Therapeutic Profile Research Articles

Efficacy and safety of immune checkpoint inhibitors combined with chemotherapy or tyrosine kinase inhibitors in advanced endometrial cancer: A systematic review and meta-analysis.

The objective of this meta-analysis was to conduct a comprehensive assessment of the therapeutic effectiveness and safety profile of the combination of immune checkpoint inhibitors (ICIs) with either chemotherapy or tyrosine kinase inhibitors (TKIs) in the treatment of advanced-stage endometrial cancer (EC). This meta-analysis conducted a thorough literature search across PubMed, Cochrane Library, Embase, and Web of Science databases from their earliest records up to November 18th, 2023, identifying qualified randomized controlled trials (RCTs), cohort studies, and single-arm trials for inclusion in the analysis. The meta-analysis were performed to quantify and analyzed the evidence from the existing literature, focusing on outcomes including the objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), progression-free survival (PFS), and adverse events (AE). A total of 13 studies were included. In terms of ICI combined with chemotherapy, the single-arm trials showed that ICI combined with chemotherapy was effective in improving the ORR, but the overall rate of AE was higher. The results based on RCT suggested that ICI combined with chemotherapy resulted in a longer PFS of 12-24 months and OS of 18-month compared to the control group in advanced EC. In terms of ICI combined with TKI, the pooled ORR was 39.0%, the pooled DCR was 79.9%, the pooled OS rate was 50.4%, and the pooled overall AE rate was 95.8%, the pooled grade ≥3 AE rate was 73.8%, the pooled median progression-free survival (mPFS) was 6.126 months, and pooled OS was 15.099 months in advanced EC. The integrative therapeutic approach combining (ICIs) with chemotherapy or (TKIs demonstrates notable clinical efficacy in advanced EC, which can prolong the survival and help to disease control. Nevertheless, it is imperative for clinicians to be vigilant regarding the potential for adverse reactions to emerge. In addition, more RCTs are needed to solidify this study's efficacy and safety further.

Unveiling the Latest Breakthroughs: A Comprehensive Review of the Therapeutic Activity and Safety Profile of Aloe vera.

The use of herbal drugs as alternative and complementary medicine has increased in popularity, raising concerns about their safety profile. Aloe vera, a plant with diverse therapeutic properties, has been extensively used for centuries. This review aims to assess the therapeutic activity and safety profile of Aloe vera. A comprehensive literature search was conducted to gather relevant information from various biomedical databases. The chemical composition, mechanism of action, and therapeutic activities of Aloe vera were analyzed. Aloe vera contains numerous active components such as vitamins, enzymes, minerals, sugars, lignin, saponins, and anthraquinones. Its mechanisms of action involve collagen synthesis, anti-inflammatory effects, immune modulation, laxative properties, and antiviral activity. Aloe vera has demonstrated potential therapeutic benefits in wound healing, diabetes management, liver and kidney protection, and glycemic control. However, it is essential to consider potential side effects, such as skin irritation and allergic reactions. This review provides evidence-based information to improve patient safety and promote informed decisions regarding the use of Aloe vera as a therapeutic agent.

