Treatment-related Abnormalities Research Articles

Distinguishing glioblastoma progression from treatment-related changes using DTI directionality growth analysis.

It is difficult to distinguish between tumor progression (TP) and treatment-related abnormalities (TRA) in treated glioblastoma patients via conventional MRI, but this distinction is crucial for treatment decision making. Glioblastoma is known to exhibit an invasive growth pattern along white matter architecture and vasculature. This study quantified lesion development patterns in treated glioblastoma lesions and their relation to white matter microstructure to distinguish TP from TRA. Glioblastoma patients with confirmed TP or TRA with T1-weighted contrast-enhanced and DTI MR scans from two posttreatment follow-up timepoints were reviewed. The contrast-enhancing regions were segmented, and the regions were coregistered to the DTI data. Lesion increase vectors were categorized into two groups: parallel (0-20 degrees) and perpendicular (70-90 degrees) to white matter. FA-values were also extracted. To test for a statistically significant difference between the TP and TRA groups, a Mann‒Whitney U test was performed. Of 73 glioblastoma patients, fifteen were diagnosed with TRA, whereas 58 patients suffered TP. TP had a 25.8% (95% CI 24.1%-27.6%) increase in parallel lesions, and TRA had a 25.4% (95% CI 20.9%-29.9%) increase in parallel lesions. The perpendicular increase was 14.7% for TP (95% CI 13.0%-16.4%) and 18.0% (95% CI 13.5%-22.5%) for TRA. These results were not significantly different (p = 0.978). FA value for TP showed to be 0.248 (SD = 0.054) and for TRA it was 0.231 (SD = 0.075), showing no statistically significant difference (p = 0.121). Based on our results, quantifying posttreatment contrast-enhancing lesion development directionality with DTI in glioblastoma patients does not appear to effectively distinguish between TP and TRA.

How to evaluate perfusion imaging in post-treatment glioma: a comparison of three different analysis methods

IntroductionDynamic susceptibility contrast (DSC) perfusion weighted (PW)-MRI can aid in differentiating treatment related abnormalities (TRA) from tumor progression (TP) in post-treatment glioma patients. Common methods, like the ‘hot spot’, or visual approach suffer from oversimplification and subjectivity. Using perfusion of the complete lesion potentially offers an objective and accurate alternative. This study aims to compare the diagnostic value and assess the subjectivity of these techniques.Methods50 Glioma patients with enhancing lesions post-surgery and chemo-radiotherapy were retrospectively included. Outcome was determined by clinical/radiological follow-up or biopsy. Imaging analysis used the ‘hot spot’, volume of interest (VOI) and visual approach. Diagnostic accuracy was compared using receiving operator characteristics (ROC) curves for the VOI and ‘hot spot’ approach, visual assessment was analysed with contingency tables. Inter-operator agreement was determined with Cohens kappa and intra-class coefficient (ICC).Results29 Patients suffered from TP, 21 had TRA. The visual assessment showed poor to substantial inter-operator agreement (κ = -0.72 – 0.68). Reliability of the ‘hot spot’ placement was excellent (ICC = 0.89), while reference placement was variable (ICC = 0.54). The area under the ROC (AUROC) of the mean- and maximum relative cerebral blood volume (rCBV) (VOI-analysis) were 0.82 and 0.72, while the rCBV-ratio (‘hot spot’ analysis) was 0.69. The VOI-analysis had a more balanced sensitivity and specificity compared to visual assessment.ConclusionsVOI analysis of DSC PW-MRI data holds greater diagnostic accuracy in single-moment differentiation of TP and TRA than ‘hot spot’ or visual analysis. This study underlines the subjectivity of visual placement and assessment.

Acute and sub-chronic toxicological evaluation of Boga -TN tablets in experimental animals

Boga-TN is a formula originating from herbal medicines that are used to treat liver disorders; however, its toxicity is not yet investigated. Therefore, this study was conducted to assess the acute and sub-chronic toxicity of Boga-TN tablets in experimental animals. Acute toxicity study was performed via Swiss mice, with a single oral dose, and followed up to seven days according to World Health Organization Guidance. No sign of acute oral toxicity was detected, and the LD50 Boga-TN was estimated to be more than 60.38 g/kg. Based onobtained results , the sub-chronic toxicity study was carried out in Wistar rats for 4 consecutive weeks by oral administration at the doses of 0.77 and 2.31 g/kg/day. After treatment, no significant treatment-related abnormalities were observed at both doses of Boga-TN, compared to the control group, except lower neutrophil but higher lymphocyte values were observed in the treated animals. Histopathology assessment did not show any significant variation between control and treatment groups during the study period.

