Implementing a behavioral physical activity program in children and adolescent survivors of childhood cancer: a pilot randomized controlled trial.

Purpose We aimed to document the acceptability (enrollment rate) and feasibility (phone call delivery rate) of implementing a behavioral PA intervention over 12 weeks, in addition to documenting its effects on patient-reported outcomes and physical functioning. This study also describes the costs of carrying out a behavioral PA intervention. A total of 40 participants were randomized in a 1:1 ratio. The tailored behavioral PA intervention was developed based on the most recent PA guidelines in pediatric oncology and on the COM-B framework to enact PA behavior changes. The prescription (frequency, intensity, time and type (FITT)) was adjusted each week during the weekly support calls. The control group did not receive the intervention. 26 males and 14 females (13.6 years old on average and 2.9 years post-cancer treatment on average) participated in our study. The acceptability rate was 90.9% and the feasibility rate was > 85%. We found that 85% improved PA frequency, 80% improved PA intensity, 100% improved PA time, and 50.0% achieved the recommended PA guidelines. No adverse events were reported over the duration of the intervention. Physical function improved with longer 6-minute walk distances in the intervention group (465.8 ± 74.5 m) than in the control group (398.7 ± 92.9 m) (p = 0.016). PROs scores for all participants were within the limits of the normal range. The estimated cost per participant of carrying out this intervention was USD $126.57. Our 12-week behavioral PA intervention, based on the COM-B framework, was found to be acceptable, feasible and safe in childhood cancer survivors. This study is an important step in the right direction to make exercise standard practice in pediatric oncology.

Chronic pain in children and adolescents diagnosed with cancer: the challenge of mitigating the pain and the potential of integrating exercise into pain management.

BACKGROUND: Pain is one of the most common and distressing symptoms experienced by children and adolescents diagnosed with cancer. It is vital that children and adolescents receive adequate pain management early on in their cancer treatments to mitigate pain and cancer-related symptoms. Exercise training shows particular promise in the management of acute and chronic pain among children and adolescents diagnosed with cancer. METHODS: This position paper comes to outline the challenge of mitigating pain in children and adolescents diagnosed with cancer, and the potential benefits of integrating exercise training to the management of chronic pain in this population in need. RESULTS: Integrating exercise training into the care and pain management of children and adolescents diagnosed with cancer who have chronic pain would have the advantage of addressing several shortcomings of pain medication. Pain medication aims to temporarily manage or reduce pain; it does not have the potential to directly improve a patient's physical condition in the way that exercise training can. The current paucity of data available on the use of exercise training as a complementary treatment to pain medications to reduce chronic pain in children and adolescents diagnosed with cancer allows only for hypotheses on the effectiveness of this pain management modality. CONCLUSION: More research on this important topic is necessary and mitigating pain effectively while also reducing the use of opioid pain medication is an important goal shared by patients, their families, clinicians, and researchers alike. Future research in this area has great potential to inform clinical care, clinical care guidelines, and policy-making decisions for pain management in children and adolescents diagnosed with cancer who experience chronic pain.

Physical activity and physical fitness assessments in adolescents and young adults diagnosed with cancer: a scoping review.

PURPOSE: This scoping review describes the assessment methodologies for physical activity (PA) and physical fitness assessments used in studies focusing on adolescents and young adults (AYAs) diagnosed with cancer. METHODS: A search of the literature was conducted in PubMed, CINAHL, Web of Science, and Cochrane Library following the PRISMA-ScR statement. A total of 34 studies were included in this review. RESULTS: PA was primarily assessed via self-reported questionnaires (30/34) either completed in-person (n = 17) or online (n = 13) at different time points and different stages along the cancer trajectory (i.e., from diagnosis onward). A total of 9 studies conducted a physical fitness assessment. CONCLUSIONS: PA and physical fitness measurements are key when trying to describe outcomes, assess for associations, track changes, measure intervention adherence, and test intervention efficacy and effectiveness. Considerable heterogeneity across studies was reported limiting the generation of formal recommendations or guidance for researchers, healthcare providers, and policy makers.

