Dose Optimization in Oncology Drug Development: An International Consortium for Innovation and Quality in Pharmaceutical Development White Paper.

The landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug Administration, stands as a groundbreaking endeavor to reform dose selection of oncology drugs, presenting both opportunities and challenges for the field. To address complex dose optimization challenges, an Oncology Dose Optimization IQ Working Group was created to characterize current practices, provide recommendations for improvement, develop a clinical toolkit, and engage Health Authorities. Historically, dose selection for cytotoxic chemotherapeutics has focused on the maximum tolerated dose, a paradigm that is less relevant for targeted therapies and new treatment modalities. A survey conducted by this group gathered insights from member companies regarding industry practices in oncology dose optimization. Given oncology drug development is a complex effort with multidimensional optimization and high failure rates due to lack of clinically relevant efficacy, this Working Group advocates for a case-by-case approach to inform the timing, specific quantitative targets, and strategies for dose optimization, depending on factors such as disease characteristics, patient population, mechanism of action, including associated resistance mechanisms, and therapeutic index. This white paper highlights the evolving nature of oncology dose optimization, the impact of Project Optimus, and the need for a tailored and evidence-based approach to optimize oncology drug dosing regimens effectively.

Antibacterial and Antioxidant Compounds from the Root Extract of Aloe debrana.

This study was conducted to isolate and identify the chemical compounds from the roots of Aloe debrana (L.) and evaluate their antioxidant and antibacterial activities. From the acetone (99.5%) extract of the roots of this plant, four anthraquinones, such as chrysophanol (1), asphodeline (2), aloesaponarin I (5), and laccaic acid D-methyl ester (6), and a new catechol derivative, 5-allyl-3-methoxybenzene-1,2-diol (3), were isolated and elucidated by different chromatographic and spectroscopic methods together with linoleic acid (4), respectively. Compounds 2, 3, and 4 were reported here for the first time from this plant and compound 3 from the genus Aloe. The compounds were evaluated for their antioxidant activity using H2O2 and DPPH assays and bactericidal activity against S. aureus and E. coli. Compounds 3 and 6 showed highest antioxidant activities with IC50 values of 19.38 ± 0.64 and 32.81 ± 0.78 µg/mL in DPPH, and 28.52 ± 1.08 and 27.31 ± 1.46 µg/mL in H2O2, respectively. The isolated compounds also demonstrated considerable activity towards S. aureus. Among these compounds, compound 3 exhibited the highest activity (91.20 ± 0.12% and 9.14 ± 0.93 mm at 1.0 mg/mL) against this bacterium. The overall results suggest that the isolated compounds may be considered as potential sources of the bioactive agents to be used in the pharmacological, food, and other industries. Moreover, their high sensitivity against S. aureus may also support the use of A. debrana plant in the traditional medicine to treat wounds. Therefore, the isolated compounds are responsible for medicinal properties of this plant.

Thoracoscopic blood patch instillation for persistent air leak in pneumothorax: a case series and systematic review.

Persistent air leaks in patients with pneumothorax can lead to significant morbidity. If a patient with persistent air leak is medically unfit for thoracic surgery, medical pleurodesis via chest tube or thoracoscopy is either an option. Thoracoscopy offers the advantage of visualizing the site of the air leak and enabling direct instillation of the pleurodesis agent or glue at that location. Autologous blood patch instillation via chest tube has been reported to be a cheap and very effective technique for the management of persistent air leaks. However, thoracoscopic blood patch instillation has not been reported in the literature. We report two cases of secondary spontaneous pneumothorax in which patients had persistent air leaks for more than seven days and were subjected to thoracoscopy to locate the site of the leak. In the same sitting, 50 mL of autologous blood patch was instilled directly at the leak site. Post-procedure, the air leak subsided in both patients, and the chest tube was removed with complete lung expansion. We also conducted a systematic review of the use of medical thoracoscopic interventions for treating persistent air leaks.

Pharmaceutical Emulsions: A Viable Approach for Ocular Drug Delivery.

Ocular disorders can lead to serious sight impairment and irreversible blindness. Generally simple topical and systemic treatments are recommended for treating these vision-threatening illnesses. The distinctive architecture of the eye complicates ocular drug delivery. The ophthalmic emulsion formulations have been found to increase bioavailability in the eye by prolonging residence time and improving permeability through the cornea. Therefore, this study highlights ophthalmic emulsions meant for both the anterior and posterior parts of the eye while examining a wide range of ocular disorders that affect individuals globally. This review presents, in brief, recent emulsion-based patented innovations, clinical trials, and marketed emulsion formulations for ocular drug delivery, which are strengthening development of the new ophthalmic drug products for managing different ocular diseases and disorders.