Apparent Diffusion Coefficient Metrics to Differentiate between Treatment-Related Abnormalities and Tumor Progression in Post-Treatment Glioblastoma Patients: A Retrospective Study.

Distinguishing treatment-related abnormalities (TRA) from tumor progression (TP) in glioblastoma patients is a diagnostic imaging challenge due to the identical morphology of conventional MR imaging sequences. Diffusion-weighted imaging (DWI) and its derived images of the apparent diffusion coefficient (ADC) have been suggested as diagnostic tools for this problem. The aim of this study is to determine the diagnostic accuracy of different cut-off values of the ADC to differentiate between TP and TRA. In total, 76 post-treatment glioblastoma patients with new contrast-enhancing lesions were selected. Lesions were segmented using a T1-weighted, contrast-enhanced scan. The mean ADC values of the segmentations were compared between TRA and TP groups. Diagnostic accuracy was compared by use of the area under the curve (AUC) and the derived sensitivity and specificity values from cutoff points. Although ADC values in TP (mean = 1.32 × 10-3 mm2/s; SD = 0.31 × 10-3 mm2/s) were significantly different compared to TRA (mean = 1.53 × 10-3 mm2/s; SD = 0.28 × 10-3 mm2/s) (p = 0.003), considerable overlap in their distributions exists. The AUC of ADC values to distinguish TP from TRA was 0.71, with a sensitivity and specificity of 65% and 70%, respectively, at an ADC value of 1.47 × 10-3 mm2/s. These findings therefore indicate that ADC maps should not be used in discerning between TP and TRA at a certain timepoint without information on temporal evolution.

Head-To-Head Comparison of PET and Perfusion Weighted MRI Techniques to Distinguish Treatment Related Abnormalities from Tumor Progression in Glioma.

The post-treatment imaging surveillance of gliomas is challenged by distinguishing tumor progression (TP) from treatment-related abnormalities (TRA). Sophisticated imaging techniques, such as perfusion-weighted magnetic resonance imaging (MRI PWI) and positron-emission tomography (PET) with a variety of radiotracers, have been suggested as being more reliable than standard imaging for distinguishing TP from TRA. However, it remains unclear if any technique holds diagnostic superiority. This meta-analysis provides a head-to-head comparison of the diagnostic accuracy of the aforementioned imaging techniques. Systematic literature searches on the use of PWI and PET imaging techniques were carried out in PubMed, Embase, the Cochrane Library, ClinicalTrials.gov and the reference lists of relevant papers. After the extraction of data on imaging technique specifications and diagnostic accuracy, a meta-analysis was carried out. The quality of the included papers was assessed using the QUADAS-2 checklist. Nineteen articles, totaling 697 treated patients with glioma (431 males; mean age ± standard deviation 50.5 ± 5.1 years) were included. The investigated PWI techniques included dynamic susceptibility contrast (DSC), dynamic contrast enhancement (DCE) and arterial spin labeling (ASL). The PET-tracers studied concerned [S-methyl-11C]methionine, 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG), O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) and 6-[18F]-fluoro-3,4-dihydroxy-L-phenylalanine ([18F]FDOPA). The meta-analysis of all data showed no diagnostic superior imaging technique. The included literature showed a low risk of bias. As no technique was found to be diagnostically superior, the local level of expertise is hypothesized to be the most important factor for diagnostically accurate results in post-treatment glioma patients regarding the distinction of TRA from TP.

