Investigation of toxicological properties and optimal therapeutic doses of compound T1084 with anti-tumor activity

The aim of this study was to evaluate serum nimodipine concentrations in patients with aneurysmal subarachnoid hemorrhage (SAH) after parenteral therapy and a following course of enteral administration. SAH patients were treated with intravenous nimodipine (2 mg/h) during the 1st week after hemorrhage, and on day 8, we switched over to enteral administration (60 mg/4 h), either orally or by gavage. Serum nimodipine concentrations were measured on days 3, 5, 8, 9 and 12. Area under the curve (AUC) was calculated during parenteral and enteral therapy. The data of 15 patients were analyzed retrospectively. In this study, 157 blood samples were obtained. In seven samples, during the administration by gavage to two patients with high-grade SAH, the serum nimodipine concentrations were negligible. The AUC values during parenteral administration (median 149.3 ng-h/ml) were significantly higher than during oral administration on days 9 (median 92.1 ng-h/ml) and 12 (median 44.1 ng-h/ml) in seven patients (p = 0.030 and p = 0.016, respectively). The AUC values during parenteral administration were significantly higher than during administration by gavage on day 9 in eight patients (median 87.9 and 34 ng-h/ml, respectively, p = 0.001). The AUC values during enteral administration were higher in patients who received nimodine orally than in those who received it by gavage (median 52.3 and 23.1 ng-h/ml, respectively, p = 0.006). Enteral administration of nimodipine showed lower bioavailability during the 2nd week after SAH compared to parenteral application during the 1st week. Negligible serum concentrations were even expected when nimodipine was given by gavage in patients with high-grade SAH, thus suggesting that parenteral administration may be the better route in these patients.

Objective: To measure plasma glutamine (GLN) levels in systemic and portal circulation after combined enteral and parenteral administration in early endotoxemic swine. We hypothesized that this combination will be more efficient than intravenous administration alone in restoring plasma levels during the course of endotoxemia. Materials and Methods: Endotoxemia was induced with Escherichia coli O111:B4 lipopolysaccharide (LPS) (250 μg/kg body weight) in 16 anes­thetized, fasted swine and maintained by constant infusion (2 μg/kg/h) over 180 min. Another 16 swine served as controls. After infusion with LPS or placebo, GLN was administered intravenously, enterally or in combination (0.5 g/kg i.v. plus 0.5 g/kg enterally) over 30 min. At 0, 15, 30, 45, 60, 120 and 180 min, blood was drawn from the systemic and portal circulation for colorimetric assessment of GLN. Results: In healthy, placebo-alone swine, GLN levels remained stable throughout the study. Intravenous and combined infusion increased systemic levels (p = 0.001), but after enteral administration alone, a smaller effect was observed (p = 0.026). Portal levels were increased after combined, enteral and intravenous administration (p = 0.001). In endotoxemia, systemic and portal levels decreased significantly. Intravenous and, to a greater extent, combined administration increased systemic levels (p = 0.001), while enteral administration only had a small effect (p = 0.001). In the portal vein, intravenous and combined treatment increased plasma levels (p = 0.001), whereas enteral supplementation alone had again a small, yet significant effect (p = 0.001). Conclusions: The findings indicate that combined GLN supplementation is superior to intravenous treatment alone, in terms of enhanced availability in systemic and portal circulations. Thus, combined treatment at the onset of endotoxemia is a beneficial practice, ensuring adequate GLN to compensate for the resulting intracellular shortage.

The uptake and distribution of glucose, galactose, fructose and inulin in dogs was investigated in the lymph of the thoracic duct and in different blood vessels after enteral and parenteral administration. Whereas inulin could be detected neither in the lymph nor in portal venous blood after enteral administration, all other sugars were found in different concentrations in blood and lymph. Although the concentration of different sugars in the lymph after enteral and parenteral application can be compared to that in serum, the amount of sugars transported via the lymphatics is so small that it can be neglected.