Biofilm-Associated Infections in Chronic Wounds and Their Management.

Chronic wounds including vascular ulcers, diabetic ulcers, pressure ulcers, and burn wounds show delayed progress through the healing process. Some of their common features are prolonged inflammation, persistent infection, and presence of biofilms resistant to antimicrobials and host immune response. Biofilm formation by opportunistic pathogens is a major problem in chronic wound management. Some of the commonly and traditionally used chronic wound management techniques are physical debridement and cleansing. In recent years, novel techniques based on anti-biofilm agents are explored to prevent biofilm-associated infections and facilitate wound healing. In this chapter, the role of biofilms formed by the ESKAPE pathogens (Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa) and Candida species in delayed wound healing have been discussed. The current and emerging techniques in the detection of biofilms for the management of wounds have been focused. The limitations of the existing therapeutics and novel wound management strategies have been deliberated.

Influence of milk fat on the physicochemical property of nanoencapsulated curcumin and enhancement of its biological properties thereof.

Curcumin, bioactive from turmeric Curcuma longa, has been known for its therapeutic properties. However, its lipophilic nature and poor bioavailability are the constraints to harnessing its properties. Encapsulation in nano-size helps to alleviate the constraints and enhance its biological properties due to its higher surface area. The study aims to encapsulate curcumin in a nanometer size range by solubilizing in lipid (milk fat) and using milk protein as a water-soluble carrier. The lipid:curcumin ratio (1:0.05, 1:0.1, 1:0.2, 1.5:0.1, 1.5:0.2, 2.0:0.1 and 2:0.2% (w/w)) produced nanoemulsion with droplets sizes 30-200 nm. The sample containing lipid: curcumin, as 1.0:0.05 resulted in an encapsulation efficiency of 92.6%, and its binding interaction with the carrier, was KD = 4.7 µM. A high solubility of curcumin in milk fat and digestion during in vitro lipolysis increased its bioaccessibility. A simulated gastro-intestinal in vitro studies showed that cumulative release percentage of nanoencapsulated curcumin was 60% at pH 7.4 compared to 0.8% of native curcumin. The anti-microbial property of nanoencapsulated curcumin was more potent than native curcumin against food pathogenic organisms such as S. aureus, B. cereus, E. coli, B. subtilis, P. aeruginosa, P. aeruginosa, C. violaceum. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-023-05684-5.

Oxidative stress and Rho GTPases in the biogenesis of tunnelling nanotubes: implications in disease and therapy.

Tunnelling nanotubes (TNTs) are an emerging route of long-range intercellular communication that mediate cell-to-cell exchange of cargo and organelles and contribute to maintaining cellular homeostasis by balancing diverse cellular stresses. Besides their role in intercellular communication, TNTs are implicated in several ways in health and disease. Transfer of pathogenic molecules or structures via TNTs can promote the progression of neurodegenerative diseases, cancer malignancy, and the spread of viral infection. Additionally, TNTs contribute to acquiring resistance to cancer therapy, probably via their ability to rescue cells by ameliorating various pathological stresses, such as oxidative stress, reactive oxygen species (ROS), mitochondrial dysfunction, and apoptotic stress. Moreover, mesenchymal stem cells play a crucial role in the rejuvenation of targeted cells with mitochondrial heteroplasmy and oxidative stress by transferring healthy mitochondria through TNTs. Recent research has focussed on uncovering the key regulatory molecules involved in the biogenesis of TNTs. However further work will be required to provide detailed understanding of TNT regulation. In this review, we discuss possible associations with Rho GTPases linked to oxidative stress and apoptotic signals in biogenesis pathways of TNTs and summarize how intercellular trafficking of cargo and organelles, including mitochondria, via TNTs plays a crucial role in disease progression and also in rejuvenation/therapy.

