Mechanisms of action of microbicides commonly used in infection prevention and control.

SUMMARYUnderstanding how commonly used chemical microbicides affect pathogenic microorganisms is important for formulation of microbicides. This review focuses on the mechanism(s) of action of chemical microbicides commonly used in infection prevention and control. Contrary to the typical site-specific mode of action of antibiotics, microbicides often act via multiple targets, causing rapid and irreversible damage to microbes. In the case of viruses, the envelope or protein capsid is usually the primary structural target, resulting in loss of envelope integrity or denaturation of proteins in the capsid, causing loss of the receptor-binding domain for host cell receptors, and/or breakdown of other viral proteins or nucleic acids. However, for certain virucidal microbicides, the nucleic acid may be a significant site of action. The region of primary damage to the protein or nucleic acid is site-specific and may vary with the virus type. Due to their greater complexity and metabolism, bacteria and fungi offer more targets. The rapid and irreversible damage to microbes may result from solubilization of lipid components and denaturation of enzymes involved in the transport of nutrients. Formulation of microbicidal actives that attack multiple sites on microbes, or control of the pH, addition of preservatives or potentiators, and so on, can increase the spectrum of action against pathogens and reduce both the concentrations and times needed to achieve microbicidal activity against the target pathogens.

Modified HT-SPOTi: An Antimicrobial Susceptibility Testing to Evaluate Formulated Therapeutic Combinations Against Bacterial Growth and Viability.

Antimicrobial resistance (AMR) poses a serious threat to global health, potentially causing 10 million deaths per year globally by 2050. To tackle AMR, researchers from all around the world have generated a selection of various formulated (viz. nanoparticulate, liposomal) therapeutic combinations to be evaluated for new antimicrobial drug discovery. To meet the urgent need for accelerating new antibacterial drug development, we need rapid but reliable whole-cell assay methods and models to test formulated therapeutic combinations against several pathogens in different in vitro conditions as models of actual infections.Over the past two decades, high-throughput spot-culture growth inhibition assay (HT-SPOTi) has been demonstrated to be a gold-standard drug susceptibility method for evaluating novel chemotherapeutic entities and existing drugs against various microbes of global concern. Our modified HT-SPOTi method serves the purpose of evaluating drug combinations against Gram-positive/negative microorganisms as well as acid-fast bacilli. The newly developed and modified HT-SPOTi assay builds upon the limitations of our previously published method to incorporate antimicrobial susceptibility testing with formulated therapeutic combinations. The modified HT-SPOTi is compared with a range of other antimicrobial susceptibility testing methods and validated using a library of existing antibiotics as well as formulated therapeutic combinations. The modified HT-SPOTi assay can serve as an efficient and reliable high-throughput drug screening platform to discover new potential antimicrobial molecules, including as part of therapeutic formulations.This chapter describes the generation of drug susceptibility profile for formulated therapeutic combinations using modified HT-SPOTi in a semi-automated system.

Exploring current and emerging therapies for porphyrias.

Porphyrias are rare, mostly inherited disorders resulting from altered activity of specific enzymes in the haem synthesis pathway that lead to accumulation of pathway intermediates. Photocutaneous symptoms occur when excess amounts of photoreactive porphyrins circulate in the blood to the skin, whereas increases in potentially neurotoxic porphyrin precursors are associated with neurovisceral symptoms. Current therapies are suboptimal and their mechanisms are not well established. As described here, emerging therapies address underlying disease mechanisms by introducing a gene, RNA or other specific molecule with the potential to cure or slow progression of the disease. Recent progress in nanotechnology and nanoscience, particularly regarding particle design and formulation, is expanding disease targets. More secure and efficient drug delivery systems have extended our toolbox for transferring specific molecules, especially into hepatocytes, and led to proof-of-concept studies in animal models. Repurposing existing drugs as molecular chaperones or haem synthesis inhibitors is also promising. This review summarizes key examples of these emerging therapeutic approaches and their application for hepatic and erythropoietic porphyrias.

