Induction Chemotherapy With 5-Fluorouracil, Cisplatin, and Cetuximab in Advanced Head and Neck Squamous Cell Carcinoma.

BACKGROUND/AIM: Chemoradiotherapy (CRT) with high-dose cisplatin has become the standard of care for larynx preservation in patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, the long-term results are unsatisfactory. Induction chemotherapy (ICT) with docetaxel/cisplatin/5-fluorouracil (TPF) is associated with hematologic toxicity, and a safer therapy with comparable efficacy is desired. We conducted a pilot study to investigate the efficacy and safety of 5-fluorouracil/cisplatin/cetuximab (FPE) therapy as a candidate regimen for ICT in comparison with TPF. PATIENTS AND METHODS: Patients with stage cN2/3 LA-SCCHN of the larynx/oropharynx/hypopharynx were treated with FPE or TPF followed by radiotherapy. We reviewed patients' medical records and evaluated treatment efficacy and safety retrospectively. RESULTS: The response rates for ICT and ICT-radiotherapy were 71% and 93%, respectively, in the FPE group and 90% and 89%, respectively, in the TPF group. The 1-year progression-free and overall survival rates were 57% and 100%, respectively, in the FPE group and 70% and 90%, respectively, in the TPF group. TPF was linked to significantly higher rates of Grade 3/4 hematologic toxicity during ICT. The rates of Grade 3 or higher toxicity did not differ between the two groups during radiotherapy. CONCLUSION: The efficacy of ICT was comparable between the FPE and TPF groups, whereas FPE was associated with less toxicity. It is suggested that FPE therapy is an alternative ICT regimen to TPF therapy, but further long-term follow-up is needed.

Efficacious interventions for improving the transition readiness of adolescents and young adult patients with chronic illness: A narrative review of randomized control trials assessed with the transition readiness assessment questionnaire.

Objective: We inspected efficacious interventions to improve the transition readiness of adolescent and young adult patients with childhood-onset chronic illnesses using the Transition Readiness Assessment Questionnaire (TRAQ). Methods: Our narrative review was conducted on randomized control studies assessed with TRAQ for outcome measurement before and after the interventions. We included all patients with chronic diseases. We searched eight electronic database(s): Allied and Complementary Medicine Database (AMED) Allied and Complementary Medicine, BioSciences Information Service of Biological Abstracts (BIOSIS) Previews, Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane Library, Embase, Ichu-shi, Medline, and Web of Science. The text words for the search of data sources were as follows: "("transition readiness assessment questionnaire" OR TRAQ) AND 2011/01:2022/06[DP] AND (clinical AND trial OR clinical trials OR clinical trial OR random* OR random allocation)." More studies were identified from the references in our reported study. This data set was independently cross-checked by two reviewers. Results: We identified 261 reports and collected three articles. The target diseases were type-1 diabetes, congenital heart disease, cystic fibrosis, and inflammatory bowel disease. All the studies excluded patients with intellectual disabilities. The age of the participants was distributed between 12 and 20 years. Nurse-provided web-based intervention of transition readiness was constructed using digital resources in two studies. The intervention ranged from 6 to 18 months. All the interventions were efficacious in improving transition readiness assessed with TRAQ scores, except for the self-advocacy score. Conclusions: We obtained three randomized control studies with TRAQ for outcome measurement. In two studies, web-based and nurse-led organized interventions were shown to improve transition readiness.

Effects of piperacillin/tazobactam or cefepime on folinate dose in patients receiving high-dose methotrexate: A retrospective cohort study using Japanese administrative claims data.

INTRODUCTION: Delayed methotrexate (MTX) clearance with the co-administration of piperacillin/tazobactam (PIPC/TAZ) has been reported. Penicillins have been associated with reduced MTX clearance but the evidence is limited. There are no cases described with cefepime but penicillins are listed as interacting with MTX. We aimed to reveal whether the co-administration of PIPC/TAZ or CFPM affects MTX clearance using data from an administrative database. METHODS: We used data from the JMDC database, a large insurance claims database constructed in Japan. We included patients who were prescribed PIPC/TAZ or CFPM between days 1 and 3 in high-dose MTX (HD-MTX). We compared one co-administration episode (with PIPC/TAZ or CFPM) to one control episode (without), as a match-control study of two different episodes in the same patient. The primary outcomes were the duration and cumulative dose of leucovorin (LV) as a surrogate indicator of delayed MTX clearance. RESULTS: Three patients who were co-administered PIPC/TAZ and 16 patients who were co-administered CFPM with HD-MTX were included. In the PIPC/TAZ group, the duration and the cumulative doses of LV were similar in co-administration and control episode (median 3.0 vs. 3.0 days and 288.0 vs. 219.0 mg). In the CFPM group, the duration and the cumulative doses of LV were not significantly different in co-administration and control episode (3.0 vs. 4.0 days and 169.5 vs. 258.0 mg). CONCLUSIONS: Our findings revealed that PIPC/TAZ did not necessarily cause a delay in MTX clearance during HD-MTX therapy. Moreover, the co-administration of CFPM with HD-MTX did not affect MTX clearance.