Case Report: Microsporidial Endophthalmitis after Penetrating Eye Trauma.

SIGNIFICANCE: In the recent past, there are increasing publications on microsporidia affecting the cornea in Asian population. However, microsporidia-causing endophthalmitis has been rarely reported. This report intends to draw the attention of eye care professionals to consider microsporidia as a differential diagnosis in cases of keratitis or endophthalmitis after ocular trauma. PURPOSE: The purpose of this study was to report a case of microsporidial endophthalmitis after corneal tear in an otherwise healthy patient. CASE REPORT: A 62-year-old healthy gentleman sustained injury to the left eye cornea with the tip of a soiled and wet screw driver. Two days after the corneal tear suturing, he complained of pain. On examination, circumcorneal congestion with hypopyon of 2 mm in height was present. Vitreous tap and intravitreal antibiotics were injected. Vitreous tap showed microsporidia. Pars plana vitrectomy was performed. His vision improved to 6/12. CONCLUSIONS: Microsporidia are an emerging cause of stromal keratitis. In the recent past, there has been an increase in microsporidial keratitis in both immunocompetent and immunocompromised individuals. History of trauma especially in rainy season and exposure to soil are reported risk factors. This is a case report on microsporidia-causing endophthalmitis after corneal tear repair. Ophthalmologists and optometrists should be aware of the possibility of microsporidia as a potential pathogen causing stromal keratitis or endophthalmitis in a setting of ocular trauma. Early treatment can result in good visual recovery.

Delivery of mGluR5 siRNAs by Iron Oxide Nanocages by Alternating Magnetic Fields for Blocking Proliferation of Metastatic Osteosarcoma Cells.

Although osteosarcoma is the most common primary malignant bone tumor, chemotherapeutic drugs and treatment have failed to increase the five-year survival rate over the last three decades. We previously demonstrated that type 5 metabotropic glutamate receptor, mGluR5, is required to proliferate metastatic osteosarcoma cells. In this work, we delivered mGluR5 siRNAs in vitro using superparamagnetic iron oxide nanocages (IO-nanocages) as delivery vehicles and applied alternating magnetic fields (AMFs) to improve mGluR5 siRNAs release. We observed functional outcomes when mGluR5 expression is silenced in human and mouse osteosarcoma cell lines. The results elucidated that the mGluR5 siRNAs were successfully delivered by IO-nanocages and their release was enhanced by AMFs, leading to mGluR5 silencing. Moreover, we observed that the proliferation of both human and mouse osteosarcoma cells decreased significantly when mGluR5 expression was silenced in the cells. This novel magnetic siRNA delivery methodology was capable of silencing mGluR5 expression significantly in osteosarcoma cell lines under the AMFs, and our data suggested that this method can be further used in future clinical applications in cancer therapy.

Testing for SARS-CoV-2: Can We Stop at 2?

The COVID-19 epidemic requires accurate identification and isolation of confirmed cases for effective control. This report describes the effectiveness of our testing strategy and highlights the importance of repeat testing in suspected cases in our cohort.

Long-term causes of death among pediatric patients with cancer.