Toxicological Evaluation of Alginic Acid, a Polysaccharide Isolated from <i>Turbinaria conoides</i> (J. Agardh) Kutzing on Wistar Albino Rats

Introduction: Alginic acid, a polysaccharide is one of the important phytochemical ingredients of brown algae, Turbinaria conoides (J. Agardh) Kutzing. T. conoides has been studied for various pharmacological activities, yet no toxicological information found in the literature therefore, preset study aimed at extraction and isolation of alginic acid and to assess the safety profile through acute and sub acute toxicity study in both male and female rats. Materials and Methods: Alginic acid was characterized through Fourier transform infrared spectroscopy, thermo gravimetric and differential scanning calorimetric analysis. In acute toxicity study, female rats received 2000 mg/kg of isolated product, at a single dose on oral administration. In subacute toxicity study, both male and female rats were given with 100, 200 and 400 mg/kg of the isolated product, orally, for a period of 28 days consecutively and behavioral changes, hematological, biochemical and histopathological investigations were verified. Results and Discussion: In acute toxicity study, no morbidity or mortality was reported with alginic acid treated animals at a dose of 2000 mg/kg. In sub-acute toxicity study, there were no treatment related abnormalities observed in hematological and biochemical parameters except, decreased red blood cell count (400 mg/kg); increased platelets (200 mg/kg) in female rats and increased levels of liver parameters (serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, gamma glutaryl transferase); lipid parameters (total cholesterol, triglycerides and blood glucose) in both male and female rats. Histopathology studies revealed a slight infiltration of cells and congestion in blood vessels in the liver; congestion of alveolar tissue in lungs with 400 mg/kg treated animals. No behavioural changes observed. Conclusion: From the obtained results it is indicated that the oral administration of alginic acid (active principle of T. conoides) did not produce any significant adverse effects in rats of both the sex. Hence, alginic acid was considered as safe to use for further therapeutic purpose.

The Effect of Nusinersen Therapy on Laboratory Parameters of Patients with Spinal Muscular Atrophy.

We evaluated the effect of nusinersen on clinical and laboratory parameters and presented its safety and effect on laboratory parameters. Two groups were formed from among patients with spinal muscular atrophy (SMA) followed up between September 2017 and June 2021: group 1, SMA type 1; group 2, SMA type 2 and 3. The laboratory parameters were evaluated in groups 1 and 2 between doses. Motor scale tests were performed on patients before each dose of nusinersen. Twenty seven patients (group 1; n = 13, group 2; n = 14) were included. The mean age (±standard deviation) at the onset of symptoms was 3 ± 1.21 (range, 1.5-6) months in group 1 and 12 ± 4.27 (range, 8-24) months in group 2. No significant laboratory treatment-related abnormalities and adverse effects were observed. The cerebrospinal fluid protein levels and the frequency of conventional LP were higher in group 1. Serum creatinine (Cr) levels were higher in group 1 before the first dose and higher in group 2 before the fifth dose (p < 0.05). With treatment, the Cr levels of group 1 decreased and group 2 remained constant or increased. We observed that the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and Hammersmith Functional Motor Scale-Expand scores increased as our patients received treatment (p < 0.05). Our results support the safety and efficacy of nusinersen. However, changes in Cr levels according to the clinical type and treatment suggested that serum Cr could be a candidate marker for treatment follow-up.

Toxicological evaluation of fucoidan, a polysaccharide isolated from Turbinaria conoides (J. agardh) Kutzing procured from mandapam coastal area, tamilnadu

Fucoidan, a sulfated polysaccharide is a well known active principle of marine brown algae, extensively used in food supplement and in pharmaceutical industry. The present study is aimed at evaluation of toxicological profile of fucoidan, isolated from Turbinaria conoides (J.Agardh) Kutzing in both male and female Wistar albino rats. Fucoidan was isolated and studied for Fourier Transform-Infrared spectroscopic analysis to confirm the functional groups. Acute and sub-acute toxicity studies were carried out by Organization for Economic Cooperation and Development guidelines 423 and 407. After treatment period all the animals were sacrificed to evaluate hematological and biochemical parameters. The weights of internal organs recorded and histopathological studies performed. Fourier Transform-Infrared spectroscopic analysis confirms the groups that are correlated with the standard. The animals did not show morbidity or mortality in acute toxicity study at single oral administration of fucoidan at a dose of 2000 mg/kg. In sub-acute toxicity, no statistically significant differences observed in body weight, relative organ weight, food and water intake when compared to control group. No treatment related abnormalities observed in hematological and biochemical parameters except increased levels of serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, total cholesterol, triglycerides and blood glucose in both male and female rats. Histopathology revealed no toxic signs at organ level compared to control. From the obtained results, the study suggested that fucoidan can be developed into a novel therapeutic agent and considered as a traditional drug as it does not show any toxic effects. Keywords: Acute toxicity, Fucoidan, Sub-acute toxicity, Turbinaria conoides.

