Torrent Pharma (India)

Abstract Objective We aimed to prospectively validate and compare published prediction models and clinician-assigned triage categories for early trauma care. Design Prospective multicentre cohort study. Setting Three public hospitals in urban India: one secondary care hospital in Mumbai and one tertiary care teaching hospitals in Delhi and Kolkata each. Participants Adult patients aged over 18 years presenting to the emergency department with a history of trauma between 2016 and 2022. A total of 13,041 patients were included in the final analysis. Methods We externally validated five published trauma prediction models (GAP, Gerdin, KTS, MGAP, and RTS) and clinician-assigned triage categories based on initial assessment. The primary outcome was 30-day all-cause mortality. Models were recalibrated using a separate updating sample prior to evaluation, and model performance was assessed in terms of discrimination (AUC), calibration (calibration slope and plots), and decision curve analysis. Results All models and clinician gestalt-based triage demonstrated excellent discrimination (AUC range: 0.90-0.96) and good calibration after updating. The GAP model achieved the highest AUC (0.96, 95% 0.94-0.97), and RTS demonstrated the highest sensitivity (0.70). Conclusion Simple, physiology-based prediction models and clinician gestalt both demonstrated excellent performance in predicting 30-day mortality among adult trauma patients in Indian emergency departments. These findings provide a practical foundation for further development of trauma triage systems.

The syntheses of therapeutically important μ-opioid receptor antagonists such as naloxone and naltrexone use noroxymorphone as a key late-stage intermediate, which is manufactured from the poppy-derived alkaloids oripavine or thebaine. However, it would be advantageous to instead use morphine as the starting material, which is cheaper and more abundant. In this paper, we describe the conversion of morphine into a dienol acetate required for installation of the C14 hydroxyl group of noroxymorphone. Our approach is more efficient than previously described approaches and uses a one-pot Albright–Goldman oxidation/dienol acetate formation sequence of an allylic alcohol as the key feature. This synthesis has been successfully applied on multikilogram scales. A brief investigation of the scope of the one-pot Albright–Goldman oxidation/dienol ester formation on other substrates is also described.

The increasing global demand for herbs and spices in food and nutraceutical industries highlights their key functional benefits, including antioxidant and anti-inflammatory properties. Ensuring authenticity and traceability is essential to counteract challenges such as geographical origin (GO) mislabelling and tissue- or variety-specific adulteration, which can undermine product quality and safety. This study employs LC-Orbitrap-MS-based untargeted metabolomics coupled with machine learning to authenticate the GO, variety, and tissue specificity of turmeric (Curcuma longa) and ashwagandha (Withania somnifera), two widely used food ingredients. Four GO-specific turmeric samples, three tissue- and variety- specific ashwagandha samples, and adulterated market samples were analysed using data-dependent acquisition mode. Machine learning algorithms identified key biomarkers and constructed robust classification models, achieving 98% specificity and accuracy in authenticating GO, variety, and tissue specificity, even in adulterated samples. These results demonstrate the value of integrating advanced metabolomics and machine learning for quality assurance and food safety in the global market.

Wound healing is a complex process with various dimensions, often presenting as a growing concern that prompts the quest for advancements. This review emphasizes the therapeutic potential of medicinal plants rich in flavonoids, terpenoids, polyphenols, alkaloids, and steroids and discusses their valuable antibacterial, antioxidant, and anti-inflammatory properties in wound management. Cross talk of the phytochemicals with the intricate phases of wound healing, encompassing hemostasis, inflammation, proliferation, and remodeling is detailed, highlighting essential cellular and molecular mechanisms crucial for effective tissue repair. Chronic wounds, a significant global health concern, underscore the importance of advancing wound care therapies. Various treatment modalities, from platelet-rich plasma (PRP) and stem cell therapy to gene therapy, offer diverse mechanisms to promote wound closure and tissue regeneration and mitigate infection risk. Challenges such as variable efficacy, cost, and limited availability necessitate ongoing research for optimal wound management strategies. Wound dressings play a pivotal role in wound care by providing protective barriers against microbial invasion, facilitating tissue regeneration, and maintaining a moist wound environment conducive to healing. The review outlines various types of dressings, including hydrocolloid, foam, alginate, hydrogel, collagen, silver, transparent film, and composite dressings, each offering specific functions and limitations. Appropriate dressing selection depends on wound type, exudate level, and desired therapeutic outcomes. This review offers valuable insights into the complex landscape of wound-healing research and treatment. Synthesizing recent advancements in natural compounds, therapeutic interventions, and wound dressing technologies provides a comprehensive overview of current understanding and future directions in wound care.