Initially, total parenteral nutrition (TPN) was not used in cancer patients because of the fear of sepsis and the potential for stimulation of tumor growth. It was used first in cancer patients who had failed all attempts at enteral nutrition and in whom adequate anticancer therapy would have been otherwise impossible. TPN candidates today remain patients with responsive tumors who cannot tolerate the toxicity of cancer therapy because they are malnourished.

Dear Editor, I have read with interest a recently published article in Acta Neurochirurgica by Abboud at al. [1], titled Serum levels of nimodipine in enteral and parenteral administration in patients with aneurysmal subarachnoid. The authors report a retrospective cohort study of 15 patients, obtaining 157 blood samples. The authors compared serum nimodipine concentrations in patients with aneurysmal subarachnoid hemorrhage (SAH) after parenteral therapy and a following course of enteral administration. Finally, the authors concluded that the area under the curve (AUC) values during parenteral administration (median 149.3 ng-h/ml) were significantly higher than during oral administration on days 9 (median 92.1 ng-h/ml) and 12 (median 44.1 ng-h/ml). They also found that nimodipine AUC values during enteral administration were higher in patients who received nimodine orally than in those who received it by gavage. Nimodipine is the most widely studied calcium antagonist in SAH, and this original study shed some new light on SAH treatment with the calcium channel blocker nimodipine. Oral nimodipine 60 mg 4 hourly was found to reduce cerebral infarction and improve outcomes after subarachnoid hemorrhage. It was undoubtly proven that oral nimodipine improves the overall outcome [4]. There are no clear data supporting the effectiveness of nimodipine when administered intravenously, and the evidence for other calcium antagonists is inconclusive. Intravenous administration of calcium antagonists cannot be recommended for routine practice on the basis of the present evidence. However, this conclusion might require further investigation, and trials with large patient cohorts would be decisive. Another calcium antagonist, nicardipine, was associated with a significant and sustained reduction in mean cerebral blood flow velocity as measured by transcranial Doppler when used in the treatment of suspected cerebral vasospasm following aneurysmal subarachnoid hemorrhage [6]. However, in randomized double-blind trials, intravenous nicardipine has been shown to provide less favorable outcomes [2]. The issue of the optimal administration of nimodipine has been debated in the literature, and the results promote oral therapy as the most beneficial. However, patients with higher Hunt-Hess grades (IV or V) are at risk of delayed gastric emptying and gastrointestinal uptake of nimodipine during the first week after subarachnoid hemorrhage. The authors have clearly proven that when considering only the serum nimodipine concentration level and AUC, intravenous administration might be more beneficial. However, in the study by Abboud et al. [1], the authors did not perform a correlation analysis between the nimodipine serum concentration and clinical results including the rate of vasospasm or delayed ischemic neurologic deficits, which makes it difficult to use these data in clinical practice. The authors mentioned that they had not included the clinical evaluation in this comparison because of the small number of patients. The clinical effect of nimodipine results in a reduction of the rate of vasospasm and associated secondary ischemia. Based on the previous studies, there was no significant difference between the enteral versus intravenous group in the incidence of delayed ischemic neurologic deficits, middle cerebral artery blood flow velocities, number of new ischemic lesions or clinical outcome [3, 5]. The interesting issue regarding the article by Abboud et al. is how these results could be transferred to daily practice in light of the well-known clinical data on the administration of nimodipine. There is also another important question about the discrepancy between the serum nimodipine concentration level and clinical outcome. These probably require new studies for clarification.

Integrated Quantitative Clinical Pharmacology Analysis Identifies Optimal Englumafusp Alfa Dose Range for Proof-of-Concept Study with Glofitamab in Second-Line Large B-Cell Lymphoma Patients