PEGylated lipid polymeric nanoparticles for management of rheumatoid arthritis

PEGylation, an extensively used surface modification method for nanoparticles (NPs), continues to hold promise for optimizing therapy for various medical conditions by achieving efficient and selective delivery of multiple therapeutics and nanocarriers. Rheumatoid arthritis is a chronic autoimmune and inflammatory disease treated mainly by disease-modifying antirheumatic drugs (DMARDs) (e.g., leflunomide); however, these drugs suffer from systemic exposure and adverse effects. Leflunomide (LEF) was loaded into PEGylated (PEG)-lecithin chitosan nanoparticles (LCNPs) to enhance its therapeutic efficacy and safety profile. LEF-PEG-LCNPs showed a particle size of 115.31 ±3.24 nm, a zeta potential of 31.3±1.8 mV, an entrapment efficiency of 89.63 ±2.25 %, and an improved release profile than non-pegylated LCNPs and LEF-pure. Fourier transform-infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and transmission electron microscopy (TEM) were also performed. The effects of orally administrated LEF-pure, LEF-marketed, LEF-LCNPs and LEF-PEG-LCNPs against Complete Freund’s Adjuvant (CFA)-induced rheumatoid arthritis (RA) in rats were investigated. LEF-PEG-LCNPs showed more significant inhibition of paw edema (72.74%), rheumatoid factor RF (40.76%), TNF-α (55.6%), IL-6 (47.42%), ALT (80.59%), and AST (39.83%) as compared to positive control. Furthermore, histopathological studies showed a nearly normal appearance of bone trabecular tissue, liver, kidney, lung, and heart. This highlights LEF-PEG-LCNPs as an exceptional anti-rheumatoid arthritis therapy compared to pure and marketed formulations.

Unveiling Wide Spectrum Therapeutic Implications and Signaling Mechanisms of Valsartan in Diverse Disorders: A Comprehensive Review.

Valsartan is an orally active non-peptide angiotensin receptor antagonist, an effective and well-tolerated anti-hypertensive drug. Besides its antihypertensive action, it has clinical implications in many other disorders, like heart failure (HF), arrhythmia, chronic kidney disease (CKD), diabetic complications (DM), atherosclerosis, etc. Besides angiotensin receptor blocking activity, valsartan reduces circulating levels of biochemical markers, such as hs-CRP, which is responsible for its anti-inflammatory and anti-oxidant activity. Moreover, valsartan also acts by inhibiting or inducing various signalling pathways, such as inducing autophagy via the AKT/mTOR/S6K pathway or inhibiting the TLR/NF-kB pathway. The current review exhaustively discusses the therapeutic implications of valsartan with specific emphasis on the mechanism of action in various disorders. The article provides a detailed spectrum of the therapeutic profile of valsartan and will likely be very useful to researchers working in the relevant research areas.

Aldose reductase with quinolone antibiotics interaction: In vitro and in silico approach of its relationship with diabetic complications

Aldose reductase (AR, EC1.1.1.21), a member of the aldo-keto reductase family, is critically implicated in the pathogenesis of chronic complications associated with diabetes mellitus, including neuropathy, nephropathy, and retinopathy. Hyperglycemia-induced AR overactivity results in intracellular sorbitol accumulation, NADPH depletion, and oxidative stress. Consequently, AR is recognized as a key mediator of oxidative and inflammatory signaling pathways involved in diverse human pathologies such as cardiovascular diseases, inflammatory disorders, and cancer. This has sparked renewed interest in developing novel AR inhibitors (ARIs) with enhanced therapeutic profiles. In this study, we evaluated the inhibitory potential of five quinolone antibiotics-gatifloxacin, lomefloxacin, nalidixic acid, norfloxacin, and sparfloxacin-as ARIs relevant to various physiological and pathological conditions. Through comprehensive in vitro and in silico analyses, we explored these antibiotics' binding interactions and affinities within the AR active site. Our findings reveal that these quinolones moderately inhibit AR at micromolar concentrations, with inhibition constants (KIs) ranging from 1.03 ± 0.13 μM to 4.12 ± 0.51 μM, compared to the reference drug epalrestat (KI of 0.85 ± 0.06 μM). The combined in vitro and in silico results underscore significant interactions between these drugs and AR, suggesting their potential as therapeutic agents against the aforementioned pathological conditions. Furthermore, these insights will aid in optimizing clinical dosing regimens and mitigating unexpected drug-drug interactions when these antibiotics are co-administered with other treatments.