Nanotechnology is an innovative field focused on manipulating matter at the molecular and atomic scale, typically below 100 nanometers. It enables the design, creation, and application of systems with enhanced properties due to nanoscale precision. Molecular nanotechnology (MNT) integrates engineering with molecular chemistry and physics, offering substantial advancements in medicine, environmental cleanup, and other fields. Significant milestones include the invention of the Scanning Tunneling Microscope (STM) in 1981 and Eric Drexler's popularization of the field with his book "Engines of Creation." Nanotechnology has revolutionized medicine with improved drug delivery systems, diagnostic tools, and medical imaging. In environmental science, it has enabled advanced filtration systems and pollution control methods. Different types of nanoparticles, such as metal, semiconductor, polymeric, lipid, carbon-based, and magnetic nanoparticles, have unique properties and applications across various industries. Despite its benefits, nanotechnology raises health and environmental concerns, leading to the emergence of nanotoxicology and nanomedicine to study and mitigate hazards. The evolution of nanotechnology has significantly impacted healthcare, electronics, energy, and materials. Regulatory challenges and health concerns present obstacles to commercialization, requiring collaborative efforts and proactive risk management.

Since June 2018, globally large numbers of pharmaceuticals have been recalled due to the unexpected presence of nitrosamines. Beginning with the class of pharmaceuticals known as sartans, subsequent lines of inquiry included antidiabetic medicines, antihistamines, and antibiotics. A critical review of the U.S. Food and Drug Administration database reveals that the highest number of productsrecall due to the presence of unacceptable levels of nitrosamines were losartan potassium drug products and their coformulations with other drug substances. The problem can be mainly attributed to naively adopted approval revisions and the lack of sufficient current analytical technologies to detect those contaminants in time. In this work, we developed a specific, selective, accurate, precise, and robust ultra-performance liquid chromatography-triple quadrupole-mass spectrometry(UPLC-TQ-MS/MS) method for the estimation of eight genotoxic nitrosamine impurities in losartan and hydrochlorothiazide (HCTZ) tablets, which is the only fixed-dosage combination approved by the USFDA to treat hypertension. All the nitrosamine impurities along with the drug substances were separated using an Agilent Pursuit XRs Ultra diphenyl column (150 × 2.0mm, 2.8μm) with mobile phase A (0.1% formic acid in water) and mobile phase B (0.1% formic acid in methanol) at a flow rate of 0.4ml/min using the gradient elution program. The proposed method was validated per ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) Q2 (R1) guidelines to ensure the method is suitable for its intended purpose. Limit of detection and limit of quantification were obtained in the range of 0.25-0.5ng/mL, which was very low compared to levels specified by the USFDA, European Medicines Agency(EMA), and other regulatory authorities that ensure the sensitivity of the method in its entire life cycle. The developed method can be incorporated into an official monograph and applied for routine quality control analysis of losartan and HCTZ fixed-dose combination tablets.

This study developed and validated a trace-level quantification inorganic impurities method using reversed-phase HPLC and performed the robustness check using quality-by-design approach by varying the multiple factors simultaneously. This method is economical and simple and exhibits its stability-indicating nature [for the determination of ferrocyanide ([Fe(CN)₆]4- ), ferricyanide ([Fe(CN)6 ]3- ), nitrate (NO3 - ), and nitrite (NO2 - )] in sodium nitroprusside (SNP) drug substance and liquid dosage form. Chromatographic separation was achieved using a USP L43 column (ACE PFP, 150×4.6 mm, 3 μm) with a simple isocratic elution. The buffer consists of potassium dihydrogen phosphate (50 mM), tetrabutylammonium hydrogen sulfate (9 mM), and tetrabutylammonium hydroxide (25 mM). The buffer pH was adjusted to 7.2 with tetrabutylammonium hydroxide. The mobile phase was mixed with the buffer and acetonitrile (68:32 v/v). The flow rate was 0.8 mL/min, column temperature was maintained at 30°C, and injection volume was 5.0 μL. The SNP impurities were monitored at 225 nm using a UV detector. Further, the method was validated per the International Council for Harmonisation (ICH) guidelines, and forced degradation studies were carried out under different stress conditions. The detector responses were plotted against concentrations, and correlation was linear (r > 0.999) over the range of 0.8-7.5 μg/mL for ferricyanide; 1.0-37.5 μg/mL for SNP; and 0.2-7.5 μg/mL for ferrocyanide, nitrite, and nitrate. The method repeatability was established for all the impurities with relative standard deviation (%), and the results were found to be less than 2.0.