ESPEN Guidelines on Parenteral Nutrition: Geriatrics

Introduction: Crohn's disease (CD) is a chronic, relapsing-remitting disorder of the gastrointestinal tract. CD patients often undergo surgical resection for treatment of their disease, though are still at risk of postoperative recurrence. Enteral nutrition (EN) is frequently used in CD as adjunct to medical therapy to manage protein-calorie malnutrition. It has also been suggested that EN may help both induce and maintain remission and promote mucosal healing. While several studies have shown decreased rates of postoperative CD recurrence following EN treatment, this association has not been well established. Objective: Assess effect of EN on postoperative clinical and endoscopic recurrence in Crohn's disease patients. Methods: A thorough search of multiple databases, including Scopus, Cochrane, MEDLINE/PubMed, and CINAHL were performed (May 2018). Studies assessing the role of pre- or postoperative enteral nutrition in preventing postoperative clinical and endoscopic recurrence of CD were included. A metaanalysis was completed using the Mantel-Haenszel model. Results: In a complete analysis of five studies, there was a 5-fold decrease risk in developing clinical recurrence at one year (OR 5.04 95% CI 2.66, 9.952, p2=80%). Sensitivity analysis excluded one study with lowest rate of recurrence in non-EN group to minimize heterogeneity there remains a dramatic decrease in clinical recurrence among patients on EN relative to no EN (OR 16.68 95% CI 6.37,43.66 p2=0%). Similar results were noted for clinical recurrence with EN at 5 year postoperatively with decreased risk for recurrence more than 24-fold in the group receiving EN compared to no EN (OR 24.61 95% CI 11.52,52.57 p2=78%). Two studies, by Wang, et al, and Yamamoto, et al, also assessed for endoscopic recurrence. Risk of endoscopic recurrence at 1 year was decreased by nearly 3-fold in the EN group relative to no EN (OR 2.69 95% CI 1.22,5.92 p=0.01, I2=48%) with EN. Conclusion: Postoperative enteral nutrition is associated with decreased rates of clinical and endoscopic recurrence after surgical resection. Further studies are needed to assess optimal duration of EN and longer-term effects.

Despite the ubiquitous role of pharmacotherapy in the care of critically ill children, descriptions of the extent of pharmacotherapy in critical illness are limited. Greater understanding of drug therapy can help identify clinically important associations and assist in the prioritization of efforts to address knowledge gaps. The objectives of this study were to describe the diversity, volume, and patterns of pharmacotherapy in critically ill children. A retrospective cohort study was performed with patient admissions to the ICU between July 31, 2006, and July 31, 2015. The study took place at a single, free-standing, pediatric, quaternary center. Eligible patient admissions were admitted to the ICU for more than 6 hours and received one or more drug administration. There were a total 17,482 patient-admissions and after exclusion of 283 admissions (2%) with no documented enteral or parenteral drug administration, 17,199 eligible admissions were studied. None. The 17,199 eligible admissions were admitted to the ICU for 2,208,475 hours and received 515 different drugs. The 1,954,171 administrations were 894,709 (45%) enteral administrations, 998,490 (51%) IV injections and 60,972 (3%) infusions. Infusions were administered for 4,476,538 hours. Twelve-thousand two-hundred seventy-three patients (71%) were administered five or more different drugs on 80,943 of patient days (75%). The 10 most commonly administered drugs comprised of 834,441 administrations (43%). Drug administration in the ICU is complex, involves many medications, and the potential for drug interaction and reaction is compounded by the volume and diversity of therapies routinely provided in ICU. Further evaluation of polytherapy could be used to improve outcomes and enhance the safety of pharmacotherapy in critically ill children.

Introduction: Photobiomodulation (PBM) has emerged as a promising intervention for mitigating oral mucositis (OM) in individuals receiving radiotherapy. However, OM can precipitate serious consequences and increase patient health risks. Objective: The aim of this prospective cohort study was to investigate the manifestation of oral mucositis and determine the degree of need for enteral nutritional support in patients with head and neck cancer who underwent combined radiotherapy and chemotherapy while receiving preventive PBM. Additionally, we sought to identify other oral conditions that could arise in these patients. Materials and methods: Sociodemographic, clinical, treatment, oral mucositis and pain data, as well as enteral nutrition use, were collected. Statistical analysis used frequency distributions, mean, median, standard deviation , and Pearson's chi-square and Fisher's exact tests . Results: The study sample comprised 22 individuals, predominantly male and self-identified as brown, and the most common diagnosis was squamous cell carcinoma. The data revealed that 21 patients developed OM throughout their oncological therapeutic course, with grades 2 (31.8%) and 3 (45.5%) representing the most severe stages. Notably, only 4 participants required enteral tube feeding, and all of them had OM grade greater than 2. Among the various oral complications observed, fungal infection, specifically pseudomembranous candidiasis , was the most common, affecting 17 patients. Conclusion: In summary, the preventive application of PBM suggests significant potential for minimizing dependence on enteral nutrition in patients with head and neck cancer undergoing radiotherapy and chemotherapy. This approach is crucial to avoid potential interruptions in oncological therapy and to prevent a decline in the overall clinical status of these patients.