BACKGROUND: The objectives of this study were to characterize the risk of death (1) from the primary cancer vs competing cause of death; and (2) from various causes of death vs the general poplation. The relative risk of death after a pediatric cancer diagnosis versus the general population and the risk of death from a primary cancer diagnosis versus competing causes of death. METHODS: This retrospective, population-based study used the Surveillance, Epidemiology, and End Results database (1980-2015) and included patients aged 0 to 19 years at the time of diagnosis. Observed deaths were calculated; the risk of death versus the general population was assessed with standardized mortality ratios (SMRs). Competing risk models for the cause of death were performed. RESULTS: There were 58,356 patients who were diagnosed, and the mortality rate was 22.8%. To assess causes of death, 6996 patients who died during the study period were included (45,580 total person-years at risk): 5128 (73%) died of their primary cancer, and 1868 (27%) died of a competing cause. Among all patients, the rate of death from the index cancer was higher than the rate of death from another cause within the first 5 years after diagnosis. The risk of death from a nonprimary cancer began to supersede the rate of death from the primary cancer 10 years after diagnosis for patients with germ cell tumors, lymphomas, and sarcomas. SMRs for the primary cancer were highest within the first 5 years after diagnosis for all cancers (SMRs, 100-50,000; P < .0001). The risk of death from competing causes (heart disease, suicide, and sepsis) was elevated (SMR, >100; P < .001). The risk of dying of heart disease was high, especially for patients with astrocytomas (SMR, 47.84; 95% confidence interval [CI], 27.87-76.59) and neuroblastomas (SMR, 98.59; 95% CI, 47.28-181.32). The risk of dying of suicide was high in most patients, particularly for those with osteosarcomas (SMR, 111.40; 95% CI, 2.82-620.69), Hodgkin lymphomas (SMR, 62.35; 95% CI, 34.89-102.83), and gonadal germ cell tumors (SMR, 28.97; 95% CI, 12.51-57.09). CONCLUSIONS: The cause of death for patients with gonadal germ cell tumors, lymphomas, and sarcomas is more commonly a secondary cancer or noncancerous cause than the primary disease; their risk of death from competing causes (heart disease, suicide, and sepsis) rises throughout life.

Deep learning algorithms for detection of critical findings in head CT scans: a retrospective study.

BACKGROUND: Non-contrast head CT scan is the current standard for initial imaging of patients with head trauma or stroke symptoms. We aimed to develop and validate a set of deep learning algorithms for automated detection of the following key findings from these scans: intracranial haemorrhage and its types (ie, intraparenchymal, intraventricular, subdural, extradural, and subarachnoid); calvarial fractures; midline shift; and mass effect. METHODS: We retrospectively collected a dataset containing 313 318 head CT scans together with their clinical reports from around 20 centres in India between Jan 1, 2011, and June 1, 2017. A randomly selected part of this dataset (Qure25k dataset) was used for validation and the rest was used to develop algorithms. An additional validation dataset (CQ500 dataset) was collected in two batches from centres that were different from those used for the development and Qure25k datasets. We excluded postoperative scans and scans of patients younger than 7 years. The original clinical radiology report and consensus of three independent radiologists were considered as gold standard for the Qure25k and CQ500 datasets, respectively. Areas under the receiver operating characteristic curves (AUCs) were primarily used to assess the algorithms. FINDINGS: The Qure25k dataset contained 21 095 scans (mean age 43 years; 9030 [43%] female patients), and the CQ500 dataset consisted of 214 scans in the first batch (mean age 43 years; 94 [44%] female patients) and 277 scans in the second batch (mean age 52 years; 84 [30%] female patients). On the Qure25k dataset, the algorithms achieved an AUC of 0·92 (95% CI 0·91-0·93) for detecting intracranial haemorrhage (0·90 [0·89-0·91] for intraparenchymal, 0·96 [0·94-0·97] for intraventricular, 0·92 [0·90-0·93] for subdural, 0·93 [0·91-0·95] for extradural, and 0·90 [0·89-0·92] for subarachnoid). On the CQ500 dataset, AUC was 0·94 (0·92-0·97) for intracranial haemorrhage (0·95 [0·93-0·98], 0·93 [0·87-1·00], 0·95 [0·91-0·99], 0·97 [0·91-1·00], and 0·96 [0·92-0·99], respectively). AUCs on the Qure25k dataset were 0·92 (0·91-0·94) for calvarial fractures, 0·93 (0·91-0·94) for midline shift, and 0·86 (0·85-0·87) for mass effect, while AUCs on the CQ500 dataset were 0·96 (0·92-1·00), 0·97 (0·94-1·00), and 0·92 (0·89-0·95), respectively. INTERPRETATION: Our results show that deep learning algorithms can accurately identify head CT scan abnormalities requiring urgent attention, opening up the possibility to use these algorithms to automate the triage process. FUNDING: Qure.ai.