α-Mangostin: A Xanthone Derivative in Mangosteen with Potent Anti-Cancer Properties

α-Mangostin, a xanthone derivative extracted from the pericarp of the mangosteen fruit (Garcinia mangostana L.), has garnered significant attention for its potential as a natural anti-cancer agent. This review provides a comprehensive analysis of the current literature on the anti-cancer properties of α-mangostin across various cancer types. Through an extensive analysis of in vitro and in vivo studies, this review elucidates the multifaceted mechanisms underlying α-mangostin’s cytotoxicity, apoptosis induction through both intrinsic and extrinsic pathways, and modulation of key cellular processes implicated in cancer progression in a diverse array of cancer cells. It causes mitochondrial dysfunction, activates caspases, and regulates autophagy, endoplasmic reticulum stress, and oxidative stress, enhancing its anti-cancer efficacy. Moreover, α-mangostin exhibits synergistic effects with conventional chemotherapeutic agents, suggesting its utility in combination therapies. The ability of α-mangostin to inhibit cell proliferation, modulate cell cycle progression, and induce apoptosis is linked to its effects on key signaling pathways, including Akt, NF-κB, and p53. Preclinical studies highlight the therapeutic potential and safety profile of α-mangostin, demonstrating significant tumor growth inhibition without adverse effects on normal cells. In summary, understanding the molecular targets and mechanisms of action of α-mangostin is crucial for its development as a novel chemotherapeutic agent, and future clinical investigations are warranted to explore its clinical utility and efficacy in cancer prevention and therapy.

Epidemiological, clinical, paraclinical, evolutionary, and therapeutic aspects of hypertensive patients infected by COVID-19: about 702 patients in our city

Abstract Introduction Hypertension (HT) is a major cardiovascular risk factor frequently observed in COVID-19 patients. This study aimed to determine the frequency of hypertensive patients infected with COVID-19 at a national hospital, describe their epidemiological, clinical, paraclinical, and therapeutic profile, their disease progression, and identify factors associated with death. Methodology A retrospective, descriptive, and analytical study was conducted over 24 months and 4 days, from 27 March 2020 to 30 March 2022, at national hospital. Included were hospitalized patients at a hospital with a confirmed COVID-19 diagnosis, known hypertensives, regardless of gender, and with a hospitalization record. COVID-19 diagnosis was based on a positive SARS-CoV-2 RT-PCR or a positive COVID Rapid Diagnostic Test. Data were collected using a survey form, with a p-value less than 0.05 considered statistically significant for bivariate analysis. Results The study enrolled 702 patients, a hospital frequency of 23.95%. The average age was 65.14 ± 12.24 years with a sex ratio of 0.81. Comorbidities were predominantly diabetes (40.5%) and dyslipidemia (4.8%). Common symptoms included cough (65%), dyspnea (42.3%), fever (47.4%), and asthenia (35.9%). Blood pressure was normal in 15.2%, high-normal in 16.8% of patients. HT was Grade I in 12.1%, Grade II in 10%, and Grade III in 6.8% of the population, with blood pressure unmeasurable in 0.3% of known hypertensive patients. SARSCOV2 infection was mild in 34.2% and moderate in 42.8% of cases. CT scans showed extensive (31.8%), severe (25.9%), moderate (25.6%), critical (8.5%), and minimal (7.9%) lung damage. Treatment mainly consisted of ACE inhibitors (29%), ACE inhibitors in combination with another antihypertensive (8.4%), and ARBs in combination with an antihypertensive (). The average hospital stay was 12.85 days with a favorable outcome in 81% and a mortality rate of 15.5%. Factors associated with death included not being vaccinated against COVID-19 (HR: 11.70; 95% CI: 1.324-103.519), critical clinical form (HR: 11.70; 95% CI: 1.324-103.519), pulmonary consolidation (HR: 8.87; 95% CI: 7.539-24.207), high creatinine (HR: 4.69; 95% CI: 1.360-16.181), critical CT thoracic level (HR: 2.42; 95% CI: 1.020-5.745), and not taking ARBs (HR: 6.02; 95% CI: 2.812-12.889). Conclusion HT can be associated with COVID-19, impacting the disease's prognosis with significant mortality. Preventing its incidence and morbidity/mortality is crucial.

Steered molecular dynamics simulation as a post-process to optimize the iBRAB-designed Fab model.