Varlitinib in combination with gemcitabine and cisplatin for treatment-naïve advanced biliary tract cancer.

439 Background: Standard first-line treatment for advanced biliary tract cancer (BTC) with gemcitabine plus cisplatin confers only modest benefits (objective response rate [ORR], 26%; Valle et al. N Engl J Med 2010;362:1273-1281) and patient prognosis is poor. Therefore, new first-line strategies are urgently required. Human epidermal growth factor receptor (HER) tyrosine kinases are commonly overexpressed in BTC. Varlitinib is a reversible small molecule pan-HER inhibitor. Methods: This was a multicentre, phase 1B/2 study in patients with advanced BTC who had not received prior systemic therapy. Using a modified 3+3+3 escalation design in phase 1B, patients received oral varlitinib twice daily (BID) every day (starting dose 200 mg BID) plus gemcitabine/cisplatin on Days 1 and 8 in a 3-week cycle. The primary objective was to determine the maximum tolerated dose (MTD) and safety profile of varlitinib in combination with gemcitabine plus cisplatin. Patients were evaluable for MTD if they had varlitinib treatment compliance of ≥80% and received 2 doses of chemotherapy in Cycle 1, or if they experienced a dose-limiting toxicity (DLT) in Cycle 1. Preliminary efficacy was a secondary objective. Results: Overall, 23 patients were enrolled in Korea (3 sites), Singapore (1 site), and Taiwan (1 site). Patient characteristics at baseline: male, 52%; median (range) age, 66 (47-82) years; ECOG PS, 0 (43%)/ 1 (57%); primary tumor site, intrahepatic bile duct (43%)/ extrahepatic bile duct (22%)/ gallbladder (22%)/ ampulla of Vater (13%). In total, 11 and 12 patients were included in the varlitinib 200 mg and 300 mg cohorts, of whom 9 and 7 were evaluable for MTD, respectively. DLTs were observed in 2 patients in the 200 mg cohort. Prior to study termination, the 300 mg dose was being assessed with 1 patient experiencing a DLT. In the overall population (n = 23), 36% of patients in the 200 mg cohort and 67% in the 300 mg cohort had at least one grade ≥3 treatment-related adverse event. Grade ≥3 treatment-related investigations abnormalities and blood and lymphatic system disorders were reported in 27% and 18% of patients in the 200 mg cohort, and 25% and 25% of those in the 300 mg cohort, respectively. Among all 23 patients, 8 had a partial response and 12 had stable disease for ≥12 weeks, giving an ORR of 35% and a disease control rate of 87%. The median (Q1-Q3) duration of objective response was 4.0 (2.8-11.0) months. At the time of analysis, 17 patients had progression events and 6 were censored. The median (Q1-Q3) progression-free survival was 6.8 (5.1-10.7) months. Conclusions: Varlitinib combined with gemcitabine plus cisplatin was well tolerated and associated with preliminary anti-tumor activity in patients with treatment-naïve advanced BTC. Clinical trial information: NCT02992340.

Teratogenicity of D-allulose

The objective of this study was to evaluate whether D-allulose has teratogenic effects on rats. A prenatal developmental toxicity test was conducted in SD rats in compliance with modified OECD guidelines test number 414, prenatal developmental toxicity study. Pregnant female rats received repeated doses of 1250, 2500, or 5000 mg/kg body weight D-allulose, or a vehicle control by gavage on GD 6–15. On GD 20, one day prior to the expected day of delivery, pregnant rats were weighed and anesthetized, and laparotomized to remove the uterine and its content were weighed. Fetuses were examined macroscopically for any soft tissue and skeletal changes. The evaluation indicators included general sign observation, body weight, food consumption, animal death, corpora lutea, numbers of embryonic or fetal deaths, and viable fetuses including live birth rate, fetal resorption rate, and stillbirth rate, as well as sex, body weights, and skeletal and soft tissue alterations of fetuses. No treatment-related abnormalities were observed in prenatal developmental toxicity and fetal malformation parameters, indicating that D-allulose had no teratogenic effects on pregnant rats and fetuses. From the findings of this prenatal developmental toxicity study, the NOAEL of D-allulose was estimated to be 5000 mg/kg/day in pregnant SD rats.