An imaging approach for determining the mechanism of enhancement of intestinal absorption of an L-theanine supplement.

BACKGROUND & OBJECTIVE: Theanine (L-glutamylethylamide) contained in green tea is a functional food component that has been attracting attention due to its relaxation effect. It was shown that the ingredients added to the theanine formulations increased the absorption of theanine. If this mechanism can be elucidated, it would be possible to contribute to development of evidence-based formulations. In this study, we investigated the effect of ingredients in the formulations on the absorption of theanine in detail. MAIN METHODS: After oral administration of a mixture of theanine and additional components to Wistar rats the plasma concentration was determined by an HPLC and the pharmacokinetic parameters were calculated. In addition, a new system for evaluating intestinal blood flow was developed since the involvement of intestinal blood flow was considered as a factor that increased absorption of theanine. KEY FINDINGS: Plasma concentration of theanine increased significantly in the combined use group with eight ingredients containing piperine as compared with theanine only group. Piperine would increase theanine absorption by increased blood flow, not an inhibition of metabolism. We succeeded to develop a visual and quantitative system to evaluate the effect of these ingredients directly including piperine on the intestinal blood flow using indocyanine green while maintaining physiological conditions. SIGNIFICANCE: Increased intestinal blood flow by these ingredients including piperine enhanced the absorption of theanine. Other mechanisms may also be considered as the mechanism by which theanine absorption is increased in addition to increased blood flow.

Altered metabolism of chloroplastic NAD kinase-overexpressing Arabidopsis in response to magnesium sulfate supplementation.

Nicotinamide adenine dinucleotide (NAD)/NAD phosphate (NADPH) is essential for numerous redox reactions and serve as co-factors in multiple metabolic processes in all organisms. NAD kinase (NADK) is an enzyme involved in the synthesis of NADP+ from NAD+ and ATP. Arabidopsis NADK2 (AtNADK2) is a chloroplast-localizing enzyme that provides recipients of reducing power in photosynthetic electron transfer. When Arabidopsis plants were grown on MS medium supplemented with 5 mM MgSO4, an AtNADK2-overexpressing line exhibited higher glutathione and total sulfur accumulation than control plants. Metabolomic analysis of major amino acids and organic acids using capillary electrophoresis-mass spectrometry demonstrated that overexpression of AtNADK2 affected a range of metabolic processes in response to MgSO4 supplementation.

Enhancement of intestinal absorption of coenzyme Q10 using emulsions containing oleyl polyethylene acetic acids.

Emulsions have often been prepared to improve absorption of lipophilic compounds that have poor solubility. Coenzyme Q10 (CoQ10) is a lipophilic compound that has been used as an anti-aging supplement. We focused on oleyl polyethyleneoxy acetic acid, an oxa acid derivative, to prepare emulsions of CoQ10 with the expectation of application to oral pharmaceutics. Oxa acids were purified and classified into four groups based on the average length of the ethylene oxide chain. The emulsion that were prepared using the four oxa acid groups were administered to rats and the plasma concentration profiles of CoQ10 were analyzed. The absorption of CoQ10 was improved in all emulsion groups compared with that in the powder group. The emulsion using oxa acid (n = 9.0) greatly increased the plasma concentration of CoQ10. Absorption was also improved by using emulsions containing larger percentage of oxa acids (6%, 15% and 23%) to compared with the same oxa acid (n = 9.0). The effects of oxa acids on cell viability were almost the same as those of conventional surfactants such as polyoxyethylene (20) sorbitan monooleate (Tween 80). The results showed that oxa acids are useful to prepare emulsions for oral administration and that the absorption of CoQ10 using oxa acids is significantly improved by using our formulations.

