Study protocol: phase II study to evaluate the effect of cetuximab monotherapy after immunotherapy with PD-1 inhibitors in patients with head and neck squamous cell cancer.

Background: Immunotherapy with programmed death receptor-1 (PD-1) inhibitors, as a single agent or in combination with chemotherapy, is the standard first-line treatment for recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC). Unfortunately, there is no established second-line treatment for the many patients who fail immunotherapy. Cetuximab is the only targeted therapy approved in HNSCC but historically has a low response rate of 13%. Objectives: We hypothesize that cetuximab monotherapy following an immune checkpoint inhibitor (ICI) will lead to increased efficacy due to a potential synergistic effect on the antitumor immune response, as a result of activation effects of both treatments on innate and adaptative immune responses. To the authors' knowledge, this is the only ongoing prospective clinical study that evaluates the combination of cetuximab and ICIs administered sequentially. Methods and analysis: In this non-randomized, open-label, phase II trial, 30 patients with R/M HNSCC who have previously failed or could not tolerate a PD-1 inhibitor as a single agent or in combination with chemotherapy will subsequently be treated with cetuximab monotherapy. Outcomes of interest include overall response rate, duration of response, progression-free survival, overall survival, and treatment toxicity, as well as treatment outcome measured by a patient-reported outcome questionnaire. Saliva and blood will be collected for correlative studies to investigate the immune response status at the end of therapy with an ICI and the effect of cetuximab on the antitumor immune response. The results will be correlated with the response to cetuximab and the time window between the last administration of an ICI and the loading dose of cetuximab. The clinical study is actively recruiting. Ethics: This study was approved by the Wake Forest Comprehensive Cancer Center Institutional Review Board: IRB00065239. Clinical trial registration: This study is registered on ClinicalTrials.gov: NCT04375384.

Hypolipidemic and antioxidant activity of aqueous extract of fruit of Withania coagulans (Stocks) Dunal in cholesterol-fed hyperlipidemic rabbit model.

Withania coagulans (family: Solanaceae, English: Indian Cheese Maker, Hindi: Doda Paneer) fruit is known for its ethanopharmacological significance in health care system of India. Diet rich in high-fat is an important risk factor for diabetes, atherosclerosis and macro and microvascular complications. Treatment with aqueous extract of fruit of W. coagulans (aqWC; 250 mg/kg body weight) in cholesterol-fed animals resulted in significant decrease in the levels of total cholesterol, triacylglycerol, low density lipoprotein, tissue lipid content and acetyl CoA carboxylase activity whereas, the level of high density lipoprotein and activity of HMGCoA reductase also recovered partially. Treatment with aqWC also significantly decreased plasma lipid peroxide levels and increased reduced glutathione and superoxide dismutase activities. These results suggest that the aqueous extract of W. coagulans has potent lipid lowering and antioxidant activities.

The aqueous extract of Withania coagulans fruit partially reverses nicotinamide/streptozotocin-induced diabetes mellitus in rats.

Withania coagulans fruit has been shown to possess antihyperglycemic properties and is used in the traditional Indian system of medicine. However, there has no systematic study of its mechanism of action. In a rat model diabetes mellitus (DM) was induced by intraperitoneal injection of nicotinamide (230 mg/kg of body weight) followed by streptozotocin at 55 mg/kg of body weight. After 96 h, mildly diabetic (MD) (fasting plasma glucose [FPG]=7-11.1 mmol/L) and severely diabetic (SD) (FPG>11.1 mmol/L) rats were treated with aqueous extract of W. coagulans fruit at doses of 125, 250, and 500 mg/kg of body weight/day orally. FPG, postprandial plasma glucose (PPPG), glycosylated hemoglobin (HbA(1c)), plasma insulin, tissue glycogen, and glucose-metabolizing enzymes were assayed at Day 30. Treatment of diabetic animals (MD and SD) with different doses of aqueous W. coagulans resulted in significantly decreased FPG, PPPG, and HbA(1c) (P<.01), whereas serum insulin increased significantly compared with that in diabetic-untreated rats (P<.01). MD and SD animals treated with aqueous W. coagulans also showed significant increases in liver and muscle glycogen compared with diabetic-untreated animals (P<.01). Moreover, activities of glucokinase and phosphofructokinase were also significantly increased (P<.01), whereas glucose-6-phosphatase activity was significantly decreased (P<.01) in MD and SD groups treated with aqueous W. coagulans compared with diabetic-untreated groups. The most effective dose of aqueous W. coagulans was 250 mg/kg of body weight. These results show that the aqueous extract of W. coagulans fruit has significant antihyperglycemic effects, which may be through the modulation of insulin levels and related enzyme activities.

Ameliorative effect of Withania coagulans on dyslipidemia and oxidative stress in nicotinamide-streptozotocin induced diabetes mellitus.