Evaluation of Acute, Subacute and LD50 values of Methanolic extract of Sphaeranthus indicus leaves in Albino mice

Sphaeranthus indicus is one of the extremely precious herbs in the Indigenous System of Medicine. The present study was carried out to acute, subacute and LD50 values of methanolic extract of S. indicus leaves in Swiss mice of both sexes. The acute toxicity studies were conducted oral administration of 1.75, 5.5, 17.5, 55, 175, 550, 2000mg/kg body weight SIME used. Observations were recorded systemically up to 24 h after dose administration for behavior related to nervous system response or autonomic functions. Food and water intake, body weight variations, hematological and biochemical parameters were assessed. In sub acute toxicity treatment there were no significant variation in the body weights and haematological parameters except dose-dependent increase in lymphocyte count was noted in both sexes supported immunostimulant activity. Pathologically, significant protective effect on hepatic, renal functions and decreased cholesterol, triglyceride levels. The results did not show any treatment related abnormalities in terms of hematological and biochemical parameters in sub-acute toxicity. After acute administration, no mortality was recorded in mice treated with the SIME orally at a dose of 1000mg/kg. The LD50 values were determined using graphical method; we found a broad therapeutic window and a high therapeutic index value showed that the LD50 of the extract is 2480mg/kg. The results suggest that the plant seems to be high margin of drug safety in mice.

A 90-Day Oral Toxicity of Hydroethanolic Root Extract of Carissa spinarum in Wistar Rats.

Background Herbal medication is a worldwide and ancient practice, mostly in developing countries, where a large part of the population is involved in this practice. Hence, studies must be conducted to evaluate their safety and efficiency to avoid or prevent toxicological risks due to their usage. In Togo, Carissa spinarum is a medicinal plant belonging to Apocynaceae family, used as an aphrodisiac or to heal some ailments including malaria, sickle cell anemia, hypertension, pain, and asthma. Notwithstanding its several ethnomedicinal benefits, just a few toxicological data associated with its chronic use are available. Objective Therefore, this study aims to assess the toxicity of an ethanolic root extract of Carissa spinarum in Wistar rats. Methods The 90-day oral toxicity process following OECD TG 408 guidelines is used. Male Wistar rats received Carissa spinarum root hydroethanolic extract at 500 and 1000 mg/kg for 90 days by oral gavage. Body weight changes, hematological and blood biochemical parameters, organ weight changes, malondialdehyde as a lipoperoxidation marker expressed according to tissue proteins, and histopathology of vital organs were assessed. Results No signs of toxicity or mortality were observed during the 90 days experiment. Hematological parameters have not shown any treatment-related abnormalities. According to biochemical parameters, an increase in the chloride ion level was observed at 1000 mg/kg (p < 0.01). There was no significant difference between the treated groups and the control group concerning the malondialdehyde concentration, body weight, and organ relative weight. No changes in necropsy and histopathology of vital organs associated with extract treatment were observed. Conclusion The results indicated that an ethanolic root extract of Carissa spinarum does not cause adverse effects, which can lead to Wistar rats' death after 90-day oral administration at 500 and 1000 mg.

Safety and efficacy of sFilm-FS, a novel biodegradable fibrin sealant, in Göttingen minipigs.

Bleeding during surgical procedures is a common complication. Therefore, hemostatic agents have been developed to control bleeding, and fibrin sealants have several benefits. sFilm-FS is a novel fibrin sealant that comprises a biodegradable co-polymeric film embedded with human fibrinogen and thrombin. Herein, the safety and efficacy of sFilm-FS were compared using a liver and spleen puncture model of Göttingen minipigs with those of the standard hemostatic techniques (control animals) and EVARREST®, a reference fibrin sealant. Hemostasis and reduced blood loss were more effectively achieved with sFilm-FS than with the standard techniques in the control animals and comparable to those achieved with EVARREST®. No treatment-related adverse effects were observed in any of the groups. Histopathological evaluation indicated that sFilm-FS was slightly and moderately reactive at the liver puncture site and spleen, respectively, compared with the standard techniques in the control animals. These changes are expected degradation reactions of the co-polymeric film and are not considered as adverse events. No treatment-related abnormalities were noted in the other evaluated organs. Additionally, no evidence of local or systemic thromboses was noted. These results support the use of sFilm-FS for hemostasis in humans.

