First-in-Human, Healthy Volunteers Integrated Protocol of ETC-206, an Oral Mnk 1/2 Kinase Inhibitor Oncology Drug.

In the last decade, drug development has tackled substantial challenges to improve efficiency and facilitate access to innovative medicines. Integrated clinical protocols and the investigation of targeted oncology drugs in healthy volunteers (HVs) have emerged as modalities with an increase in scope and complexity of early clinical studies and first-in-human (FIH) studies in particular. However, limited work has been done to explore the impact of these two modalities, alone or in combination, on the scientific value and on the implementation of such articulated studies. We conducted an FIH study in HVs with an oncology targeted drug, an Mnk 1/2 small molecule inhibitor. In this article, we describe results, advantages, and limitations of an integrated clinical protocol with an oncology drug. We further discuss and indicate points to consider when designing and conducting similar scientifically and operationally demanding FIH studies.

Effect of sarpogrelate on altered STZ-diabetes induced cardiovascular responses to 5-hydroxytryptamine in rats.

Sarpogrelate, a specific 5-HT2A receptor antagonist is reported to produce a number of beneficial cardiovascular effects in diabetes mellitus. In the present investigation we have studied the effects of sarpogrelate on 5-HT receptors in heart and platelets in streptozotocin (STZ)-diabetic rats. Diabetes was induced by a single tail vein injection of STZ (45 mg/kg) and sarpogrelate (1 mg/kg, i.p.) was administered daily for 6 weeks. Injection of STZ produced significant loss of body weight, polyphagia, polydypsia, hyperglycemia, hypoinsulinemia, hypertension and bradycardia. Treatment with sarpogrelate significantly lowered fasting glucose levels with corresponding increase in insulin levels. It also significantly prevented STZ-induced polydypsia, hyperphagia, hypertension, and bradycardia but not the loss of body weight. 5-HT produced dose-dependent positive inotropic effect that was found to be decreased significantly in STZ-diabetic rats. Hearts obtained from sarpogrelate treated diabetic rats did not show any decrease in responsiveness to 5-HT. Relative platelet aggregation per se was found to be higher in STZ-diabetic rats as compared to control and this was significantly prevented by sarpogrelate treatment. 5-HT produced a dose-dependent increase in platelet aggregation in non-diabetic and sarpogrelate treated diabetic rats. However, 5-HT failed to produce any increase in platelet aggregation in untreated diabetic rats. Our data suggest that STZ-induced diabetes may produce down-regulation of cardiac 5-HT2A receptors and increased platelet aggregation. Treatment with sarpogrelate seems to prevent STZ-induced down-regulation of 5-HT receptors and increase in platelet activity in diabetic rats.

Effect of chronic treatment with losartan on streptozotocin-induced renal dysfunction.

The present investigation was undertaken to study the effect of chronic treatment with angiotensin (AT1) receptor antagonist losartan (2 mg/kg, p.o., 6 weeks) on streptozotocin (STZ) induced (45 mg/kg, i.v., single dose) renal dysfunctions in diabetic rats. Injection of streptozotocin produced not only the cardinal symptoms of diabetes mellitus like loss of body weight, hyperglycemia, and hypoinsulinemia but also the renal dysfunctions. Losartan treatment significantly prevented all these changes except STZ-induced hypoinsulinemia. There was a significant elevation of blood pressure in diabetic rats and treatment with losartan significantly brought it back to normal. Renal dysfunction in diabetic rats was characterized by a significant decrease in creatinine clearance, elevated levels of electrolytes and renal hypertrophy. Treatment with losartan prevented these changes. A good correlation was found between biochemical parameters and histopathological abnormalities. Our data suggests that, losartan may be considered as the drug of choice when there is a co-existence of diabetes mellitus and hypertension with compromised kidney function.

Fenoldopam treatment improves peripheral insulin sensitivity and renal function in STZ-induced type 2 diabetic rats.