Implementing the practice of early skin-to-skin contact among infants ≥35 weeks gestation born vaginally: a quality improvement study.

BACKGROUND: Early skin-to-skin contact (SSC) at birth has been shown to improve neonatal outcomes due to enhanced cardiorespiratory stability, thermoregulation and breastfeeding success. LOCAL PROBLEM: The practice of early SSC was virtually non-existent in our delivery room (DR). METHODS AND INTERVENTIONS: The study was conducted in a newly established tertiary care teaching hospital in Western Rajasthan, India. We aimed to improve the median duration of early SSC from 0 min to at least 60 min over 24 weeks in our DR. A quality improvement (QI) team was formed, and all inborn infants ≥35 weeks born vaginally from 9 March 2017 were included. Using the tools of point-of-care QI, we found the lack of standard operating procedure, lack of knowledge among nursing staff regarding early SSC, routine shifting of all infants to radiant warmer, the practice of prioritising birthweight documentation and vitamin K administration as the major hindrances to early SSC. Various change ideas were implemented and tested sequentially through multiple plan-do-study-act (PDSA) cycles to improve the duration of early SSC. Interventions included framing a written policy for SSC, sensitising the nursing staff and resident doctors, actively delaying the alternate priorities, making early SSC a shared responsibility among paediatricians, obstetricians, nursing staff and family members, and continuing SSC in the recovery area of the DR complex. RESULTS: The duration of early SSC increased from 0 to 67 min without any additional resources. The practice of SSC got well established in the system as reflected by a sustained improvement of 63 min and 72 min, respectively, at the end of 2 months and 4 years after study completion. CONCLUSION: Using the QI approach, we established and sustained the practice of early SSC for more than 60 min in our unit by using system analysis and testing change ideas in sequential PDSA cycles.

Mobocertinib: Mechanism of action, clinical, and translational science.

Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations represent ~6%-12% of all EGFR-mutated non-small cell lung cancer (NSCLC) cases. First-, second-, and third-generation tyrosine kinase inhibitors (TKIs) have limited clinical activity against EGFR ex20ins mutations. Mobocertinib is a first-in-class oral EGFR TKI that selectively targets in-frame EGFR ex20ins mutations in NSCLC; accelerated approval in the United States was granted for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations whose disease has progressed on or after platinum-based chemotherapy. Accelerated approval was based on the results from the three-part, open-label, multicenter, pivotal phase I/II nonrandomized clinical trial (NCT02716116) that enrolled 114 patients with locally advanced or metastatic EGFR ex20ins mutation-positive NSCLC who were previously treated with platinum-based chemotherapy and received mobocertinib at the recommended dosage of 160 mg once daily. At the November 1, 2021, data cutoff date, the confirmed objective response rate per independent review committee (IRC) was 28%, median duration of response was 15.8 months, median progression-free survival per IRC was 7.3 months, and median overall survival was 20.2 months. The most common treatment-emergent adverse events were gastrointestinal- and skin-related. The phase III EXCLAIM-2 study evaluated mobocertinib versus chemotherapy as first-line therapy for locally advanced or metastatic EGFR ex20ins-positive NSCLC; however, the primary end point was not met, resulting in initiating voluntary withdrawal of mobocertinib worldwide. This mini-review article summarizes the mechanism of action, pharmacokinetic characteristics, key clinical trials, and clinical efficacy and safety data for mobocertinib.

Efficacy and safety of Once-Daily Vilanterol/Fluticasone furoate MDI in persistent asthma: Phase 3 OD-INHALE Study.

INTRODUCTION: Once-daily inhalers have been shown to improve adherence leading to lesser discontinuation compared to twice- or thrice-daily inhalers in management of asthma. Combination of Vilanterol and Fluticasone Furoate (VI/FF) is approved for management of asthma and COPD and is available as a dry powder inhaler. Pressurized-Metered Dose Inhalers (pMDIs) offer ease-of-use and therapy alternatives for patients with low inspiratory flow. This study assessed the efficacy and safety of a new once-daily pMDI containing VI/FF in individuals diagnosed with persistent asthma. METHODS: This phase 3, double-blind, randomized controlled study assessed the non-inferiority of VI/FF (12.5 mcg/50 mcg & 12.5 mcg/100 mcg; 2 puffs once-daily) over Formoterol Fumarate and Fluticasone Propionate (FOR/FP, 6 mcg/125 mcg & 6 mcg/250 mcg; 2 puffs twice-daily) in patients with persistent asthma. Primary outcome was change from baseline in trough FEV1 at the end of study (12 weeks). Adverse events and number of exacerbations were used to evaluate safety. RESULTS: A total of 330 patients were randomized into VI/FF (165) and FOR/FP (165). Trough FEV1 significantly improved in both the groups at week 12, with a mean difference (VI/FF minus FOR/FP) being 54.75 mL (95% CI, 8.42-101.08 mL, p = 0.02). The low dose VI/FF had similar efficacy to that of low dose FOR/FP and high dose VI/FF had similar efficacy to high dose FOR/FP. No serious adverse events were reported during the study. CONCLUSION: Once daily VI/FF pMDI was non-inferior to twice daily FOR/FP pMDI in patients with persistent asthma.