Toxicity Studies of Striga hermonthica (Delile) Benth Leaf Extract in Rats

Striga hermonthica is a ubiquitous hemi-parasitic plant commonly known as witch-weed and is used in West Africa as a traditional herbal medicine for the treatment of an array of diseases. In this study, methanol leaf extract of S. hermonthica was used to investigate the acute and sub-acute toxicity effects in male Wistar rats. In the acute toxicity studies, Wistar rats were divided into six groups comprising of negative control and extract treated groups (250, 500, 1000, 1500 and 2000 mg/kg of extract orally). The rats were observed for 72 hours while in the sub-acute oral toxicity studies, the rats were divided into 4 groups consisting of 5 rats per group. The extract was administered orally at doses of 25, 50 and 100 mg/kg daily for 28 days to groups II, III and IV respectively while group I (negative control) received 2 ml of distilled water. The dose of 2000 mg/kg did not cause any mortality or signs of toxicity in the treated rats during the acute and subacute toxicity studies did not show any treatment-related abnormalities in the hematological (RBC, Hb, WBC, Lymphocytes) and biochemical (AST, ALT, ALP, TB, Glucose, HDL, LDL, Total protein, Albumin) parameters while the liver revealed lesions in the histopathology studies, there were no treatment-related lesions observed in the heart, lungs, pancreas and kidney whereas, the weight of rats did not show significant difference (p &gt; 0.05) between the control and the treated groups. The study showed that S. hermonthica caused hepatotoxicity and could be potentially harmful for use. A more comprehensive research is recommended to investigate on its safe use and mode of action.

Cytotoxicity, Acute, and Subacute Study of Hydroalcoholic Root Extract of Carissa spinarum L. on Wistar Rats.

Carissa spinarum L. (Apocynaceae) is used traditionally, in Africa, to treat many diseases such as malaria, sickle cell anemia, epilepsy, helminthoses, and sexual weakness. The aim of this study is to investigate the cytotoxicity on Artemia salina, the acute and subacute (28 days) oral toxicity of C. spinarum hydroalcoholic root extract on Wistar rats. The cytotoxicity was performed on A. salina larvae. The acute and subacute toxicity was performed using Organization of Economic Cooperation and Development guideline. Malondiadehyde as lipoperoxidation marker was evaluated and expressed according to tissue proteins. The cytotoxicity has shown that the lethal concentration 50 (LC50) was 0.9 mg/mL. The limit test dose of 5000 mg/kg did not provoke death or toxicity signs. For the subacute toxicity, no signs of toxicity or mortality were observed during the experiment. Results of biochemical and hematological parameters have not shown any treatment-related abnormalities, except a significant decrease of alkaline phosphatase at 1000 mg/kg (P < .05) and an increase of chloride ion level at 500 mg/kg (P < .01). There was no significant difference between the treated group and the control group concerning the malondialdehyde concentration, the body weight, and the organs relative weight (P < .05), except for testis at 500 mg/kg (P < .05). According to our results, the hydroalcoholic extract of C. spinarum roots is safe when administrated at 500 mg and 1000 mg/kg to Wistar rats for 28 days.

Safety evaluation of the interchangeable use of robenacoxib in commercially-available tablets and solution for injection in cats