The objective of this study is to develop a universally applicable approach for establishing the optimal dose range for the irradiation of plant and animal products. The approach involves the use of the optimization function for establishing the optimal irradiation dose range for each category of plant and animal product to maximize the suppression of targeted pathogens while preserving the surrounding molecules and biological structures. The proposed function implies that pathogens found in the product can be efficiently suppressed provided that irradiation is performed with the following criteria in mind: a high irradiation dose uniformity, a high probability of irradiation hitting pathogens and controlled heterogeneity of radiobiological sensitivity of pathogens. This study compares the optimal dose ranges for animal and plant products using beef tenderloin and seed potato tubers as examples. In a series of experiments, our team traced the dose dependencies of myoglobin oxidation in beef and the amount of potential damage to albumin's native structure. The behavior patterns of myoglobin derivatives and the amount of potential damage to albumin found in this study determined the optimal dose range, which appeared to be wider for beef irradiation compared to that for seed potato tubers, as they do not require uniform irradiation of the entire volume since targeted phytopathogens are predominantly found within the surface layers of the tubers. The use of proprietary methods involving spectrophotometry and high-performance liquid chromatography-mass spectrometry provides a novel perspective on the quantitative assessment of the myoglobin oxidation level and the potential damage to albumin's native structure.

e17568 Background: Although numerous factors have been reported to increase RT/RTCT toxicity, identification of patients with high risk of toxicities is lacking. Methods: The monocentric NutriNeck study (NCT02900963) recruited all HNSCC patients between 2014 and 2018 treated by RT or RTCT. Patients fed by enteral nutrition before RT initiation were excluded. All clinical and biological, planned RT or RTCT parameters were collected at baseline. A daily monitoring of the weight and a weekly evaluation of clinical, biological and food intake during RT/RTCT were performed. A nutritional intervention by enteral feeding was systematically proposed in case of 2 kg weight loss under treatment. Complete treatment was defined as full planned RT doses without more than 3 days interruption, and full planned doses of cisplatin and cetuximab if indicated. Primary endpoint assessed factors associated with non-completion of the planned treatment. Secondary endpoint assessed factors associated with use of enteral nutrition during treatment. A p value < 0.01 was considered significant. Results: Among the 249 HNSCC patients included, 118 (47%) were treated by RT and 131 (53%) by RTCT. 63 patients (25%) did not complete treatment: 3/118 (2.5%) in the RT group compared to 60/131 (45.8%) the RTCT group, p < 0.0001. Median weight lost during treatment (7 vs 3.8 kg, p < 0.0001) and grade 3 toxicities (53 vs 33%, p = 0.006) were more frequent in patients with incomplete RT/RTCT. Nutritional intervention was performed in 111 patients: 28 (23.7%) with RT and 83 (62.6%) with RTCT (p < 0.0001). Week 4 was associated with the higher rate of enteral nutrition initiation in both RT and RTCT groups. Among RTCT group, weight loss during treatment (OR 1.2 for each kg, p < 0.0001) and use of enteral feeding (OR 2.7, p = 0.005) were associated with incomplete treatment in multivariate analysis. Of note, 48 patients refused enteral nutrition while indicated, they had comparable grade 3 toxicities and weight loss during treatment compared to the 111 patients who accepted enteral nutrition. Conclusions: Incomplete treatment is overwhelmingly associated with RTCT rather than RT. Baseline clinical, biological features or treatment volume/dose are not associated with incomplete treatment. Enteral nutrition initiated during treatment is poorly efficient.