Predictive Abilities of Machine Learning Techniques May Be Limited by Dataset Characteristics: Insights From the UNOS Database.

BACKGROUND: Traditional statistical approaches to prediction of outcomes have drawbacks when applied to large clinical databases. It is hypothesized that machine learning methodologies might overcome these limitations by considering higher-dimensional and nonlinear relationships among patient variables. METHODS AND RESULTS: The Unified Network for Organ Sharing (UNOS) database was queried from 1987 to 2014 for adult patients undergoing cardiac transplantation. The dataset was divided into 3 time periods corresponding to major allocation adjustments and based on geographic regions. For our outcome of 1-year survival, we used the standard statistical methods logistic regression, ridge regression, and regressions with LASSO (least absolute shrinkage and selection operator) and compared them with the machine learning methodologies neural networks, naïve-Bayes, tree-augmented naïve-Bayes, support vector machines, random forest, and stochastic gradient boosting. Receiver operating characteristic curves and C-statistics were calculated for each model. C-Statistics were used for comparison of discriminatory capacity across models in the validation sample. After identifying 56,477 patients, the major univariate predictors of 1-year survival after heart transplantation were consistent with earlier reports and included age, renal function, body mass index, liver function tests, and hemodynamics. Advanced analytic models demonstrated similarly modest discrimination capabilities compared with traditional models (C-statistic ≤0.66, all). The neural network model demonstrated the highest C-statistic (0.66) but this was only slightly superior to the simple logistic regression, ridge regression, and regression with LASSO models (C-statistic = 0.65, all). Discrimination did not vary significantly across the 3 historically important time periods. CONCLUSIONS: The use of advanced analytic algorithms did not improve prediction of 1-year survival from heart transplant compared with more traditional prediction models. The prognostic abilities of machine learning techniques may be limited by quality of the clinical dataset.

The National Physicians Cooperative: transforming fertility management in the cancer setting and beyond.

Once unimaginable, fertility management is now a nationally established part of cancer care in institutions, from academic centers to community hospitals to private practices. Over the last two decades, advances in medicine and reproductive science have made it possible for men, women and children to be connected with an oncofertility specialist or offered fertility preservation soon after a cancer diagnosis. The Oncofertility Consortium's National Physicians Cooperative is a large-scale effort to engage physicians across disciplines - oncology, urology, obstetrics and gynecology, reproductive endocrinology, and behavioral health - in clinical and research activities to enable significant progress in providing fertility preservation options to children and adults. Here, we review the structure and function of the National Physicians Cooperative and identify next steps.

Meta-analysis of polycystic kidney disease expression profiles defines strong involvement of injury repair processes.

Polycystic kidney disease (PKD) is a major cause of end-stage renal disease. The disease mechanisms are not well understood and the pathogenesis toward renal failure remains elusive. In this study, we present the first RNASeq analysis of a Pkd1-mutant mouse model in a combined meta-analysis with other published PKD expression profiles. We introduce the PKD Signature, a set of 1,515 genes that are commonly dysregulated in PKD studies. We show that the signature genes include many known and novel PKD-related genes and functions. Moreover, genes with a role in injury repair, as evidenced by expression data and/or automated literature analysis, were significantly enriched in the PKD Signature, with 35% of the PKD Signature genes being directly implicated in injury repair. NF-κB signaling, epithelial-mesenchymal transition, inflammatory response, hypoxia, and metabolism were among the most prominent injury or repair-related biological processes with a role in the PKD etiology. Novel PKD genes with a role in PKD and in injury were confirmed in another Pkd1-mutant mouse model as well as in animals treated with a nephrotoxic agent. We propose that compounds that can modulate the injury-repair response could be valuable drug candidates for PKD treatment.

Insulin-like growth factor 1 receptor activation promotes mammary gland tumor development by increasing glycolysis and promoting biomass production.