Enrichment strategy and initial characterization of heterodimers enriched from a co-formulated cocktail of therapeutic antibodies against SARS-COV-2.

Co-formulation of multiple drug products is an efficient and convenient approach to simultaneously deliver multiple biotherapeutics with the potentially added benefit of a synergistic therapeutic effect. However, co-formulation also increases the risk of heteromeric interactions, giving rise to unique impurities with unknown efficacy and immunogenicity. Therefore, it is critical to develop methods to evaluate the risk of heteromers as an impurity that could affect potency, efficacy, and/or immunogenicity. The most direct strategy to evaluate antibody heteromers is via specific enrichment. However, the fact that antibody heterodimers generated from the co-formulated cocktail share highly similar molar mass and size properties as homodimers natively present in each individual antibody drug product poses a unique purification challenge. Here, we report the path to successful enrichment of heterodimers from co-formulated REGEN-COVⓇ and discuss its potential impacts on drug quality.

Effect of biotin on currently used Beckman thyroglobulin assay and newly reformulated thyroglobulin assay not affected by biotin.

OBJECTIVES: Biotin causes negative interference with thyroglobulin measurement using the Access thyroglobulin assay. Recently, Beckman reformulated the thyroglobulin assay to overcome biotin interference. We investigated the effect of biotin on both current and newly formulated assays. METHODS: Four serum pools were prepared using specimens containing various amounts of thyroglobulin. Then aliquots of each pool were supplemented with various amounts of biotin, and thyroglobulin concentrations were measured by both the current and the new assays. In addition, 3 volunteers ingested 10 mg biotin, and specimens were drawn before and 2 hours after taking biotin. Thyroglobulin concentrations before and 2 hours after taking biotin were measured by both assays. RESULTS: In the presence of biotin, thyroglobulin concentrations were reduced significantly using the current assay, but no significant change was observed using the newly formulated assay. We observed similar results in vivo. CONCLUSIONS: The newly formulated thyroglobulin assay by Beckman is free from biotin interference.

Assessment of Nano-Formulated Conventional Insecticide-Treated Sugar Baits on Mosquito Control and the Effect on Non-Target Aphidophagous Coccinella septempunctata.

Mosquitoes, as disease vectors causing global morbidity and mortality through diseases like malaria, dengue, and Zika, necessitate mosquito population control methods. This study investigated the efficacy of nano-formulated insecticide-based sugar baits in controlling Anopheles gambiae populations and assessed their potential non-target impact on Coccinella septempunctata. This laboratory-based study employed thiolated polymer-coated attractive toxic sugar bait (ATSB) nano-formulations, delivering pesticides via nano-carriers. Adult and larvae populations of insects were collected from rice and cotton fields subjected to bioassays with 0.5% and 1% concentrations of each nano-formulated and conventional insecticide within ATSB solution, alongside a control 100% attractive sugar bait (ASB). Mosquitoes interacted overnight with insecticide-treated baits, and mortality was assessed. Further observations up to 72 h were conducted for potential delayed toxic effects. Results highlighted nano-ATSB carbosulfan's effectiveness, particularly among organophosphates and pyrethroids. Among pyrethroids, nano-ATSB cypermethrin exhibited high efficacy, while Deltamethrin displayed lower mortality. Among organophosphates, nano-ATSB chlorpyrifos induced substantial mortality. The nano-formulations of insecticide were harmless against C. septempunctata compared to their conventional form. Nano-formulations demonstrated enhanced mortality rates and prolonged efficacy against mosquitoes, having a benign impact on non-target beetles. We expect these results to aid in developing effective plant protection products suitable for IPM practices.