TRC150094, a novel mitochondrial modulator, can restore metabolic flexibility by improving insulin resistance in preclinical studies. This study primarily aims to evaluate the safety, tolerability, and pharmacokinetics (PK) of oral TRC150094 after conducting two double-blind, randomized, Phase-I studies, single ascending dose (SAD) and multiple ascending dose (MAD), with n = 46, in overweight/obese adult and elderly subjects. In addition, the effect of TRC150094 on pharmacodynamic (PD) efficacy markers was evaluated. PK assessments, including maximum concentration (Cmax), area under the plasma concentration (AUC), time to Cmax (Tmax), and elimination half-life (t½), were assessed at pre-specified time points. PD assessments included apolipoprotein B (ApoB), triglycerides, hepatic fat by magnetic resonance spectroscopy (MRS) and cardiopulmonary exercise testing (CPET) parameters. TRC150094 was rapidly absorbed, and the AUC of TRC150094 increased in a dose-dependent manner across all doses in non-elderly and elderly cohorts. Cmax was more than the dose-proportional for all doses in all cohorts. Tmax ranged from 0.25 to 4 h, and t½ ranged from 15 to 18 h, making TRC150094 suitable for once-daily dosing. Food did not interfere with the overall absorption of the drug. The metabolites of TRC150094 were glucuronide and sulfate conjugates, and 20% of the drug was excreted unchanged in the urine. TRC150094 at 50 mg showed an improving trend in triglycerides. A significant reduction in Apo B was observed after 50 mg dose (−2.34 vs. 13.24%, p = 0.008), which was, however, not the case after 150 mg (8.78 vs. 13.24%, p = 0.1221). Other parameters such as hepatic fat and insulin sensitivity indices (HOMA-IR, MATSUDA Index derived from OGTT) showed an improving trend for the dose of 50 mg. In terms of safety, all the AEs reported were mild to moderate in severity. None of the adverse events was considered definitely or probably related to treatment, and there were no abnormal laboratory findings. In conclusion, the PK of TRC150094 was linear with no clinically significant food effect. TRC150094 and its metabolites suggest a lesser likelihood of drug-drug interactions. Overall, TRC150094 ensured safety and exhibited suitability for all subjects.Clinical Trial Registration: EUDRA CT: 2009-014941-10 (SAD) and CTR-India registration: CTRI/2009/091/000601 (MAD)

Abstract KRAS along with other RAS genes represents the most prevalent oncogene in human cancers. Atypical Ras signaling has been identified in more than 30% of all human cancers with the most common being lung, colon, and pancreatic cancers. In particular, K-Ras has been identified as the most important Ras protein in cancer research, implicated in over 21% of human cancers. Current strategies drug only specific K-Ras mutants, leaving open an unmet need for new agents that can address a broader patient population. A new opportunity is emerging for the development of a therapeutic Pan Ras inhibitor by targeting the upstream guanine nucleotide exchange factor (GEF) protein SOS (Son of sevenless). Disruption of SOS1- K-Ras mutant interaction is a good strategy to inhibit activation of mutant K-Ras. SOS1 inhibition through the protein-protein interaction (PPI) disruption assists in keeping K-Ras in the GDP inactive, rather than its active GTP-bound state. Inhibition of SOS1 results in blockade of the RAS-MEK-ERK pathway and lowering proliferation, in both WT and all mutant Ras forms. Here we discuss our approach to target SOS1 to control aberrant Ras signaling in NSCLC and colon cancers. We report the identification of novel potent SOS1-K-Ras disruptors using the SOS1-K-Ras PPI TR-FRET assay. Multiple series have been identified, with a good SAR trend. We have identified low nanomolar potent compounds that translate to modulation of p-ERK in cell based assays in K-Ras mutant cell lines. These compounds exhibited good ADME properties like solubility and metabolic stability. Further profiling of these compounds is ongoing. Citation Format: Sanjita Sasmal, Anuradha Ramanathan, Venkatesham Boorgu. Identification of novel SOS1-K-Ras disruptors for NSCLC and colon cancers with K-Ras mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB117.

In the present era of drug development, quantification of drug concentrations following pharmacokinetic studies has preferentially been performed using plasma as a matrix rather than whole blood. However, it is critical to realize the difference between measuring drug concentrations in blood versusplasmaand the consequences thereof. Pharmacokinetics using plasma data may be misleading if concentrations differ between plasma and red blood cells (RBCs) because of differential binding in blood. In this review, factors modulating the partitioning of drugs into RBCs are discussed andthe importance of determining RBC uptake of drugs for drug candidate selection is explored. In summary, the choice of matrix (plasma vs whole blood) is an important consideration to be factored induring drug discovery.