BACKGROUND: The insulin-like growth factor 1 (IGF1) signaling axis plays a major role in tumorigenesis. In a previous experiment, we chronically treated mice with several agonists of the IGF1 receptor (IGF1R). We found that chronic treatment with insulin analogues with high affinity towards the IGF1R (IGF1 and X10) decreased the mammary gland tumor latency time in a p53R270H/+WAPCre mouse model. Frequent injections with insulin analogues that only mildly activated the IGF1R in vivo (glargine and insulin) did not significantly decrease the tumor latency time in this mouse model. METHODS: Here, we performed next-generation RNA sequencing (40 million, 100 bp reads) on 50 mammary gland tumors to unravel the underlying mechanisms of IGF1R-promoted tumorigenesis. Mutational profiling of the individual tumors was performed to screen for treatment-specific mutations. The transcriptomic data were used to construct a support vector machine (SVM) classifier so that the phenotypic characteristics of tumors exposed to the different insulin analogue treatments could be predicted. For translational purposes, we ran the same classifiers on transcriptomic (micro-array) data of insulin analogue-exposed human breast cancer cell lines. Genome-scale metabolic modeling was performed with iMAT. RESULTS: We found that chronic X10 and IGF1 treatment resulted in tumors with an increased and sustained proliferative and invasive transcriptomic profile. Furthermore, a Warburg-like effect with increased glycolysis was observed in tumors of the X10/IGF1 groups and, to a lesser extent, also in glargine-induced tumors. A metabolic flux analysis revealed that this enhanced glycolysis programming in X10/IGF1 tumors was associated with increased biomass production programs. Although none of the treatments induced genetic instability or enhanced mutagenesis, mutations in Ezh2 and Hras were enriched in X10/IGF1 treatment tumors. CONCLUSIONS: Overall, these data suggest that the decreased mammary gland tumor latency time caused by chronic IGF1R activation is related to modulation of tumor progression rather than increased tumor initiation.

Low rates of pregnancy screening in adolescents before teratogenic exposures in a national sample of children's hospitals.

BACKGROUND: Adolescents with cancer engage in sexual behaviors and are exposed to teratogenic chemotherapy. There are no data regarding pregnancy screening patterns for adolescents before chemotherapy exposure. METHODS: A cross-sectional study of leukemia and emergency room (ER) admissions in the Pediatric Health Information System from 1999 to 2011 was conducted. Females who were 10 to 18 years old and 1) had newly diagnosed acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) or 2) had ER visits with computed tomography (CT) of the abdomen/pelvis were included. The exposure was a hospital visit with either chemotherapy or an abdominal/pelvic CT scan. The main outcome was a pregnancy test billed on the same day or before the teratogenic exposure within the same index admission. Log-binomial regressions were used to compute prevalence ratios and 95% confidence intervals comparing pregnancy screening in the leukemia and ER cohorts. RESULTS: A total of 35,650 admissions were identified. The proportion of visits with an appropriately timed pregnancy test was 35%, 64%, and 58% in the ALL (n = 889), AML (n = 127), and ER cohorts (n = 34,634), respectively. Patients with ALL were significantly less likely to have a pregnancy test than the ER cohort (adjusted prevalence ratio, 0.71; 95% confidence interval, 0.65-0.78), but there was no significant difference between the AML and ER cohorts (adjusted prevalence ratio, 1.12; 95% confidence interval, 0.99-1.27). There was substantial hospital-level variation in pregnancy screening patterns. CONCLUSIONS: Adolescents with acute leukemia and ER visits have low rates of pregnancy screening before teratogenic exposures. Standardized practice guidelines for pregnancy screening among adolescents may improve screening rates. Cancer 2016;122:3394-3400. © 2016 American Cancer Society.

microRNA-34c is a novel target to treat dementias.