Parthenium hysterophorus derived nanostructures as an efficient carbocatalyst for the electrochemical sensing of mercury(II) ions.

The sustainable utilization of resources motivate us to create eco-friendly processes for synthesizing novel carbon nanomaterials from waste biomass by minimizing chemical usage and reducing energy demands. By keeping sustainability as a prime focus in the present work, we have made the effective management of Parthenium weeds by converting them into carbon-based nanomaterial through hydrothermal treatment followed by heating in a tube furnace under the nitrogen atmosphere. The XPS studies confirm the natural presence of nitrogen and oxygen-containing functional groups in the biomass-derived carbon. The nanostructure has adopted a layered two-dimensional structure, clearly indicated through HRTEM images. Further, the nanomaterials are analyzed for their ability towards the electrochemical detection of mercury, with a detection limit of 6.17 µM, while the limit of quantification and sensitivity was found to be 18.7 µM and 0.4723 µM µA-1 cm-2, respectively. The obtained two-dimensional architecture has increased the surface area, while the nitrogen and oxygen functional groups act as an active site for sensing the mercury ions. This study will open a new door for developing metal-free catalysts through a green and sustainable approach by recycling and utilization of waste biomass.

Neonatal hypocalcaemic seizures unmasking asymptomatic maternal primary hyperparathyroidism.

Hypocalcaemia is a common cause of neonatal seizures. Here, we present a breastfed neonate with smooth perinatal transition and no family history of seizures presenting at 3 weeks with recurrent multifocal clonic seizures. On evaluation, the neonate was found to have low iCa and total calcium. 25-hydroxy vitamin D (25(OH)D) level was low and intact parathyroid hormone (iPTH) was inappropriately normal. The maternal evaluation revealed high calcium and low phosphate levels. iPTH was very high and 25(OH)D was very low in the mother. Sestamibi scan showed a left inferior parathyroid adenoma in the mother. Maternal primary hyperparathyroidism causing hypercalcaemia can suppress parathyroid activity in the fetus, resulting in inappropriate parathyroid response to hypocalcaemia after birth causing recurrent hypocalcaemic seizures. So neonatal hypocalcaemic seizures need careful evaluation of the neonate and the mother at times and can help both mother and neonate.

Pirfenidone: A Promising Drug in Ocular Therapeutics.

Pirfenidone, initially indicated for lung fibrosis, has gone beyond its original purpose, and shown promise in eye care. This detailed review tracks its evolution from lung treatment to aiding eye healing as evidenced by published literature. Pirfenidone's multifaceted attributes extend to mitigating corneal fibrosis, inflammation, and trauma. Through rigorous investigations, its efficacy emerges in diabetic retinopathy, macular degeneration, and postoperative glaucoma interventions. As an unheralded protagonist, pirfenidone reshapes ocular care paradigms, inviting renewed research opportunities.

Correlation of severity & clinical outcomes of COVID-19 with virus variants: A prospective, multicentre hospital network study.