Therapeutic monoclonal antibodies are an effective method of treating acute infectious diseases. However, knowing which of the produced antibodies in the vast number of human antibodies can cure the disease requires a long time and advanced technology. The previously introduced iBRAB method relies on studied antibodies to design a broad-spectrum antibody capable of neutralizing antigens of many different Influenza A viral strains. To evaluate the antigen-binding fragment as an applicable drug, the therapeutic antibody profiles providing guidelines collected from clinically staged therapeutic antibodies were used to access different measurements. Although the evaluated values were within an accepted range, the modification in the amino acid sequence is required for better properties. Thus, using the steered molecular dynamics(SMD) simulation to determine the binding capacity of amino acids in the functional region, the profile of interacted amino acids of Fab with the antigen was established for modified reference. As a result, the model was modified with amino acids elimination at positions 96-97 in the heavy chain and 26-27, 91, 96-97, and 102-103 in the light chain, which has better Therapeutic Antibody Profiler evaluations than the original designation. Thus again, SMD simulation is a promising computational approach for post-modification in rational drug design.

Gastrointestinal Microbiota in Gastric Cancer: Potential Mechanisms and Clinical Applications-A Literature Review.

Emerging evidence highlights the crucial role of gastrointestinal microbiota in the pathogenesis of gastric cancer. Helicobacter pylori (H. pylori) infection stands out as a primary pathogenic factor. However, interventions such as anti-H. pylori therapy, gastric surgeries, immunotherapy, and chronic inflammation significantly remodel the gastric microbiome, implicating a broader spectrum of microorganisms in cancer development. These microbial populations can modulate gastric carcinogenesis through various mechanisms, including sustained chronic inflammation, bacterial genotoxins, alterations in short-chain fatty acids, elevated gastrointestinal bile acids, impaired mucus barrier function, and increased concentrations of N-nitrosamines and lactic acid. The dynamic changes in gut microbiota also critically influence the outcomes of anti-cancer therapies by modifying drug bioavailability and metabolism, thus affecting therapeutic efficacy and side effect profiles. Additionally, the effectiveness of radiotherapy can be significantly impacted by gut microbiota alterations. Novel therapeutic strategies targeting the microbiome, such as dietary interventions, probiotic and synbiotic supplementation, and fecal microbiota transplantation, are showing promise in cancer treatment. Understanding the intricate relationship between the gut microbiota and gastric cancer is essential for developing new, evidence-based approaches to the prevention and treatment of this malignancy.

Engaging a New Treatment Paradigm: Elranatamab in Relapsed/Refractory Multiple Myeloma.

To review the therapeutic profile of elranatamab, a novel bispecific T-cell-redirecting therapy, in treating relapsed or refractory (R/R) multiple myeloma (MM). A PubMed search was conducted for English-language articles published from January 2000 through June 2024, using the search terms: PF-06863135, elranatamab, Elrexfio, and "Multiple Myeloma." Additional data were obtained from ClinicalTrials.gov and other pertinent publications and meeting abstracts. Clinical trials, guidelines, and prescribing information pertaining to elranatamab were included. The phase II MagentisMM-3 trial demonstrated an overall response rate of 61.0% (95% confidence interval, 51.8-69.6) in patients naïve to B-cell maturation antigen targeting therapy (cohort A, n = 123), establishing elranatamab monotherapy as a viable treatment option for patients with R/R MM who have received at least 4 prior lines of therapy. The duration of response and progression-free survival at 12 months were 75.3% and 56.6%, respectively. Despite the promising activity of elranatamab in R/R MM, the significant treatment-related adverse effects (AEs) associated with this therapy necessitate careful monitoring and expert management. Common AEs include cytokine release syndrome, neurotoxicity, hematologic toxicity, and infectious complications. The cost-effectiveness of elranatamab has yet to be evaluated. Elranatamab is approved by the Food and Drug Administration as a treatment option for patients with heavily pretreated R/R MM. Further studies are warranted to identify the optimal treatment strategy for elranatamab and other bispecific antibodies in the management of R/R MM.

