Challenges and Opportunities in Implementing the FDA Default Parametric Tolerance Interval Two One-Sided Test for Delivered Dose Uniformity of Orally Inhaled Products

The goal of this article is to discuss considerations regarding implementation of the parametric tolerance interval two one-sided test (PTI-TOST) for delivered dose uniformity (DDU) of orally inhaled products (OIPs). That test was proposed by FDA in 2005 as an alternative to the counting test described in the 1998 draft FDA guidance for metered dose inhalers and dry powder inhalers. The 2005 PTI-TOST, however, still has not found much use in practice despite the general desirability of parametric approaches in modern pharmaceutical quality control. A key reason for its slow uptake is that it rejects, with high probability, batches whose quality is considered acceptable by all other published regulatory and pharmacopeial standards as well as by the DDU specifications for many approved OIPs. Manufacturers therefore continue using nonparametric counting tests for control of DDU. A simulated case study presented here compares the consequences of the PTI-TOST compared to the counting test. The article discusses three possibilities that would help increase the uptake of the PTI-TOST approach, namely: product-specific quality standards, a different default standard suitable for the majority of OIPs, and integration of the PTI-TOST with a continuous verification control strategy rather than using it as an isolated-batch (transactional) end-product testing. In any of these efforts, if a parametric test is used, it is critical not to set the target quality close to, or at the boundary of the process/product capabilities, because PTI tests are designed to reject with high probability the identified target quality.     

Serine/threonine protein phosphatase 6 modulates the radiation sensitivity of glioblastoma

Increasing the sensitivity of glioblastoma cells to radiation is a promising approach to improve survival in patients with glioblastoma multiforme (GBM). This study aims to determine if serine/threonine phosphatase (protein phosphatase 6 (PP6)) is a molecular target for GBM radiosensitization treatment. The GBM orthotopic xenograft mice model was used in this study. Our data demonstrated that the protein level of PP6 catalytic subunit (PP6c) was upregulated in the GBM tissue from about 50% patients compared with the surrounding tissue or control tissue. Both the in vitro survival fraction of GBM cells and the patient survival time were highly correlated or inversely correlated with PP6c expression (R²=0.755 and −0.707, respectively). We also found that siRNA knockdown of PP6c reduced DNA-dependent protein kinase (DNA-PK) activity in three different GBM cell lines, increasing their sensitivity to radiation. In the orthotopic mice model, the overexpression of PP6c in GBM U87 cells attenuated the effect of radiation treatment, and reduced the survival time of mice compared with the control mice, while the PP6c knocking-down improved the effect of radiation treatment, and increased the survival time of mice. These findings demonstrate that PP6 regulates the sensitivity of GBM cells to radiation, and suggest small molecules disrupting or inhibiting PP6 association with DNA-PK is a potential radiosensitizer for GBM.     

D-Chiro-Inositol – Its Functional Role in Insulin Action and its Deficit in Insulin Resistance

In this review we discuss the biological significance of D-chiro-inositol, originally discovered as a component of a putative mediator of intracellular insulin action, where as a putative mediator, it accelerates the dephosphorylation of glycogen synthase and pyruvate dehydrogenase, rate limiting enzymes of non-oxidative and oxidative glucose disposal.Early studies demonstrated a linear relationship between its decreased urinary excretion and the degree of insulin resistance present. When tissue contents, including muscle, of type 2 diabetic subjects were assayed, they demonstrated a more general body deficiency. Administration of D-chiro-inositol to diabetic rats, Rhesus monkeys and now to humans accelerated glucose disposal and sensitized insulin action.A defect in vivo in the epimerization of myoinositol to chiro-inositol in insulin sensitive tissues of the GK type 2 diabetic rat has been elucidated. Thus, administered D-chiro-inositol may act to bypass a defective normal epimerization of myo-inositol to D-chiro-inositol associated with insulin resistance and act to at least partially restore insulin sensitivity and glucose disposal.