[Study of Formulation Development Based on the Pharmacokinetic Properties of Functional Food Components].

Preventive medicine and anti-aging medicine have received much attention recently due to an increase in the proportion of elderly people in the population, and to an increase in patients with lifestyle diseases. Oxidative stress is involved in the onset of lifestyle diseases, and various antioxidant supplements and antioxidant-fortified functional foods have recently become available. Many epidemiological studies have shown relationships between the consumption of polyphenol and carotenoid-rich foods and the prevention of lifestyle diseases. We have focused on the absorption mechanism of these food components that show low bioavailability, and have made efforts to improve their poor absorption based on their pharmacokinetic properties. In this report, as examples, we describe the enhancement of the absorption of coenzyme Q10 (CoQ10) and lutein. To improve the absorption of CoQ10, we focused on the component of emulsion. We found that a higher plasma concentration of CoQ10 could be obtained by creating an emulsion containing a surfactant with a higher hydrophile-lipophile balance (HLB) value. For the improvement of lutein absorption, we prepared a solid dispersion and self-emulsifying drug delivery system. It was shown that the plasma concentrations of lutein in these two formulation groups were increased compared with that in the powder group. The absorption of lutein was also evaluated by its cumulative amount in the lymph system. Our data showed that lutein is transferred from the small intestine into the lymph stream, rather than into the blood stream. Further investigations to improve the absorption of these components are in progress.

Inhibitory effect of ezetimibe can be prevented by an administration interval of 4 h between α-tocopherol and ezetimibe.

Tocopherol is used not only as an ethical drug but also as a supplement. In 2008, it was reported that α-tocopherol is partly transported via an intestinal cholesterol transporter, Niemann-Pick C1-Like 1 (NPC1L1). Ezetimibe, a selective inhibitor of NPC1L1, is administered for a long time to inhibit cholesterol absorption and there is a possibility that the absorption of α-tocopherol is also inhibited by ezetimibe. This study investigated the influence of ezetimibe on the absorption of α-tocopherol with single administration and long-term administration. An approach to avoid its undesirable consequence was also examined. α-Tocopherol (10 mg/kg) and ezetimibe (0.1 mg/kg) were administered to rats, and the plasma concentration profiles of α-tocopherol and tissue concentrations were investigated. The plasma concentration of α-tocopherol was decreased by the combination use of ezetimibe in the case of concurrent single administration. On the other hand, inhibition of the absorption of α-tocopherol was prevented by an administration interval of 4 h. In a group of rats administered for 2 months with a 4 h interval, not only the plasma concentration but also the liver concentration was increased compared with those in a group with concurrent combination intake of α-tocopherol and ezetimibe. The absorption of α-tocopherol was inhibited by ezetimibe. The inhibitory effect of ezetimibe can be prevented by an administration interval of 4 h, although ezetimibe is a medicine of enterohepatic circulation. Attention should be paid to the use of ezetimibe and components of NPC1L1 substrates such as α-tocopherol. Copyright © 2016 John Wiley & Sons, Ltd.

Emulsification using highly hydrophilic surfactants improves the absorption of orally administered coenzyme Q10.

Coenzyme Q10 (CoQ10) is an essential component in the electron-transport systems of mitochondria and bacteria and is often used as a supplementary treatment for some diseases. We previously reported that the bioavailability of CoQ10 powder was less than 10%. In this study, we investigated various preparations to improve the intestinal absorption of CoQ10 with focus on the effect of emulsification. We prepared a suspension and some emulsions with four types of surfactants and investigated the plasma concentration profile after oral administration to rats. The absorption of CoQ10 was improved by an emulsion formulation although there was little absorption of CoQ10 when a suspension was administered. However, little CoQ10 was absorbed in the bile duct-ligated group even when the emulsion formulation was administered (about 50% of the control group). Bile and emulsion formulation are essential for absorption of CoQ10. When the preparations containing Tween20 (polysorbate (20) sorbitan monolaurate) and Tween80 (polyoxyethylene (20) sorbitan monooleate) were administered, plasma concentrations of CoQ10 were higher than those obtained with preparations containing Tween65 (polyoxyethylene (20) sorbitan tristearate) and Span20 (sorbitan monolaurate). Tween20 and Tween80 have higher hydrophile-lipophile balance (HLB) values than those Tween65 and Span20. Our study suggests that highly lipophilic compounds like CoQ10 would diffuse the unstirred water layer and would easily access the intestinal apical membrane by an emulsion containing a surfactant with a high HLB value. Attention must be given to CoQ10 supplementation for patients whose bile is not excreted to the intestine such as patients with cholestasis.