A Decade of Insights into Bilateral Adrenal Masses: Epidemiology, Clinical Profiles, and Therapeutic Approaches

Bilateral adrenal masses (BAMs) are rare, accounting for 10-15% of adrenal masses. Their diagnostic and therapeutic approaches differ from those of unilateral masses. This study aimed to analyze the epidemiological, clinical, paraclinical, and therapeutic profiles of BAMs. It is based on a retrospective analysis of 30 patient records from the Endocrinology, Diabetology, and Nutrition Department at CHU Hassan II in Fez, over a 12-year period. The average age of the patients was 53 years, with a male predominance (53.3%). BAMs were symptomatically revealed in 46.7% of cases, incidentally discovered in 23.3%, identified during tumor staging in 20%, and associated with a genetic syndrome in 10% of cases. Clinical examination revealed hypertension in 23.3% of patients, an abdominal mass in 10%, signs of adrenal insufficiency in 10%, hypercortisolism in 6.67%, and hyperandrogenism in 16% of cases. Biological assessment showed elevated urinary or plasma metanephrine derivatives in 9 patients, hypercortisolism in 3 patients, adrenal insufficiency in 3 patients, 11-β-hydroxylase enzyme block in 3 patients, and primary hyperaldosteronism in 1 patient. Adrenal computed tomography (CT) was performed in 29 patients. A staging workup, including PET scan, was requested in 20% of cases. MIBG scintigraphy was performed in 23.3% of patients. The investigations revealed 53% of BAMs were secreting and 47% non-secreting. There were 9 cases of pheochromocytomas, including 5 associated with a syndrome (3 MEN2a, 1 MEN2b, 1 VHL), 8 cases of non-secreting adenomas, 3 cases of congenital adrenal hyperplasia due to 11-β-hydroxylase enzyme block, 2 cases of adrenal metastases, 2 cases of adrenocortical carcinoma, 2 cases of adrenal cysts, 1 case of Conn’s adenoma, 1 case of cortisol-secreting adenoma, 1 case of primary adrenal lymphoma, and 1 case of adrenal hematoma. Treatment included the management of emergencies and preoperative preparation for patients eligible for surgery. Bilateral adrenalectomy was performed in 33.3% of patients, and unilateral adenectomy in 1 case of cortisol-secreting adenoma. Medical treatment was initiated in 16.6% of cases, and palliative treatment in 13.33% of cases. Surveillance alone was implemented in the remaining 33.3%. Prognosis depends on the type of adrenal mass, with outcomes marked by the death of one case of malignant adrenocortical carcinoma and one case of primary adrenal lymphoma. Our study, involving 30 cases of BAMs, highlights their clinical, biological, radiological, therapeutic, and prognostic characteristics. Data in the literature are limited compared to unilateral adrenal masses. Future larger studies are desirable for optimal management.

Clinical research vehicles as a modality for medical research education and conduct of decentralized trials, supporting justice, equity, and diversity in research.

Current clinical research lacks diversity in those that participate. This lack of diversity is concerning given its importance for successful drug development. The frequency and severity of many diseases, along with the pharmacological properties of therapies, can display significant differences based on patient diversity. A clinical trial population that is more reflective of these differences will help researchers better understand the therapeutic profile of the treatment and provide generalizable knowledge to the medical community. The advent of decentralized clinical trial designs is meant to help address this lack of diversity by using portable digital health technologies and virtual interactions to enhance clinical trial access and broaden participation. By leveraging these technologies, trial conduct can occur at locations other than traditional research sites. This shift in trial location may help address some of the logistical, educational, engagement, and trust barriers that have historically prevented enrollment of diverse populations. However, these types of trials still have limitations. Ethical concerns around justice, equity, and diversity will still exist with decentralized clinical trials, which could be mediated using clinical research vehicles. When utilized, this modality may enhance the scientific design and conduct of clinical trials and better follow these ethical principles. These enhancements and improved ethical direction could be accomplished through increasing community involvement, improving health literacy, supporting more diverse trial sites, creating community-based research footholds, fostering connections with researchers, limiting technical challenges, and preventing data security issues.