Successful outpatient conservative management of chyle leak after laparoscopic left hemicolectomy / Éxito de tratamiento conservador ambulatorio de paciente con ascitis quilosa tras hemicolectomía izquierda laparoscópica

Chyle leak is a pathological extravasation of chyle into the peritoneal cavity after a surgical injury. It is an uncom-mon complication in colorectal surgery. In most cases, conservative treatment is effective, although it often entails prolonged hospital stays.We present the case of a 60-year-old female with chyle leak after laparoscopic left hemicolectomy with complete mesocolic excision who underwent successful outpatient conservative management. We found no other cases of suc-cessful conservative outpatient treatment in the consulted literature. Adequate outpatient management may provide significant benefits by reducing hospital costs and improv-ing patient’s quality of life, while maintaining the possibility of starting adjuvant treatment if indicated (AU)

La ascitis quilosa es una acumulación patológica de quilo en la cavidad peritoneal tras una lesión quirúrgica. Es una complicación infrecuente de la cirugía colorrectal. En la mayoría de los casos, el tratamiento conservador suele ser eficaz, aunque conlleva estancias hospitalarias prolongadas.Se presenta el caso de una paciente de 60 años que de-sarrolló ascitis quilosa trasuna hemicolectomía izquierda laparoscópica, con escisión completa del mesocolon, que se resolvió con éxito mediante manejo conservador ambu-latorio. No se han encontrado casos exitosos de tratamien-to conservador ambulatorio en la bibliografía consultada. Un manejo ambulatorio como el propuesto puede aportar importantes beneficios en términos de reducción de costes hospitalarios y mejora de la calidad de vida del paciente, manteniendo la posibilidad de iniciar un tratamiento adyu-vante si está indicado (AU)

Oscillatoria sancta Cultivation Using Fruit and Vegetable Waste Formulated Media and Its Potential as a Functional Food: Assessment of Cultivation Optimization.

The most cost-effective technique to cultivate microalgae is with low-cost resources, like fruit and vegetable peels. This study examined the viability of culturing microalgae (Oscillatoria sancta PCC 7515) isolated from a waterlogged region of Punjab, India, in a low-cost medium (fruit and vegetable waste peels) for pharmaceutical use. 16S rRNA sequencing discovered O. sancta PCC 7515. Fruit and vegetable peels were mineralized and chemically analyzed. At a 5% Bacillus flexus concentration, fruit and vegetable peels were liquefied at room temperature for 24 h. Response Surface Methodology (RSM) was used to assess and improve important cultural variables. The RSM predicted the best results at 10 pH, 30 days of incubation, 5% inoculum concentration, and 5% fruit and vegetable waste liquid leachate. The optimum conditions yielded more biomass than the basal conditions (0.8001 g/L). O. sancta PCC 7515 produced more lipids, proteins, Chl a, and Chl b in a formulated alternate medium than standard media. This study shows that O. sancta PCC 7515 may thrive on fruit and vegetable peel media. Fruit and vegetable waste (FVW) media assure low-cost microalgae-based functional foods.

Segregation of formulated powders in direct compression process and evaluations by small bench-scale testers.

Powder segregation can cause severe issues in processes of pharmaceutical drugs for control of content uniformity if the powder is likely to be free or easy flowing. Assessing segregation intensity of formulated powders in a process is challenging at the formulation stage because of the limited availability of samples. An advanced segregation evaluation using small bench-scale testers can be useful for formulation decisions and suggestions of operation conditions in the process, which has not been practically investigated before. In this study, eight formulations (two co-processed excipients blended with one active pharmaceutical ingredient at different ratios) were used for the segregation study on two types of bench-scale testers (air-induced and surface rolling segregation tester), and a pilot simulation process rig as a comparative study. The results show that segregation measured on the bench-scale testers can give a good indication of the segregation intensity of a blend if the segregation intensity is not more than 20%. The comparison also shows that both the bench-scale testers have a good correlation to the process rig, respectively, which means either segregation tester can be used independently for the evaluation. A linear regression model was explored for prediction of segregation in the process.