Intracellular uptake mechanism of lutein in retinal pigment epithelial cells.

PURPOSE: Lutein is a carotenoid mainly found in green leafy vegetables and is located in the macula lutea in the human eye. It has received much attention recently due to its preventive effect on age-related macular degeneration, and it has been consumed as a supplement. However, little information about the pharmacokinetic properties of lutein is available. Detailed knowledge of pharmacokinetic properties of lutein is needed for the development of pharmaceutics. In this study, we focused on the macular accumulation of lutein and investigated the uptake mechanism into human retinal pigment epithelial cells. METHODS: ARPE-19 cells were used for the study on the accumulation mechanism of lutein. The concentration of lutein was determined using an HPLC system. Involvement of scavenger class B type 1 (SR-B1) in the accumulation of lutein in ARPE-19 cells was suggested from the results of an inhibition study using block lipid transport 1 (BLT-1), a selective inhibitor of SR-B1. To investigate the involvement of SR-B1 in more detail, small interfering RNA (siRNA) was transfected and the mRNA and protein expression levels of SR-B1 were assessed by quantitative real-time reverse transcription polymerase chain reaction and Western blotting, respectively. RESULTS: We confirmed a sufficient siRNA knockdown effect in both mRNA and protein expression levels of SR-B1. We then found that lutein uptake was significantly decreased by siRNA knockdown of SR-B1. CONCLUSION: The uptake of lutein was significantly decreased by 40% compared with the control uptake level. This suggested that active transport of lutein into ARPE-19 cells is mainly via SR-B1, given the result that lutein uptake at 4ºC was about 40% less that that at 37ºC.

Characterization of preptin-induced insulin secretion in pancreatic ß-cells.

We aimed to characterize the effects of preptin on insulin secretion at the single-cell level, as well as the mechanisms underlying these changes, with respect to regulation by intracellular Ca(2+) [Ca(2+)](i) mobilization. This study assessed the effect of preptin on insulin secretion and investigated the link between preptin and the phospholipase C (PLC)/protein kinase C (PKC) pathway at the cellular level using fura-2 pentakis(acetoxymethyl) ester-loaded insulin-producing cells (Min 6 cells). Our results demonstrate that preptin promotes insulin secretion in a concentration-dependent manner. Using a PLC inhibitor (chelerythrine) or a PKC inhibitor (U73122) resulted in a concentration-dependent decrease in insulin secretion. Also, preptin mixed with IGF2 receptor (IGF2R) antibodies suppressed insulin secretion in a dose-dependent manner, which indicates that activation of IGF2R is mediated probably because preptin is a type of proIGF2. In addition, preptin stimulated insulin secretion to a similar level as did glibenclamide. The activation of PKC/PLC by preptin stimulation is highly relevant to the potential mechanisms for increase in insulin secretion. Our results provide new insight into the insulin secretion of preptin, a secreted proIGF2-derived peptide that can induce greater efficacy of signal transduction resulting from PLC and PKC activation through the IGF2R.

[A case of hypomagnesemia linked to refractory hypokalemia and hypocalcemia with short bowel syndrome].

We report a case of a 59-year old Japanese woman with short bowel syndrome, whose hypokalemia and hypocalcemia were successfully treated with magnesium (Mg) supplementation. Two years previously, she underwent Mile's operation for advanced rectal cancer, which could have been the cause of subsequent extensive resection of the small intestine by strangulation. After serial resection, she gradually developed chronic diarrhea and anorexia. Three weeks before admission, she developed general fatigue and tetany, and was hospitalized at another hospital. On admission, her serum K and Ca were 2.5 mEq/L and 4.3 mg/dL, respectively, hence regular fluid therapy containing potassium (K) and calcium (Ca) was provided following admission. However, her hypokalemia and hypocalcemia persisted, and she also displayed renal dysfunction and thereafter was transferred to our department for further evaluation and treatment. Since the laboratory tests revealed severe hypomagnesemia (0.4 mg/dL), we started intravenous Mg supplementation together with fluid therapy containing K and Ca. After the combination therapy, her clinical symptoms and electrolyte disorders were remarkably improved within a week. As Mg is essential for PTH secretion in response to hypocalcemia and to inhibit the K channel activity that controls urinary K excretion, hypomagnesemia can cause hypocalcemia and hypokalemia, which is refractory to repletion therapy unless Mg is administered. Therefore, for patients who present with signs of Mg deficiency, early and accurate diagnosis of Mg deficiency should be made and corrected.