BACKGROUND OBJECTIVES: The clinical course of COVID-19 and its prognosis are influenced by both viral and host factors. The objectives of this study were to develop a nationwide platform to investigate the molecular epidemiology of SARS-CoV-2 (Severe acute respiratory syndrome Corona virus 2) and correlate the severity and clinical outcomes of COVID-19 with virus variants. METHODS: A nationwide, longitudinal, prospective cohort study was conducted from September 2021 to December 2022 at 14 hospitals across the country that were linked to a viral sequencing laboratory under the Indian SARS-CoV-2 Genomics Consortium. All participants (18 yr and above) who attended the hospital with a suspicion of SARS-CoV-2 infection and tested positive by the reverse transcription-PCR method were included. The participant population consisted of both hospitalized as well as outpatients. Their clinical course and outcomes were studied prospectively. Nasopharyngeal samples collected were subjected to whole genome sequencing to detect SARS-CoV-2 variants. RESULTS: Of the 4972 participants enrolled, 3397 provided samples for viral sequencing and 2723 samples were successfully sequenced. From this, the evolution of virus variants of concern including Omicron subvariants which emerged over time was observed and the same reported here. The mean age of the study participants was 41 yr and overall 49.3 per cent were female. The common symptoms were fever and cough and 32.5 per cent had comorbidities. Infection with the Delta variant evidently increased the risk of severe COVID-19 (adjusted odds ratio: 2.53, 95% confidence interval: 1.52, 4.2), while Omicron was milder independent of vaccination status. The independent risk factors for mortality were age >65 yr, presence of comorbidities and no vaccination. INTERPRETATION CONCLUSIONS: The authors believe that this is a first-of-its-kind study in the country that provides real-time data of virus evolution from a pan-India network of hospitals closely linked to the genome sequencing laboratories. The severity of COVID-19 could be correlated with virus variants with Omicron being the milder variant.

Evaluation of the drug-drug interaction potential of brigatinib using a physiologically-based pharmacokinetic modeling approach.

Brigatinib is an oral anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive metastatic non-small cell lung cancer. In vitro studies indicated that brigatinib is primarily metabolized by CYP2C8 and CYP3A4 and inhibits P-gp, BCRP, OCT1, MATE1, and MATE2K. Clinical drug-drug interaction (DDI) studies with the strong CYP3A inhibitor itraconazole or the strong CYP3A inducer rifampin demonstrated that CYP3A-mediated metabolism was the primary contributor to overall brigatinib clearance in humans. A physiologically-based pharmacokinetic (PBPK) model for brigatinib was developed to predict potential DDIs, including the effect of moderate CYP3A inhibitors or inducers on brigatinib pharmacokinetics (PK) and the effect of brigatinib on the PK of transporter substrates. The developed model was able to predict clinical DDIs with itraconazole (area under the plasma concentration-time curve from time 0 to infinity [AUC∞] ratio [with/without itraconazole]: predicted 1.86; observed 2.01) and rifampin (AUC∞ ratio [with/without rifampin]: predicted 0.16; observed 0.20). Simulations using the developed model predicted that moderate CYP3A inhibitors (e.g., verapamil and diltiazem) may increase brigatinib AUC∞ by ~40%, whereas moderate CYP3A inducers (e.g., efavirenz) may decrease brigatinib AUC∞ by ~50%. Simulations of potential transporter-mediated DDIs predicted that brigatinib may increase systemic exposures (AUC∞) of P-gp substrates (e.g., digoxin and dabigatran) by 15%-43% and MATE1 substrates (e.g., metformin) by up to 29%; however, negligible effects were predicted on BCRP-mediated efflux and OCT1-mediated uptake. The PBPK analysis results informed dosing recommendations for patients receiving moderate CYP3A inhibitors (40% brigatinib dose reduction) or inducers (up to 100% increase in brigatinib dose) during treatment, as reflected in the brigatinib prescribing information.

Comparative yield of transbronchial cryo-nodal biopsy, transbronchial intra-nodal forceps biopsy, and transbronchial needle aspiration for mediastinal lesions at a tertiary care center in India (COLD-FORCEPS study).

Endobronchial ultrasound (EBUS) guided mediastinal cryobiopsy, and intranodal forceps biopsy are newer modalities for sampling mediastinal lymph nodes. The data regarding the diagnostic yield of both modalities is scarce. Patients were recruited retrospectively from our existing database. Patients who had undergone both an EBUS guided mediastinal cryobiopsy and an intranodal forceps biopsy were enrolled in the study. The final diagnosis was made with a clinical-pathological-radiological assessment and clinico-radiological follow-up after one month. A total of 34 patients were enrolled in the study who had undergone both EBUS guided mediastinal cryobiopsy and intranodal forceps biopsy and had complete data available, including 1-month follow-up data. The sample adequacy rate of EBUS-transbronchial needle aspiration (EBUS-TBNA), EBUS-TBNA with mediastinal cryobiopsy, and EBUS-TBNA with intranodal forceps biopsy was 94.11%, 97.05%, and 94.11%, respectively (p=0.56). The diagnostic yield achieved in EBUS-TBNA, EBUS-TBNA with mediastinal cryobiopsy, and EBUS-TBNA with intranodal forceps biopsy was 73.52%, 82.35%, and 79.41%, respectively (p=0.38). No major complications were seen in any patient. To conclude, adding EBUS guided mediastinal cryobiopsy and intranodal forceps biopsy to EBUS-TBNA may not be superior to routine EBUS-TBNA.