Efficacy of Atezolizumab Plus Bevacizumab Combined with Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma: A Real-World Study.

Transarterial chemoembolization (TACE), when used in combination with immunotherapy and antiangiogenic therapy, has been shown to have synergistic anticancer effects. The aim of this study was to further assess the efficacy and safety of TACE combined with atezolizumab and bevacizumab in the treatment of unresectable hepatocellular carcinoma (HCC) in the real world. Between August 2021 and September 2023, clinical information was collected from consecutive HCC patients who received treatment via TACE-Atezo/Bev at four tertiary institutions. This study evaluated the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) as outcomes. Predictors for OS and PFS were also analyzed. Treatment-related adverse events (TRAEs) were recorded and assessed. Ninety-two patients were enrolled in this study, with a median follow-up duration of 14.1 months. The ORRs based on the modified Response Evaluation Criteria in Solid Tumors (RECIST) and RECIST 1.1 criteria were 54.3% and 41.3%, respectively. The median OS and PFS of the patients were 15.9 months [95% confidence interval (CI), 14.5-17.2 months] and 9.1 months (95% CI, 7.4-10.8 months), respectively. Multivariate analyses revealed that the Eastern Cooperative Oncology Group score and neutrophil‒lymphocyte ratio were independent risk factors for OS, whereas tumor size and extrahepatic metastasis were independent risk factors for PFS. Grade 3/4 TRAEs occurred in 16.3% (15/92) of the patients and were controlled conservatively. The combination of Atezo/Bev with TACE demonstrated acceptable synergistic therapeutic effects and manageable safety profiles in patients with unresectable HCC.

180 (PB168): DB-1314, a novel DLL3-targeting ADC with DNA topoisomerase I inhibitor, exhibits promising therapeutic efficacy and safety profile in preclinical

180 (PB168): DB-1314, a novel DLL3-targeting ADC with DNA topoisomerase I inhibitor, exhibits promising therapeutic efficacy and safety profile in preclinical

RUTHENIUM ORGANOMETALLIC COMPOUNDS IN CANCER TREATMENT

Organometallic complexes with ruthenium have shown promise as potential anticancer agents. These complexes represent a class of compounds that can exhibit unique mechanisms of action, and they may offer advantages or overcome some limitations associated with platinum-based drugs, such as cisplatin. Ruthenium-based complexes can have diverse mechanisms of action. They may interact with DNA, proteins, or other cellular components, leading to cytotoxic effects on cancer cells. The versatility of ruthenium coordination chemistry allows for the design of complexes with specific properties. Some cancers that become resistant to platinum-based drugs may still respond to ruthenium-based compounds. This reduced cross-resistance is attributed to differences in the mechanisms of action between platinum and ruthenium complexes. Researchers can design ruthenium complexes to target specific cellular pathways or processes associated with cancer. This targeted approach aims to enhance the selectivity of the treatment for cancer cells while minimizing the impact on normal cells. Ruthenium complexes often have unique structural features that contribute to their stability and reactivity. These features can be tailored to optimize the pharmacological properties of the compounds. Ruthenium-based complexes may be explored in combination with other anticancer agents to achieve synergistic effects and enhance overall treatment efficacy. Ongoing research continues to explore the potential of ruthenium-based organometallic complexes, and preclinical studies have demonstrated promising results. As with any emerging field, further investigations and clinical trials are needed to fully understand the therapeutic potential and safety profiles of these compounds for various types of cancers.