BackgroundRobenacoxib (Onsior™) is a non-steroidal anti-inflammatory drug developed for canine and feline use for the control of pain and inflammation. It is available as both tablets and solution for injection.The objective of this study was to evaluate the safety of the interchangeable use of commercially available robenacoxib formulations when administered to cats orally using 6 mg tablets and subcutaneously using a solution for injection containing 20 mg/mL. Thirty-four naïve healthy 4-month old cats were enrolled in this 37-day study and were randomized to four groups (three robenacoxib and one control). One robenacoxib group received the maximum recommended dose (MRD) rate of each formulation, while the other two received two and three times this dose rate. The cats underwent three 10-day treatment cycles comprised of seven days of once daily oral administration followed by three days of subcutaneous administration. The third cycle was followed by an additional seven days of oral treatment. The control group received oral empty gelatin capsules or subcutaneous saline injections. Assessment of safety was based on general health observations, clinical observations, physical, ophthalmic, electrocardiographic and neurological examinations, clinical pathology evaluations, food consumption, body weight, and macroscopic and microscopic examinations. Blood samples were collected for toxicokinetic evaluation.ResultsBlood concentrations of robenacoxib confirmed systemic exposure of all treated cats. All cats were in good health through study termination and there were no serious adverse events during the study. There were no changes in body weight, food consumption, ophthalmic, physical or neurological examinations during the study. Treatment-related abnormalities were of low occurrence at all doses and included injection site changes (transient edema with minimal or mild, subacute/chronic inflammation histologically) and prolongation of the QT interval. These findings were consistent with previously observed findings in studies with robenacoxib administered separately orally or subcutaneously in cats. Thus, there were no adverse effects that could be attributed specifically to the interchangeable use of oral and injectable robenacoxib.ConclusionsThis 37-day laboratory study supports the safety of interchanging robenacoxib injection at a daily dose of 2 mg/kg with robenacoxib tablets at a daily dose of 1 mg/kg, or vice versa.

English

Camellia hakodae Ninh (CHN) is an ornamental plant of Vietnam, whose extracts is used as a potential phytotherapeutic beverage due to its good improvement in the immune system, reduction of inflammation and assisting the treatment of some chronic diseases. CHN production may be useful for health during this coronavirus epidemic period. This study aimed to evaluate the safety, acute and sub-chronic toxicity of aqueous extracts of CHN leaf in mice. In the acute toxicity study, CHN leaf at doses from 24.0 to 120.0 g/kg/day was given to 5 groups of Swiss mice by oral administration (equivalent in humans is 0.2 to 10 g/kg/day). Mice were observed for general behavioral changes, adverse effects and mortality up to 7 days post-treatment to find the highest dose that did not kill mice (the dose of death 0% (LD0)), the lowest dose that completely killed the mice (the dose of death 100% (LD100)) and the intermediate doses (LD50). In sub-chronic toxicity studies, CHN was given orally to 2 groups of Wistar rats at doses of 2.8 and 14 g CHN/kg/day (equivalent in humans is 0.4 and 2 g/kg) for 28 days taking CHN daily. After 28 days of taking CHN, mice were operated to observe the whole organ for histopathology. The microscopic structure of the liver, spleen, and kidney of at least 30% of mice in each group was randomly checked. The acute toxicity study in all the doses used did not cause any significant change as no LD50 was found. In addition, the sub-chronic toxicity study did not show any treatment-related abnormalities with regard to hematological and biochemical parameters. These results demonstrated that the CHN leaf aqueous extract is safe and does not appear to exert toxicity. Key words: Camellia hakodae Ninh, golden tea, acute and sub-chronic administration, Vietnamese tea. &nbsp

Nivolumab (NIVO) plus ipilimumab (IPI) with two cycles of chemotherapy (chemo) in first-line metastatic non-small cell lung cancer (NSCLC): CheckMate 568 Part 2.

