Breakthrough Pain Associated with a Reduction in Serum Buprenorphine Concentration during Dialysis.

PURPOSE: To describe a case of breakthrough pain associated with a reduction in serum buprenorphine concentration during dialysis. METHODS: Pharmacokinetic sampling of total and free buprenorphine and norbuprenorphine in an 80 year old male undergoing haemodialysis three times per week who received 5760 µg oral and transdermal buprenorphine daily was performed. The patient's serum albumin concentration was 23g/l (reference range: 35-52 g/l). FINDINGS: Pharmacokinetic sampling revealed a free buprenorphine fraction of 32% (consistent with the hypoalbuminaemia), which was markedly reduced at the end of dialysis (free buprenorphine concentration 2.4 µg/l before vs. <0.1 µg/l after dialysis). IMPLICATIONS: Clinicians should be aware that some patients may require extra buprenorphine doses during dialysis to prevent significant falls in the concentration of active drug.

Copeptin as a serum biomarker of febrile seizures.

BACKGROUND AND OBJECTIVES: Accurate diagnosis of febrile seizures in children presenting after paroxysmal episodes associated with fever, is hampered by the lack of objective postictal biomarkers. The aim of our study was to investigate whether FS are associated with increased levels of serum copeptin, a robust marker of arginine vasopressin secretion. METHODS: This was a prospective emergency-setting cross-sectional study of 161 children between six months and five years of age. Of these, 83 were diagnosed with febrile seizures, 69 had a febrile infection without seizures and nine had epileptic seizures not triggered by infection. Serum copeptin and prolactin levels were measured in addition to standard clinical, neurophysiological, and laboratory assessment. CLINICAL TRIAL REGISTRATION: NCT01884766. RESULTS: Circulating copeptin was significantly higher in children with febrile seizures (median [interquartile range] 18.9 pmol/L [8.5-36.6]) compared to febrile controls (5.6 pmol/L [4.1-9.4]; p < 0.001), with no differences between febrile and epileptic seizures (21.4 pmol/L [16.1-46.6]; p = 0.728). In a multivariable regression model, seizures were the major determinant of serum copeptin (beta 0.509; p < 0.001), independently of clinical and baseline laboratory indices. The area under the receiver operating curve for copeptin was 0.824 (95% CI 0.753-0.881), significantly higher compared to prolactin (0.667 [0.585-0.742]; p < 0.001). The diagnostic accuracy of copeptin increased with decreasing time elapsed since the convulsive event (at 120 min: 0.879 [0.806-0.932] and at <60 min: 0.975 [0.913-0.997]). CONCLUSIONS: Circulating copeptin has high diagnostic accuracy in febrile seizures and may be a useful adjunct for accurately diagnosing postictal states in the emergency setting.

Glutaminolysis activates Rag-mTORC1 signaling.

Amino acids control cell growth via activation of the highly conserved kinase TORC1. Glutamine is a particularly important amino acid in cell growth control and metabolism. However, the role of glutamine in TORC1 activation remains poorly defined. Glutamine is metabolized through glutaminolysis to produce α-ketoglutarate. We demonstrate that glutamine in combination with leucine activates mammalian TORC1 (mTORC1) by enhancing glutaminolysis and α-ketoglutarate production. Inhibition of glutaminolysis prevented GTP loading of RagB and lysosomal translocation and subsequent activation of mTORC1. Constitutively active Rag heterodimer activated mTORC1 in the absence of glutaminolysis. Conversely, enhanced glutaminolysis or a cell-permeable α-ketoglutarate analog stimulated lysosomal translocation and activation of mTORC1. Finally, cell growth and autophagy, two processes controlled by mTORC1, were regulated by glutaminolysis. Thus, mTORC1 senses and is activated by glutamine and leucine via glutaminolysis and α-ketoglutarate production upstream of Rag. This may provide an explanation for glutamine addiction in cancer cells.