Hyperglycemia modulates M1/M2 macrophage polarization in chronic diabetic patients with pulmonary tuberculosis infection.

Increased susceptibility to bacterial infections like tuberculosis (TB) is one of the complications of type 2 diabetes, however the underlying mechanisms remains poorly characterized. To explore how chronic hyperglycemia in diabetes affects progression of active TB, we examined mRNA expression of M1 (proinflammatory) and M2 (anti-inflammatory) cytokines/markers, in monocyte-derived macrophages obtained from patients with PTB + DM (pulmonary TB + diabetes mellitus type 2), patients with DM alone, patients with PTB alone, and healthy individuals (controls). Our findings indicate a dysregulated cytokine response in patients with both PTB and DM, characterized by decreased expression levels of interferon-gamma (IFN-γ) and inducible nitric oxide synthase (iNOS), along with increased expression levels of interleukin-1 beta (IL-1ß) and CD206. Furthermore, we observed a positive correlation of IL-1ß and CD206 expression with levels of glycosylated hemoglobin (HbA1c) in both PTB + DM and DM groups, while IFN-γ showed a positive correlation with HbA1c levels, specifically in the PTB + DM group. Additionally, M1 cytokines/markers, IL-1ß and iNOS were found to be significantly associated with the extent of sputum positivity in both PTB and PTB + DM groups, suggesting it to be a function of increased bacterial load and hence severity of infection. Our data demonstrates that tuberculosis in individuals with PTB + DM is characterized by altered M1/M2 cytokine responses, indicating that chronic inflammation associated with type 2 diabetes may contribute to increased immune pathology and inadequate control of tuberculosis infection.

90 versus 60 min of early skin-to-skin contact on exclusive breastfeeding rate in healthy infants' ≥35 weeks: A randomised controlled trial.

AIM: To compare the effect of 90 versus 60 min of early skin-to-skin contact (SSC) among vaginally born healthy infants ≥35 weeks of gestation on their exclusive breastfeeding rates and breastfeeding behaviour. METHODS: This parallel-group, open-label, randomised controlled trial enrolled healthy term and late preterm infants born vaginally. Infants in the intervention group received early SSC for 90 min compared to 60 min in the control group. The primary outcome was the proportion of infants on exclusive breastfeeding at 60 ± 12 h. RESULTS: One hundred ninety-eight mother-infant dyads were randomised (99 in each group). The infants in the 90-min SSC group were more likely to be exclusively breastfed at 60 ± 12 h as compared to the 60-min SSC group (RR, 95% CI-1.44, [1.15-1.79], p < 0.01). The modified infant breastfeeding assessment tool score at 60 ± 12 h was significantly higher in the 90-min SSC group (median [IQR]-9, [8, 10] versus 8 [7, 10], p = 0.03]. The proportion of infants on exclusive breastfeeding at 6, 10, and 14 weeks of age was also significantly higher in the 90-min SSC group (RR, 95% CI-1.39 [1.11-1.74], 1.36 [1.08-1.07], and 1.38 [1.08-1.75], respectively). CONCLUSION: Increasing the duration of early SSC showed a dose-response benefit on exclusive breastfeeding rates and breastfeeding behaviour. TRIAL REGISTRATION: CTRI/2018/09/015632, registered on 06/09/2018.

Nitrogen and sulfur functionalized microporous carbon nanomaterial derived from waste coconut husk for the efficient detection and removal of ofloxacin.

This study uses waste coconut husk to synthesize carbon quantum dots decorated graphene-like structure for sustainable detection and removal of ofloxacin. The XRD spectrum shows the carbon nanomaterial's layered structure with turbostratic carbon stacking on its surface. The FESEM and HRTEM studies claim the successful development of quantum dots decorated 2D layered structure of carbon nanomaterial. The functionalization of sulfur and nitrogen is well observed and studied through XPS, while Raman spectra have provided insight into the surface topology of the as-synthesized nanostructure. The BET surface area was found to be 1437.12 m2/g with a microporous structure (pore width 2.0 nm) which interestingly outcompete many reported carbon-based nanomaterials such as graphene oxide, reduced graphene oxide and quantum dots. The detection and removal processes are monitored through UV-visible spectroscopy and the obtained detection limit and adsorption capacity were 2.7 nM and 393.94 mg/L respectively. Additionally, 1 mg carbon nanomaterial has removed 49 % ofloxacin from water in just 1 h. In this way, this study has successfully managed the coconut husk waste after its utilization for environmental remediation purposes.