Evaluating Therapeutic Potential and Safety Profile of Desidustat for Anaemia Management in Patients with CKD: A Prospective, Open-Label, Single-Centre Study

Evaluating Therapeutic Potential and Safety Profile of Desidustat for Anaemia Management in Patients with CKD: A Prospective, Open-Label, Single-Centre Study

Lithium’s renaissance: From psychiatric staple to multifaceted medical marvel

Abstract: Lithium, long established as a cornerstone in the treatment of bipolar disorder, has recently emerged as a potential therapeutic agent across a broad spectrum of medical fields. This narrative review examines the expanding role of lithium in contemporary medicine, highlighting its transition from a psychiatric staple to a versatile therapeutic tool. The objective of the study was to synthesize and critically evaluate recent literature on lithium’s applications beyond psychiatry, focusing on its mechanisms of action, therapeutic potential, and challenges in various medical domains. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science databases, focusing on peer-reviewed articles published within the last 5 years. Keywords included “lithium” combined with terms such as “neuroprotection,” “cancer,” “stem cells,” “viral infections,” and “aging.” Case studies, clinical trials, systematic reviews, and meta-analyses were included to provide a broad perspective on lithium’s emerging roles. Recent studies have revealed lithium’s potential in several key areas: neuroprotection in neurodegenerative disorders, cancer therapy enhancement, stem cell mobilization for regenerative medicine, antiviral properties, cardioprotection against ischemia-reperfusion injury, circadian rhythm regulation, and potential effects on longevity and healthy aging. Lithium’s renaissance in medical research reveals its potential as a multifaceted therapeutic agent. While challenges remain, including its narrow therapeutic index and side effect profile, ongoing research into novel delivery methods and personalized medicine approaches may optimize its use. The expanding applications of lithium underscore the need for continued investigation to fully harness its therapeutic potential across various medical disciplines.

Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis.

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis. Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. Here, we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models, including mice exhibiting advanced pulmonary disease, can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

Harnessing Pharmacogenomics in Clinical Research on Psychedelic-Assisted Therapy.

Psychedelics have recently re-emerged as potential treatments for various psychiatric conditions that impose major public health costs and for which current treatment options have limited efficacy. At the same time, personalized medicine is increasingly being implemented in psychiatry to provide individualized drug dosing recommendations based on genetics. This review brings together these topics to explore the utility of pharmacogenomics (a key component of personalized medicine) in psychedelic-assisted therapies. We summarized the literature and explored the potential implications of genetic variability on the pharmacodynamics and pharmacokinetics of psychedelic drugs including lysergic acid diethylamide (LSD), psilocybin, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), ibogaine and 3,4-methylenedioxymethamphetamine (MDMA). Although existing evidence is limited, particularly concerning pharmacodynamics, studies investigating pharmacokinetics indicate that genetic variants in drug-metabolizing enzymes, such as cytochrome P450, impact the intensity of acute psychedelic effects for LSD and ibogaine, and that a dose reduction for CYP2D6 poor metabolizers may be appropriate. Furthermore, based on the preclinical evidence, it can be hypothesized that CYP2D6 metabolizer status might contribute to altered acute psychedelic experiences with 5-MeO-DMT and psilocybin when combined with monoamine oxidase inhibitors. In conclusion, considering early evidence that genetic factors can influence the effects of certain psychedelics, we suggest that pharmacogenomic testing should be further investigated in clinical research. This is necessary to evaluate its utility in improving the safety and therapeutic profile of psychedelic therapies and a potential future role in personalizing psychedelic-assisted therapies, should these treatments become available.

Synthesis and in vitro evaluation of tetrazole containing 1,5-benzothiazepines as new anticancer, antitubercular, antibacterial, and antifungal agents

Heterocyclic scaffolds have attracted great attention of organic chemists and medicinal chemists, also because of their wide range of synthetic applicability and broad spectrum of biological profile. Therefore, in the present research work, a series of tetrazole containing 1,5-benzothiazepines have been synthesized for evaluation of their biological activities to determine the potential therapeutic profile of these compounds across various medicinal domains. Of the synthesized compounds, five compounds (6f, 8e, 8f, 8g, and 8h) have been screened for anticancer, antitubercular, antibacterial, and antifungal activities. After evaluation of these biological activities, it was found that these compounds possess very limited anticancer activity, moderate antibacterial and antifungal activity, and very strong antitubercular activity, which indicate their great pharmacological applications as subjects for future investigations of novel therapeutic agents for the treatment of tuberculosis.