Dopamine and diabetes mellitus are reported to have close link between them. We have studied the effect of six-week treatment with D1 receptor agonist fenoldopam (1 mg/kg, i.p., daily) on glucose, lipid, and renal profile in streptozotocin (STZ)-induced (non-insulin dependent) type 2 diabetic rats. Streptozotocin (90 mg/kg, i.p.) was injected to two day old Sprague-Dawley pups. Streptozotocin produced hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertension, increase in serum urea and creatinine by the time animals were 10 week old. Treatment with fenoldopam significantly decreased serum glucose, insulin, cholesterol, triglyceride, urea, creatinine, and blood pressure. During oral glucose tolerance test (OGTT), diabetic rats showed increase in AUC(glucose) and AUC(insulin). Fenoldopam significantly decreased AUC(glucose) in diabetic rats. Diabetic rats showed lower insulin sensitivity index (K(TTT)) that was significantly increased by treatment with fenoldopam in diabetic rats. Diabetic rats showed decrease in urinary sodium. Fenoldopam treatment significantly increased urine output as well as urinary sodium indicating reduced sodium retention. Our data indicates fenoldopam treatment improves peripheral insulin sensitivity and renal function in STZ-induced type 2 diabetic rats.

Rosiglitazone treatment restores renal dopamine receptor function in obese Zucker rats.

Earlier we have reported a defective dopamine D1-like receptor function, which was accompanied by a decrease in D1 receptor numbers and the inability of dopamine to inhibit Na,K-ATPase and Na,H-exchanger in proximal tubules of hyperinsulinemic obese Zucker rats. The present study was designed to test the hypothesis that the defect in dopamine receptor function is a result of hyperinsulinemia in obese rats. We designed experiments to study D1 receptor function in obese Zucker rats treated with rosiglitazone, as it lowers plasma insulin by improving insulin sensitivity. A group of untreated lean and obese rats served as controls. Rosiglitazone treatment (10 mg/kg orally, 4 weeks) caused significant decreases in plasma insulin, blood glucose, and blood pressure while causing an increase in renal sodium excretion compared with untreated obese rats. In the isolated proximal tubules obtained from untreated lean rats, dopamine caused concentration-dependent inhibition of the Na,K-ATPase activity, but this inhibitory effect was absent in untreated obese rats. In rosiglitazone-treated obese rats, the inhibitory effect of dopamine on Na,K-ATPase was significantly restored. This was accompanied by a complete restoration of D1 receptor numbers in proximal tubular membranes of treated obese rats. In another set of experiments, treatment of primary proximal tubule epithelial cells in culture medium with insulin caused a significant decrease in the D1 receptor abundance, suggesting a direct role of insulin on D1 receptor regulation. We conclude that hyperinsulinemia causes downregulation of D1 receptor function and lowering of plasma insulin levels leads to restoration of renal D1 receptor function.

Beneficial effects of fenoldopam treatment on renal function in streptozotocin-induced diabetic rats.

We have studied the effect of chronic treatment with dopamine D1 receptor agonist fenoldopam (1 mg/kg, i.p. daily for 6 weeks) on renal function and metabolic parameters in streptozotocin (STZ)-diabetic rats. Diabetes was induced by a single tail vein injection of STZ (45 mg/kg). STZ produced severe hyperglycemia, hypoinsulinemia, hypercholesterolemia, hypertriglyceridemia, hypertension and bradycardia. Fenoldopam treatment significantly reduced fasting but not fed blood glucose levels and lowered the blood pressure in diabetic animals. Significant change was not observed in insulin, cholesterol, triglyceride levels. Diabetic animals showed increase in AUCglucose and decrease in AUCinsulin during oral glucose tolerance test. Fenoldopam treatment did not significantly change these values in diabetic animals. STZ produced increase in serum urea, creatinine and blood urea nitrogen. Diuresis and urinary sodium retention was observed in diabetic animals. Renal hypertrophy was observed as seen from increased kidney weight/body weight ratio and increased total RNA content as well as decreased total DNA content. Fenoldopam treatment significantly lowered serum urea, creatinine and blood urea nitrogen. Urinary sodium retention was significantly reduced and renal hypertrophy was prevented with fenoldopam treatment as seen from the improved kidney weight/body weight ratio. Fenoldopam treatment significantly prevented reduction in total DNA content and increase in total RNA content further substantiating reduced renal hypertrophy. Our data suggest that STZ induced diabetes is associated with renal dysfunctions and fenoldopam treatment could be beneficial in a condition where diabetes mellitus co-exists with hypertension and compromised renal function.