Low-dose of olanzapine has ameliorating effects on cancer-related anorexia

Hideki Okamoto,1 Koyo Shono,2 Natsuko Nozaki-Taguchi2 1Department of Kampo Medicine (Japanese Traditional Medicine), School of Medicine, International University of Health and Welfare, Tokyo, Japan; 2Palliative Care Center, Chiba University Hospital, Chiba, Japan Background: Olanzapine (OLZ) has become well-known for its antiemetic effects on chemotherapy-induced nausea and vomiting. However, it remains unclear whether OLZ also has efficacy for treating cancer-related anorexia. This study, therefore, retrospectively examined whether or not OLZ administration affects the food intake in anorexic cancer patients who exhibit neither nausea nor vomiting. Methods: Eighty patients prescribed OLZ were extracted from 951 inpatients who consulted with our palliative care team at Chiba University Hospital from April 2008 to March 2016. Their food intake described on a nursing record was compared before and after OLZ administration. The observation period was 3 days before and after the start of OLZ treatment, because most inpatients whose food intake increased were discharged in 3 days. Results: In those 80 patients, the average dose of OLZ for 3 days was 2.28±0.87 (mean±SD) mg/day. First, the food intake in 80 patients was significantly higher after than before starting OLZ, and the relative change in food intake was 149% on average (P<0.0001, Student’s paired t-test). Second, OLZ increased the food intake even in 40 out of 80 patients without nausea or vomiting, and the relative change in food intake was 143% on average (P<0.001, Student’s paired t-test). Third, the average food intake increased in 13 out of 40 patients who were prescribed 1.5 mg/day of OLZ, and the relative change in food intake was 124% on average (P<0.01, Student’s paired t-test). There was no significant difference in food intake between a dose of 1.5 mg/day and a dose of >1.5 mg/day of OLZ (P=0.18, Welch’s unpaired t-test). Conclusion: We have herein reported OLZ’s ameliorating efficacy in cancer-related anorexia at the low dose of 1.5 mg/day. Although our study has many limitations, low-dose OLZ can be a promising treatment for cancer-related anorexia. Keywords: chemotherapy, nausea, cachexia, appetite, end-of-life care, tranquilize

Peroxisome dependency of alkyl-containing GPI-anchor biosynthesis in the endoplasmic reticulum

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) play various roles in cell–cell and cell–environment interactions. GPI is synthesized in the endoplasmic reticulum (ER) from phosphatidylinositol (PI) through step-wise reactions including transfers of monosaccharides and preassembled GPI is transferred en bloc to proteins. Cellular PI contains mostly diacyl glycerol and unsaturated fatty acid in the sn-2 position, whereas mammalian GPI-APs have mainly 1-alkyl-2-acyl PI and almost exclusively stearic acid, a saturated chain, at the sn-2 position. The latter characteristic is the result of fatty acid remodeling occurring in the Golgi, generating GPI-anchors compatible with raft membrane. The former characteristic is the result of diacyl to alkyl-acyl change occurring in the third GPI intermediate, glucosaminyl-inositolacylated-PI (GlcN-acyl-PI). Here we investigated the origin of the sn-1 alkyl-chain in GPI-APs. Using cell lines defective in the peroxisomal alkyl-phospholipid biosynthetic pathway, we demonstrated that generation of alkyl-containing GPI is dependent upon the peroxisomal pathway. We further demonstrated that in cells defective in the peroxisome pathway, the chain composition of the diacyl glycerol moiety in GlcN-acyl-PI is different from those in the first intermediate N-acetylglucosaminyl-PI and cellular PI, indicating that not only diacyl to alkyl-acyl change but also diacyl to diacyl change occurs in GlcN-acyl-PI. We therefore propose a biosynthetic step within GlcN-acyl-PI in which the diacyl glycerol (or diacyl phosphatidic acid) part is replaced by diradyl glycerol (or diradyl phosphatidic acid). These results highlight cooperation of three organelles, the ER, the Golgi, and the peroxisome, in the generation of the lipid portion of GPI-APs