proteins. This study concludes that phenolic acids are not equal in the capacity to protect against intestinal cell dysfunction despite some indication of biological activity.

Blood Cell Count Ratios at Baseline are Associated with Initial Clinical Response to Clozapine in Treatment-Resistant, Clozapine-Naïve, Schizophrenia-Spectrum Disorder.

Clozapine is the recommended treatment for managing treatment-resistant schizophrenia (TRS), and immunological mechanisms may be involved in its unique antipsychotic efficacy. This study investigated whether baseline immune abnormalities measured with blood cell count ratios can predict the clinical response after initiating treatment with clozapine in patients with clozapine naïve TRS. A longitudinal design was developed, involving 32 patients diagnosed with treatment-resistant, clozapine-naïve schizophrenia-spectrum disorder. Patients were evaluated at baseline before clozapine starting and 8 weeks of follow-up. Psychopathological status and immune abnormalities (blood cell count ratios: neutrophil-lymphocyte ratio [NLR], monocyte-lymphocyte ratio [MLR], platelet-lymphocyte ratio [PLR] and basophil-lymphocyte ratio [BLR]) were evaluated in each visit. Baseline NLR (b=- 0.364; p=0.041) and MLR (b =- 0.400; p=0.023) predicted the change in positive symptoms over the 8-week period. Patients who exhibited a clinical response showed higher baseline NLR (2.38±0.96 vs. 1.75±0.83; p=0.040) and MLR (0.21±0.06 vs. 0.17±0.02; p=0.044) compared to non-responders. In the ROC analysis, the threshold points to distinguish between responders and non-responders were approximately 1.62 for NLR and 0.144 for MLR, yielding AUC values of 0.714 and 0.712, respectively. No statistically significant differences were observed in the blood cell count ratios from baseline to the 8-week follow-up. Our study emphasizes the potential clinical significance of baseline NLR and MLR levels as predictors of initial clozapine treatment response in patients with TRS. Future studies with larger sample sizes and longer follow-up periods should replicate our findings.

Abstract 6713: TICTE, A trispecific T-cell engager with immune checkpoint modulation for solid tumors

Abstract Background: Bispecific T-cell engager (BiTE) is a targeted cancer immunotherapy which bridges T-cells to cancer cells, leading to activation of T-cells and killing cancer cells. While BiTEs have shown promising therapeutic efficacy in the treatment of hematological malignancies, therapeutic benefit of T-cell engagers are still in exploration for the treatment of solid tumors. Upregulation of immune checkpoints presents one of the major resistant mechanisms of the BiTE therapy. Here, we report a Trispecific Immune Check-point T-Cell Engager (TICTE) platform that targets both CD3 and PD-L1 simultaneously, which activates the T-cells as well as modulates the immune checkpoint blockade through the PD/PD-L1 axis, respectively. Our in vitro and in vivo studies demonstrate that the TICTEs induce dramatic and superior antitumor activity compared to its counterpart BiTE alone and the BiTE with anti-PD-L1 combination. These studies suggest that the TICTE (CD3xTAAxPD-L1), a single-agent with dual function of T-cell activation and immune checkpoint modulation, may provide an efficacious therapy to patients with solid tumors. Methods: Various TICTEs and BiTEs formats using the human IgG like architecture in three different TAA examples were generated. Their biophysical and biological activities were characterized. The cell binding activity and antigen density of cell lines were determined using flow cytometry. TDCC activity was measured using xCELLigence RTCA eSight system. In vitro efficacy was evaluated with multiple cancer cell lines and toxicity was evaluated with normal cell lines. The humanized xenograft models were utilized to investigate the TICTEs efficacy in vivo. Results: All TICTEs adopted their intended forms and showed robust biophysical properties. The TICTEs demonstrated the blockade activity of PD1/PD-L1 axis, as well preferentially targeted tumor cells expressed both TAAs and PD-L1. Large therapeutic windows were observed in three TAA (cMET, Her2 and Trop2) TICTEs. TICTEs showed a superior efficacy compared to counterpart BiTEs and combination of BiTE with a PD-L1 inhibitor in vitro and in vivo. Low cytokine release was observed compared to combination of BiTEs with a PD-L1 inhibitor, signifying the reduced risk of cytokine release syndrome (CRS) often associated with BiTE therapy. Conclusion: A single agent of the TICTE platform with unique biological property, superior efficacy and low cytokine release could represent an alternative combination immunotherapy for solid tumors. Citation Format: Xiufeng Wu, Xiaoshan Min, Yinan Wu, Lin Liu, Jing Zhou, Silvia Hudson, Shih-ping Chen, Jennifer Li, Will Draper, Subhadra Dash, Shidong Ma, Hang Chen, Zhulun Wang. TICTE, A trispecific T-cell engager with immune checkpoint modulation for solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6713.

Quantitative methods in the analysis of clozapine in human matrices – A scoping review

Abstract Clozapine (CLZ) has retained its clinical utility in the management of schizophrenia despite the discovery of novel antipsychotics, as it possesses unique efficacy in the setting of treatment resistant schizophrenia while causing minimal extrapyramidal symptoms. However, these benefits are offset by the risk of agranulocytosis and other side effects, and therapeutic drug monitoring (TDM) is routinely recommended for patients undergoing treatment with CLZ. A multitude of approaches for the quantification of CLZ have been developed for different settings such as TDM, quality control of pharmaceutical dosage forms, and toxicology studies. Primarily, these approaches fall under one of three branches of analysis, namely, chromatography, electrochemical analysis, and spectrophotometry. This study provides a scoping review of the recent advances in the methods of quantification for CLZ and highlights the potential utility of novel methods in the field of drug quantification.

Unique Psychological Mechanisms Underlying Psilocybin Therapy Versus Escitalopram Treatment in the Treatment of Major Depressive Disorder

The mechanisms by which Psilocybin Therapy (PT) improves depression remain an important object of study, with scientists actively exploring acute psychological experiences and neurobiological processes as candidates. In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we investigated whether acute psychological experiences could meaningfully account for the unique efficacy of PT versus Escitalopram Treatment over a core 6-week trial period. An exploratory-factor-analysis-derived single-factor of depression was used as the outcome. Among a comprehensive set of acute experiences related to psilocybin, so-called “mystical experience” and “ego dissolution” were unique in mediating the effect of treatment condition on depressive response with high specificity. Higher reported levels of mystical experience, emotional breakthrough, and intense responses to music-listening were furthermore associated with greater antidepressant response. These results provide qualified support for the causal mechanistic role of acute psychological experiences in the treatment of depression via PT.