Quantitative Structure Use Relationships: Highlights from a technical summit meeting.

The Quantitative Structure Use Relationship (QSUR) Summit, held on November 2-4, 2022, focused on advancing the development, refinement, and use of QSURs to support chemical substance prioritization and risk assessment and mitigation. QSURs utilize chemical structures to predict the function of a chemical within a formulated product or an industrial process. This presumed function can then be used to develop chemical use categories or other information necessary to refine exposure assessments. The invited expert meeting was attended by 38 scientists from Canada, Finland, France, the UK, and the USA, representing government, business, and academia, with expertise in exposure science, chemical engineering, risk assessment, formulation chemistry, and machine learning. Workshop discussions emphasized the importance of collection and sharing of data and quantification of relative chemical quantities to progress QSUR development. Participants proposed collaborative approaches to address key challenges, including mechanisms for aggregating information while still protecting proprietary product composition and other confidential business information. Discussions also led to proposals for applications beyond exposure and risk modeling, including sustainable formulation discovery. In addition, discussions continue to construct, conduct, and circulate case studies tied to various specific problem formulations in which QSURs supply or derive information on chemical functions, concentrations, and exposures.

Systematic Review of Management of Moderate Wasting in Children over 6 Months of Age.

The effective management of the 33 million children with moderate acute malnutrition (MAM) is key to reducing childhood morbidity and mortality. In this review, we aim to evaluate the effectiveness of specially formulated foods (SFFs) compared to non-food-based approaches to manage MAM in children >6 months old. We conducted a search on ten databases until 23 August 2021 and included five studies, covering 3387 participants. Meta-analysis of four studies comparing SFFs to counselling or standard of care showed that SFFs likely increase recovery rate, reduce non-response, and may improve weight-for-height z-score, weight-for-age z-score and time to recovery, but have little or no effect on MUAC gain. One study on a multicomponent intervention (SFFs, antibiotics and counselling provided to high-risk MAM) compared to counselling only was reported narratively. The intervention may increase weight gain after 24 weeks but may have little or no effect on weight gain after 12 weeks and on non-response and mortality after 12 and 24 weeks of enrollment. The effect of this intervention on recovery was uncertain. In conclusion, SFFs may be beneficial for children with moderate wasting in humanitarian contexts. Programmatic recommendations should consider context and cost-effectiveness.

Lipid profile and cost of enteral nutrition formula with addition of fish oil used in a public hospital.

BACKGROUND & AIMS: The present study evaluated the lipid profile of enteral nutrition formulas with added fish oil used in a public hospital, with an emphasis on the fatty acid (FA) composition. METHODS: FA composition was determined using gas chromatography coupled to a flame ionization detector (GC-FID). Nine enteral nutrition formulas were evaluated and the results obtained were compared with those reported on the formulas labels. RESULTS: The sample with the highest percentage of added fish oil according to the label information had the lowest total amounts of eicosapentaenoic acid and docosahexaenoic acid (EPA + DHA) (p < 0.05). In the evaluation of the total amount of polyunsaturated fatty acids/saturated fatty acids (ΣPUFA/ΣSFA) ratio, five samples were not within the values recommended by Brazilan and international health regulatory agencies. Regarding the n-6/n-3 fatty acids ratio, five samples showed values higher than the recommended ratio. It was observed that EPA + DHA content was positively correlated with the cost of the diet. Importantly, we also found that there was a significant difference between the results of our analysis and the descriptions found on the labels for fatty acids n-6, n-3, EPA, DHA, SFA, PUFA and MUFA. CONCLUSIONS: We conclude that the discrepancies for fatty acids between the values obtained in the analyses and the values reported on the labels highlight the need for more rigorous inspection when public hospitals purchase enteral nutrition formulas with added fish oil, since the administration of formulas with inadequate levels of FA in hospitalized patients can compromise clinical results during the hospitalization period.

Current topics in pediatric enteral nutrition safety.