MicroRNAs are key regulators of transcriptome plasticity and have been implicated with the pathogenesis of brain diseases. Here, we employed massive parallel sequencing and provide, at an unprecedented depth, the complete and quantitative miRNAome of the mouse hippocampus, the prime target of neurodegenerative diseases such as Alzheimer's disease (AD). Using integrative genetics, we identify miR-34c as a negative constraint of memory consolidation and show that miR-34c levels are elevated in the hippocampus of AD patients and corresponding mouse models. In line with this, targeting miR-34 seed rescues learning ability in these mouse models. Our data suggest that miR-34c could be a marker for the onset of cognitive disturbances linked to AD and indicate that targeting miR-34c could be a suitable therapy.

Oxidative stress and tissue pathology caused by subacute exposure to ammonium acetate in rats and their response to treatments with alpha-ketoglutarate and N-acetyl cysteine.

Ammonia is a widely used industrial chemical that is recognized as a potent neurotoxin and environmental pollutant. The present study addresses the oxidative stress and tissue pathology caused by 4 weeks of exposure to ammonium acetate (AMA; 100 mg/kg daily; orally) in rats, and their response to oral treatments with alpha-ketoglutarate (A-KG; 1.0 g/kg), a potential cyanide antidote, and/or N-acetyl cysteine (NAC; 10 mg/kg), an antioxidant. The organ-body weight index of brain and liver was significantly increased by AMA but kidney was unaffected. Also, plasma ammonia levels were significantly elevated without any concomitant change in blood gas status and hematology but levels of catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and reduced glutathione (GSH) in the brain and liver were diminished, accompanied by elevated levels of malondialdehyde. Levels of glutathione disulfide (GSSG) were unaffected, but the ratio of GSH:GSSG was reduced. Plasma alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase and total bilirubin were raised but urea, uric acid and creatinine levels were not altered. AMA also caused temporal, hepatic and renal pathology. However, the renal pathology was not supported by any biochemical alterations. A-KG or NAC alone afforded less protection against AMA as compared to both given together. The protective efficacy of A-KG can be ascribed to its ability to detoxify ammonia and additionally both A-KG and NAC have antioxidant properties as well. The study suggests a new therapeutic regimen for ammonia poisoning.

Accelerated stability and bioassay of a new oral α-ketoglutarate formulation for treating cyanide poisoning.

CONTEXT: Due to several limitations of existing cyanide antidotes, α-ketoglutarate (α-KG) has been proposed as a promising treatment for cyanide. OBJECTIVE: This study reports the accelerated stability and bioassay of a new oral α-KG formulation. MATERIALS AND METHODS: Amber-colored PVDF bottles containing 100 ml of 10% α-KG in 70% sorbitol, preservative (sodium methyl paraben and sodium propyl paraben), sweetener (sodium saccharine), flavor (American ice-cream soda and peppermint) and color (tartrazine), at pH 7.0-8.0 were stored in stability chamber (40 ± 2 °C and 75 ± 5% humidity) for 6 months in a GMP compliant facility. Various physical (pH, color, evaporation, extractable volume and clarity), chemical (identification and quantification of active ingredient) and microbiological (total aerobic count) analyses, together with protection studies were carried periodically in mice. Acute toxicity of the formulation and bioavailability of α-KG were assessed in rats at the beginning of the experiment. RESULTS: No physical changes and microbiological growth were observed in the formulation. After 6 months, α-KG content in the formulation diminished by ∼24% but its protective efficacy against cyanide remained at 5.9-fold. Protection was further characterized spectrophotometrically by disappearance of α-KG spectrum in the presence of cyanide, confirming cyanohydrin formation. Oral LD50 of α-KG formulation in rats was >7.0 g/kg body weight, and did not produce any acute toxicity of clinical significance. Also, an appreciable amount of α-KG was measured in blood. CONCLUSION: As per the guidelines of International Conference on Harmonization, the new α-KG formulation exhibited satisfactory stability, bioefficacy and safety as cyanide antidote.