Present study aims to evaluate the effect of Withania coagulans fruit (aqWC) on diabetic-dyslipidemia and antioxidant/oxidant status in DM. Diabetic animals were treated with aqWC at a dose of 250 mg/kg bw for 30 days. Lipid profile, MDA, GSH, SOD, FRAP, HMG CoA reductase and acetyl CoA carboxylase activities were estimated in blood and tissues. Total cholesterol, TAG and LDL were significantly elevated whereas HDL was decreased in diabetic animals (p<0.05), simultaneously the lipid content and HMG CoA reductase activities were also increased, whereas acetyl CoA carboxylase activity decreased significantly in tissues of diabetic animals. MDA was increased and antioxidants such as SOD, GSH and FRAP decreased significantly in DM (p<0.05). Oral administration of aqWC to diabetic animals produced significant improvement in serum lipid profile and tissue lipid content. Activity of HMG CoA reductase decreased, whereas acetyl CoA carboxylase activity increased significantly in tissues after aqWC treatment. Administration of aqWC to diabetic animals also showed significant increase in antioxidant levels i.e., GSH, SOD, FRAP and reduced level of MDA in blood and tissue homogenates as compared to diabetic controls (p<0.05). These results suggest that aqWC treatment improved lipid profile and decreased oxidative stress in diabetes mellitus.

Antidiabetic and antihyperlipidemic effects of the stem of Musa sapientum Linn. in streptozotocin-induced diabetic rats.

BACKGROUND: Musa sapientum Linn. is a herbaceous plant of the Musaceae family. It has been used in India for the treatment of gastric ulcer, hypertension, diarrhea, dysentery, and diabetes. The antidiabetic effect of the fruit, root, and flower has been demonstrated. The aim of the present study was to assess the antidiabetic and antihyperlipidemic effects of the stem of M. sapientum Linn. METHODS: Diabetes was induced in rats by streptozotocin injection (45 mg/kg, i.p.). Diabetic rats were treated for 2 weeks with different doses of lyophilized stem juice of M. sapientum Linn. (25, 50, and 100 mg/kg) to select the most effective dose. The effects of 4 weeks treatment with this dose (50 mg/kg) on fasting and postprandial plasma glucose (FPG, PPG) levels, body weight, lipid profile, HbA1c, insulin, liver enzymes (i.e. glucokinase, glucose-6-phosphatase and 3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase) and muscle and liver glycogen were evaluated. RESULTS: The most effective dose of lyophilized stem juice of M. sapientum Linn. was 50 mg/kg. Four weeks treatment with this dose resulted in significant decreases in FPG and PPG (P < 0.05). Serum insulin increased (P < 0.05) whereas HbA1c decreased (P < 0.05). Diabetes-induced changes to the lipid profile, muscle and liver glycogen, and enzyme activity (i.e. glucokinase, glucose-6-phosphatase, and HMG-CoA reductase) were restored near to normal levels (P < 0.05). CONCLUSION: Diabetic rats responded favorably to treatment with lyophilized stem juice of M. sapientum Linn., which exhibits antidiabetic and antihyperlipidemic effects.

Hepatoprotective effect of stem of Musa sapientum Linn in rats intoxicated with carbon tetrachloride.

METHODS: The study was designed to evaluate the hepatoprotective activity of aqueous extract of central stem of Musa sapientum (AqMS) against carbon tetrachloride induced hepatotoxicity in rats. Animals were divided into six groups. Group I served as normal control. Group II, III, IV, V & VI were administered CCl(4) mixed with olive oil 1:1 (1.5 mL/kg) I.P., twice a week for 5 weeks. Group II was maintained as CCl(4) intoxicated control. Group III, IV and V received AqMS at a dose of 25, 50 and 100 mg/kg. Group VI received silymarin 100 mg/kg for 5 weeks orally once daily. Marker enzymes of hepatic functions estimated in serum were AST, ALT and ALP. Antioxidant parameters estimated were MDA and GSH in blood and liver and SOD in blood, after fifth week, animals were sacrificed, livers dissected out and evaluated for histomorphological changes. RESULTS: There was significant rise in AST, ALT and ALP in CCl(4) intoxicated control group II. Treatment with AqMS prevented rise in levels of these enzymes. There was significant rise in MDA and fall in GSH in blood and liver in group II, indicating increased lipid peroxidation and oxidative stress upon CCl(4) administration. Treatment with AqMS prevented rise in MDA & increased GSH in treated group. SOD levels were decreased in group II while groups treated with AqMS showed significant rise (p < 0.05). Maximum hepatoprotective effect was observed with 50 mg/kg dose. Hepatoprotective effect observed with this dose was comparable to standard hepatoprotective drug silymarin. The results of pathological study also support the results of biochemical findings. CONCLUSION: the results of the present study indicate that stem of Musa sapientum possess hepatoprotective effect and probably it is due to it's antioxidant property.