9560 Background: In Part 1 of the phase II CheckMate 568 study (NCT02659059), NIVO + IPI was active and tolerable in patients (pts) with advanced NSCLC. The addition of chemo to dual immune checkpoint inhibitor therapy may further improve initial disease control. We report results from Part 2 of CheckMate 568, which evaluates NIVO + IPI combined with 2 cycles of chemo in pts with advanced treatment-naive NSCLC. Methods: Adult pts with untreated stage IV NSCLC received NIVO 360 mg Q3W + IPI 1 mg/kg Q6W combined with 2 cycles of histology-based platinum-doublet chemo, followed by NIVO + IPI without chemo until disease progression/unacceptable toxicity for ≤ 2 years. The primary endpoints were dose-limiting toxicity (DLT) within the first 9 weeks and safety/tolerability. Treatment was considered safe if ≤ 25% of at least 22 evaluable pts had a DLT. DLTs included but were not limited to: uncontrolled grade 3 non-skin treatment-related adverse events (TRAEs), grade 4 TRAEs, grade 2 treatment-related pneumonitis not resolved within 14 days, and treatment-related hepatic function abnormalities. Results: In total, 36 pts received treatment; 97% of pts completed 2 cycles of chemo combined with NIVO + IPI. Three pts discontinued IPI while continuing NIVO. Minimum follow-up was 14.9 months. Only 1 (3%) pt experienced a DLT (transient, asymptomatic grade 3 AST and ALT elevation) within the first 9 weeks. The elevation occurred on cycle 1, day 21 and resolved 2 weeks later with discontinuation of IPI, delay of NIVO, and treatment with prednisone; chemo was continued throughout and NIVO was restarted thereafter without recurrent toxicity. Grade 3–4 TRAEs occurred in 21 (58%) pts. Eight (22%) pts experienced a TRAE leading to discontinuation, most commonly colitis, encephalopathy, pneumonitis, and arthralgia (each in 2 [6%] pts); these events occurred outside of the 9-week window for DLT assessment. The most common select TRAEs (defined as AEs of potential immunologic causes) were skin related (18 [50%] pts); the most common grade 3–4 select TRAEs were endocrine (3 [8%] pts), skin related, gastrointestinal, and pulmonary (each in 2 [6%] pts). No treatment-related deaths occurred. Updated safety in addition to efficacy data will be presented. Conclusions: In pts with untreated advanced NSCLC, the addition of 2 cycles of platinum-doublet chemo to NIVO + tumor-optimized IPI was tolerable. No unexpected safety signals were observed. Clinical trial information: NCT02659059 .

Acute and sub-acute toxicity of Echinops kebericho decoction in rats

BackgroundEchinops kebericho is widely used for treatment of a variety of diseases including infectious, non-infectious disease and fumigation during child birth. Antibacterial, antimalarial, anti-leshimania, anti-diarrheal and insect repellent activities have been elucidated. Its toxicity profile is not yet investigated and thus this study was to investigate acute and sub-acute toxicity of E. kebericho decoctions.MethodsAcute toxicity study was performed in female Wistar albino rats with single oral dose and followed up to 14 days. The sub-acute oral dose toxicity studies were conducted in rats of both sexes in accordance with the repeated dose 28-day oral toxicity study in rodent OECD guidelines. Physical observations were made regularly during the study period while body weight was measured weekly. Organ weight, histopathology, clinical chemistry and hematology data were collected on the 29th day. Results were presented as mean ± standard deviation. One-way analysis of variance (ANOVA) was performed if assumptions were met; otherwise Kruskal-Wallis analysis was performed.ResultOral administration of E. kebericho decoction showed no treatment-related mortality in female rats up to the dose of 5000 mg/kg. In sub-acute toxicity studies, no significant treatment-related abnormalities were observed compared to negative controls. Food consumption, body weight, organ weight, hematology, clinical chemistry, and histopathology did not show significant variation between controls and treatment groups. However, creatinine, relative lung weight, triglycerides, and monocytes were lower in treated compared to control groups. Significant variations between male and female groups in food consumption, relative organ weight, hematology, clinical chemistry were observed. Histolo-pathology of high-dose treated groups showed fatty liver.ConclusionEchinops kebericho showed LD50 of greater than 5000 mg/kg in acute toxicity study and is well tolerated up to the dose of 600 mg/kg body weight in sub-acute toxicity study.

Acute and Sub-Acute Toxicity Assessment of the Hydroalcoholic Extract of Madhuca Longifolia Leaves in Wistar Rats

ABSTRACTThe in vivo acute and sub-acute toxicity of the hydroalcoholic leaf extract of Madhuca longifolia (HAEML) were evaluated as per the OECD guidelines. In the acute toxicity study, Albino Wistar rats were administered orally with 2000 mg kg−1 b.w. of HAEML and the animal behavior, adverse effect and mortality were observed for 14 d. Sub- acute toxicity study was conducted by oral administration of the extracts at daily doses of 200 and 400 mg kg−1 b.w. for 28 d. At the end of the treatment period the rats were sacrificed for hematological, biochemical and histopathological studies. No toxic signs or mortality were observed during the experimental period. Hence, the LD50 of the HAEML extracts was determined to be greater than 2000 mg kg−1 b.w. In repeated dose sub-acute toxicity study, the results did not reveal any treatment-related abnormalities in terms of body weight, relative organ weight and biochemical parameters. However, there was a notable difference in hematological profile and antioxidant enzymes. No gross morphological alteration was observed in histopathological studies.