Chronic diseases have emerged as a significant challenge in global public health due to their complex etiologies, prolonged disease courses, and high treatment costs. With the aging population and changes in lifestyle, the number of patients with chronic diseases has increased dramatically, which has brought heavy burden to families and society. Chronic diseases are often accompanied by digestive and absorptive disorders as well as metabolic disorders, resulting in insufficient nutrient intake, further worsening the condition and weakening the physique. Therefore, the importance of nutritional intervention in chronic disease management has become increasingly prominent. As an important means of nutritional intervention, enteral nutrition plays a key role in improving the nutritional status of patients, promoting rehabilitation, shortening hospital stay and so on, thereby providing a new solution for chronic disease management. This article reviews the current application status, mechanism of action and comprehensive benefit of enteral nutrition in the clinical management of chronic diseases. Through systematic review and analysis of existing research findings, the specific application effects and mechanisms of enteral nutrition in chronic disease management are clarified. This review aims to promote the popularization and application of enteral nutrition, in order to effectively improve patients' treatment outcomes and quality of life, provide scientific evidence for the optimization of clinical management strategies for chronic diseases, and offer theoretical support for the development of enteral nutrition products, and thereby drive the continuous improvement of chronic disease management.

Cardiogenic shock is a common diagnosis in patients in the intensive care unit (ICU), and is characterized by a decreased cardiac output in the presence of adequate intravascular volume associated with an inadequate tissue perfusion including a physiological reduction in the splanchnic territory. It may occur in isolation as a reflection of cardiac pathology, or it may be part of a shock syndrome involving other pathogenic mechanisms. As the use of enteral nutrition (EN) is associated with an increase in mesenteric arterial output, EN could be deleterious by overwhelming the mechanisms of mesenteric adaptation. Accordingly, EN has been suspected to increase the risk of mesenteric ischaemia, bacterial translocation and sepsis in ICU patients with cardiogenic shock. International guidelines recommend a cautious use of EN within 72 h following cardiogenic shock. Recent evidence indicates that mesenteric arterial output may decrease during parenteral nutrition administration, suggesting that parenteral nutrition could have a protective effect on splanchnic organs in ICU patients with cardiogenic shock. Contrary to former beliefs, several meta-analyses have shown that parenteral nutrition is not associated with increased mortality. Exclusive EN is associated with negative energy balance and the combination of EN with supplemental parenteral nutrition during the first days following ICU admission has been proposed to prevent negative energy balance. Such a nutritional strategy could also be beneficial for the mesenteric circulation in cardiogenic shock, and consequently may improve the clinical outcome of patients with cardiogenic shock. Clinical trials are warranted to verify these hypotheses.

Severe acute pancreatitis (SAP) causes local and systemic complications leading to high catabolic, hypermetabolic and hyperdynamic stress states with marked morbidity and mortality. In the last decade, nutritional support has become a key element in the treatment of SAP. Thus, specialized nutrition is indicated from admission, with enteral nutrition being preferred to parenteral nutrition. Enteral nutrition should be initiated early using infusion through the jejunum beyond the ligament of Treitz to minimize pancreatic stress. There are no specific studies that establish the type of diet to be used but experts recommend the use of polymeric diets. Parenteral nutrition, without a specific formula, is indicated in patients with SAP who are intolerant to enteral nutrition or when the clinical signs of pancreatitis are exacerbated or aggravated by enteral nutrition. Even so, a minimal level of enteral infusion should be maintained to preserve the trophic effect of the intestinal mucosa. In the last few years, several studies of the administration of immunomodulatory diets in patients with SAP have been carried out to demonstrate their effects on the course of the disease. However, there are few clear recommendations on the prognostic benefits of pharmaconutrient enriched diets in these patients. There is substantial scientific evidence suggesting that the only clear indication for pharmaconutrition in patients with SAP is parenteral glutamine administration, which is recommended by all clinical guidelines with distinct grades of evidence.