Drug Shortages: Patients and Health Care Providers Are All Drawing the Short Straw.

Drug shortages have been reported for > 35 years. Attention to this problem increased recently after the Sandoz crisis, in which a warning letter by the Food and Drug Administration caused supply changes that suspended the availability of numerous medications. The frequency of drug shortages has increased recently. In 2011-2012 alone, Canadian supply shortages occurred for > 1000 drugs (including 150 for cardiovascular diseases). These shortages lasted for an average of 4-5 months, increasing the workload for health care providers, producing impaired health, stress, and anxiety for patients, and increasing the risk of errors. The critical importance of drug shortages is increasingly recognized by members of the public, and health care providers must sometimes make major efforts to minimize their adverse consequences. Although data are limited, such efforts come at a price that patients and the health care system should not have to bear; they divert pharmacists and physicians from their already busy clinical duties and often require complex and risky adjustments in medical regimens. If drug shortages are here to stay, clinicians, drug manufacturers, and relevant organizations should work together to increase accountability for drug availability and adaptation to shortages, and to create more effective tools with which to anticipate and respond to critical supply fluctuations.

Lithium chloride and staurosporine potentiate the accumulation of phosphorylated glycogen synthase kinase 3ß/Tyr216, resulting in glycogen synthase kinase 3ß activation in SH-SY5Y human neuroblastoma cell lines.

Glycogen synthase kinase 3ß (GSK3ß) activity is regulated by phosphorylation processes and regulates in turn through phosphorylation several proteins, including eukaryotic initiation factor 2B (eIF2B). Serine 9 phosphorylation of GSK3ß (pGSK3ßSer9), usually promoted by activation of the PI3K/Akt survival pathway, triggers GSK3ß inhibition. By contrast, tyrosine 216 phosphorylation of GSK3ß (pGSK3ßTyr216) increases under apoptotic conditions, leading to GSK3ß activation. Lithium chloride (LiCl) is usually described to increase pGSK3ßSer9 through the PI3K/Akt pathway, resulting in GSK3ß inhibition. The purpose of this study is to demonstrate that in some cases LiCl is also able to increase pGSK3ßTyr216, resulting in GSK3ß activation. For this, we used SH-SY5Y cells and primary neuronal cultures and investigated the effects of LiCl on the two phosphorylated forms of GSK3ß under staurosporine (STS)-intoxicated conditions. The ratios between the phosphorylated and total forms of GSK3ß and eIF2B were determined by Western blotting. Our results revealed that, besides its ability to increase pGSK3ßSer9, LiCl is also able to increase pGSK3ßTyr216 greatly in STS-intoxicated SH-SY5Y cells but not in STS-intoxicated primary neuronal cultures. This accumulation of both Ser9 and Tyr216 phosphorylation results in GSK3ß activation in STS-intoxicated SH-SY5Y cells in spite of the presence of LiCl. These findings indicate that LiCl treatment is not necessarily correlated with GSK3ß inhibition even though it generates Ser9 phosphorylation. Consequently, the ratio pGSK3ßSer9/pGSK3ßTyr216, which takes into account the balance between the two inactive (Ser9) and active (Tyr216) forms of GSK3ß, could be more useful for predicting GSK3ß inhibition.