Enteral nutrition is a cornerstone of nutrition support therapy in patients of all ages and across the care continuum. Safe delivery of enteral nutrition to patients is paramount. This review article will focus on current topics in enteral nutrition safety primarily in children including safety with home-made blenderized feeds, recent infant and enteral formula shortages largely due to formula contamination at the manufacturer level, and concerns with importing infant formulas.

Evaluating the Compliance, Efficacy, and Cost of Formulated Vitamins Versus Separate Supplements in Post-bariatric Surgery Patients.

OBJECTIVE: Micronutrient deficiencies are common complications after bariatric surgery as alterations to the gastrointestinal tract change absorption. Patients are recommended to take supplements including multivitamins, B complex, calcium, vitamin D, and iron after bariatric surgery, and can take these as specifically formulated vitamins for post-bariatric patients or separate vitamin supplements. We investigated the compliance, efficacy, and cost of specifically formulated vitamins for post-bariatric patients in comparison to separate vitamin supplements. METHODS: We surveyed 126 post-bariatric adult patients between February 1, 2022, and August 31, 2022, who had undergone bariatric surgery between 2014 and 2021 to assess the type of supplements taken, compliance, and cost. Demographics, type of bariatric surgery, and serum micronutrient levels were evaluated for all patients. RESULTS: There were 51 patients taking formulated vitamins and 75 patients taking separate vitamins. The formulated vitamin group demonstrated greater adherence to optimal vitamin dosage (formulated vitamin group, 76.5% vs. separate supplement group, 30.7%; p < 0.001) and higher compliance (formulated vitamin group, 90.2% vs. separate supplement group, 66.7%; p = 0.002). The costs associated with both groups were comparable. No significant difference was observed in the incidence of micronutrient deficiency between the groups. CONCLUSIONS: Our study shows that formulated vitamins do not offer significant difference in micronutrient levels or cost compared to separate standard vitamin supplements. However, formulated bariatric vitamins have improved compliance compared to separate vitamin supplements.

Ultra-processed foods: Processing versus formulation.

The four-tiered NOVA food classification defines foods based on their degree of processing and ranges from native unprocessed foods to so-called "ultra-processed" foods. Recent publications have suggested that foods classified as ultra-processed are unhealthy and contribute to the obesity epidemic. It is important to distinguish between formulation and processing of a food. In most cases it is the formulation more than the processing that results in foods that are not recommended as part of a healthy diet. Such "ultra-formulated" foods are unhealthy because they are high in added sugar and other caloric sweeteners, refined flours saturated fats and salt to increase palatability. The understanding that processing and formulation are distinct will assist health professionals in identifying the types of foods that are unhealthy and contribute to overconsumption and obesity. It furthermore will help to destigmatize food technology and promote discussions amongst health professionals, food scientists, corporate scientists, government officials and the general public. Novel food processing techniques are urgently needed in times of population growth, climate change and war-induced food shortages.

A Novel Therapeutic Formulation for the Improved Treatment of Indian Red Scorpion (Mesobuthus tamulus) Venom-Induced Toxicity-Tested in Caenorhabditis elegans and Rodent Models.

Indian Red Scorpion (Mesobuthus tamulus) stings are a neglected public health problem in tropical and sub-tropical countries, including India. The drawbacks of conventional therapies using commercial anti-scorpion antivenom (ASA) and α1-adrenoreceptor antagonists (AAA) have prompted us to search for an adequate formulation to improve treatment against M. tamulus stings. Novel therapeutic drug formulations (TDF) of low doses of commercial ASA, AAA, and ascorbic acid have remarkably improved in neutralising the in vivo toxic effects of M. tamulus venom (MTV) tested in Caenorhabditis elegans and Wistar strain albino rats in vivo models. The neutralisation of MTV-induced production of free radicals, alteration of the mitochondrial transmembrane potential, and upregulated expression of genes involved in apoptosis, detoxification, and stress response in C. elegans by TDF surpassed the same effect shown by individual components of the TDF. Further, TDF efficiently neutralized the MTV-induced increase in blood glucose level within 30 to 60 min post-treatment, organ tissue damage, necrosis, and pulmonary oedema in Wistar rats, indicating its clinical application for effecting treating M. tamulus envenomation. This study demonstrates for the first time that C. elegans can be a model organism for screening the neutralization potency of the drug molecules against a neurotoxic scorpion venom.

Predicting Factors of Plasma HIV RNA Undetectability after Switching to Co-Formulated Bictegravir, Emtricitabine, and Tenofovir Alafenamide in Experienced HIV-1 Patients: A Multicenter Study.

Switching to bictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) from other antiretroviral regimens is safe and effective for virologically suppressed people living with HIV (PLWH). The term virological suppression includes both low but detectable HIV viremia and undetectable HIV viremia, and the latter is possibly associated with a lower immune activation state. Herein, we describe a 24-month follow-up of experienced PLWH with plasma HIV RNA undetectable or detectable < 50 copies/ml switching to BIC/FTC/TAF. A previous 12-month monitoring was available, and the factors correlated with treatment efficacy. This retrospective multicenter study included PLWH who switched to BIC/FTC/TAF in the period of 2019-2022, and who were HBsAg and HCV RNA negative. The follow-up study times were 6 (T6), 12 (T12), 18 (T18), and 24 (T24) months after the switch (T0). Survival analysis with multiple-failure-per-subject design, Kaplan-Meier survival estimates, multivariate analysis of variance, multilevel linear regression, and a hierarchical ordered logistic model were applied. A total of 329 PLWH had plasma HIV RNA which was either undetectable or detectable at <50 copies/mL at T0, and 197 responded to all inclusion criteria: M/F 140/57; the median CD4+ cell count was 677 cells/mm3; and HIV RNA at T0 was undetectable in 108 patients. Most of the 197 patients (122, 61.9%) were on a previous INSTI-based regimen. HIV RNA undetectability was more frequent at each follow-up point in patients with HIV RNA that was undetectable at T0, and it showed a higher frequency throughout the follow-up period in patients with always-undetectable HIV RNA in the 12 months before the switch. A higher nadir CD4 cell count had a predictive role, and HBcAb positivity had no influence. In conclusion, the switch could be programmed and possibly delayed on a case-by-case basis in order to achieve persistent plasma HIV RNA undetectability. Undiagnosed loss of HBcAb has no detrimental consequences on the response to BIC/FTC/TAF.

Exploration on the development of public hospital-sponsored telemedicine platform: A case study in China.

BACKGROUND: As a result of recent advancements, Internet hospitals have been a typic kind of telemedicine platform in China. The platforms can now provide a wide range of medical services while breaking through the limitations of time and space with excellent accessibility. OBJECTIVE: This study aims to give a comprehensive description on the role extension of a public hospital-sponsored Internet hospital in China from the aspects of the characteristics, patient's benefit and satisfaction, the workload of pharmacists and pharmaceutical care. METHODS: The total number of online prescriptions and detailed information were obtained automatically from the Internet hospital information system from Huashan Hospital Fudan University. Age, sex, associated prescription departments, time of prescription, payment methods, expenditure, drug category and delivery region were included in the analysis. A follow-up questionnaire was distributed as an electronic form that was collected and analyzed through the Internet to evaluate patients' satisfaction and time/economic benefits. RESULTS: A total of 51,777 patients visited Internet hospital and purchased required drugs from May 2020 to March 2022. The top 5 online prescription departments were dermatology (83.11%), neurology (6.85%), infectious diseases (3.27%), gastroenterology (2.35%) and cardiology (2.03%) departments. During this period, the audit pharmacists reviewed an average of 240 prescriptions per day, and the consultant pharmacists replied to about 42 consultations per day. 77.89% patients living in westsourth China benefited most from the Internet hospitals. They saved longest time (5 days) and the most expenses ($450-600). We observed an average patient satisfaction score higher than 4.5 in majority dimensions, including drug accessibility, effective in communication and confidence in medical staff. During closed-off management period between April to May in 2022, a total of 194,388 drugs were prescribed and delivered to 19,442 patients with the total payments of $1,547,001.2. Compared with those before closed-off management, the proportion of patients visiting dermatology department reduced from 83.11% to 54.87%. There was a significant increase in the number of patients visited general practice medicine department. The pharmacists extended their working hours by 5 h per day. In 2 months close-off management, the audit pharmacists reviewed an average of 320 prescriptions per day, and the consultant pharmacists replied to about 138 consultations per day. CONCLUSIONS: The characteristics of patients in terms of department and disease profiles in the Internet hospital were consistent with those preponderant disciplines in the entity hospital. Patients benefited from the Internet hospital not only in saving times, but also in reducing medical expenses. During the close-off management period, the distribution of departments and disease profiles changed dramatically. These changes indicated that the Internet hospital was no longer just an extension of in-hospital services, but played an important role in fighting the epidemic, changed the mode of patients' medical treatment and hospital diagnosis and treatment at special times.

Do market pressure and social network affect farmers' adoption of low-carbon fertilization practices? Evidence from China.

Excessive applications of agricultural chemical fertilizers contribute to environmental pollution and climate change. Although chemical fertilizers ensure high grain yields, it is crucial to regulate fertilization practices and avoid excessive application to achieve sustainable agricultural development. The overall goal of this study is to examine how market pressure and social network affect farmers' adoption of low-carbon fertilization practice. Data analyses were based on 1255 observations collected from a field survey in Anhui Province of China in 2021. The results showed that 32.1% of farmers had adopted low-carbon fertilization practices. The findings showed that market pressure, including consumption pressure and sales pressure, had positive impacts on the farmers' adoption of low-carbon fertilization practices. Findings also revealed that consumption pressure has a more significant influence on farmers' adoption of low-carbon fertilization practices than sales pressure. Social network has a significant positive influence on the farmers' adoption of low-carbon fertilization practices. Further analysis revealed that organizational network has a more significant influence on farmers' adoption of low-carbon fertilization practices than production networks. Therefore, the government should utilize market pressure and strengthen farmers' social network to improve the adoption rate of low-carbon fertilization practices. The results and policy implications of this study are significant for sustainable agricultural development under climate change in China and other countries.

New ecological first derivative synchronous spectrofluorimetric method for simultaneous quantification of carvedilol and ivabradine in tablets.

A new, rapid, selective, green, and highly sensitive method has been established to determine ivabradine and carvedilol simultaneously. The first derivative synchronous spectrofluorimetric approach was applied for the determination of the studied drugs. Assessment of the first derivative amplitude of carvedilol and ivabradine has been done at 339 nm and 298 nm respectively which are the zero crossing points of each other. The method validation is estimated and was found to be consistent with International Conference on Harmonization guidelines. Linearity was found to be in the range of 10.0 to 90.0 ng/mL for carvedilol and from 80.0 to140.0 ng/mL for ivabradine. The detection limits were found to be 1.2 ng/ mL and 3.3 ng/mL and the quantitation limits were 3.7 ng / mL and 10.0 ng /mL for carvedilol and ivabradine, respectively. The method was effectively applied for the determination of both drugs in their synthetic mixture in different ratios and in their prepared co-formulated tablets. The results were compared with those of comparison HPLC methods. Ethanol was used as a green solvent. The proposed method is suitable for the determination of ivabradine and carvedilol with satisfactory accuracy and precision. The greenness of the method was evaluated using four assessment tools, i.e. NEMI, GAPI, Eco-scale, and AGREE. The proposed method is simple with a low cost compared to HPLC methods.