Parathyroid hormone-related protein has an anorexigenic activity via activation of hypothalamic urocortins 2 and 3.

Cancer cachexia is reported to be a major cause of cancer-related death. Since the pathogenesis is not entirely understood, only few effective therapies have been established. Since myriad tumors produce parathyroid hormone-related protein (PTHrP), plasma concentrations of PTHrP are increased in cancer cachexia. We measured the food intake, gastric emptying, conditioned taste aversion (CTA), and gene expression of hypothalamic neuropeptides in mice after administering PTHrP intraperitoneally. We administered PTHrP intravenously in rats and examined the gastroduodenal motility and vagal nerve activities. We also examined whether chronic administration of PTHrP influenced the food intake and body weight. Peripherally administered PTHrP induced negative energy balance by decreasing the food intake and gastric emptying; however, it did not induce CTA. The mechanism involved the activation of hypothalamic urocortins 2 and 3 through vagal afferent pathways and the suppression of gastroduodenal motor activity. The continuous infusion of PTHrP reduced the food intake and body weight gain with a concomitant decrease in the fat and skeletal muscle. Our findings suggest that PTHrP influences the food intake and body weight; therefore, PTHrP can be considered as a therapeutic target for cancer cachexia.

Case-control study of coffee consumption and the risk of endometrial endometrioid adenocarcinoma.

This study examined the association between coffee consumption and the risk of endometrial endometrioid adenocarcinoma (EEA) in Japan by a case-control design. The cases consisted of 107 women less than 80 years of age from two medical centers who had been histopathologically diagnosed to have EEA. The controls, selected from the participants of a cancer-screening program, were 214 women, with two controls selected for each case (matched for age and for area of residence). A self-administered questionnaire containing questions to determine dietary and beverage consumption, as well as reproductive history, was distributed to the cases and controls. Conditional logistic regression analysis was used to estimate the odds ratio (OR) of EEA for three levels of coffee consumption with adjustment for potential confounding factors. The multivariate-adjusted OR of EEA for individuals in the highest tertile of coffee consumption (2 to 3 cups or more/day) was 0.4 [95% confidence interval (CI), 0.2-0.9], and that of cases in the intermediate tertile (5 to 6 times/week-1 cup/day) was 0.6 (95% CI, 0.3-1.2), relative to the individuals in the lowest tertile of coffee consumption (3 to 4 times or less/week) (P for trend=0.014). The above association was observed in postmenopausal women (P for trend=0.016), but not in premenopausal women (P for trend=0.90). This study thus revealed an inverse dose-response relationship between coffee consumption and the risk of EEA, and its strong association in postmenopausal women but not in premenopausal women.

Characterization of the disposition of lutein after i.v. administration to rats.

Lutein is a carotenoid that has antioxidant effects. Although lutein has received much attention recently due to its antioxidant activities, little information about the pharmacokinetic properties of lutein is available. The disposition of lutein after i.v. administration has not been investigated because lutein is now used as a supplement. The present study was undertaken to acquire additional data on the disposition of lutein after i.v. administration. After i.v. administration, lutein is preferentially distributed to the liver, spleen and lung. Intravenous administration of lutein may provide effective antioxidant activities in these tissues, not only the eye. The results of this study should provide valuable data for drug development.

Impact of non-dietary nutrients intake on misclassification in the estimation of nutrient intake in epidemiologic study.

BACKGROUND: Few previous epidemiologic studies have evaluated the effects of non-dietary nutrient intake, such as supplements, over the counter (OTC) drugs, and prescription drugs containing vitamins or minerals, in examining the relationship between dietary factors and health outcomes. METHODS: To examine the influence of the non-dietary intake of vitamins and calcium on the estimation of nutrient intake, we conducted a cross-sectional study with 1,168 community-dwelling Japanese subjects aged 70 years or older in 2002. The subjects were asked to bring their non-dietary nutrient sources to the examining site. The dietary and non-dietary intakes of vitamins B1, C, E and calcium were obtained and the subjects were grouped into quartiles according to their dietary intake and their dietary plus non-dietary intake. The degree of agreement between these two classifications was examined to estimate the degree of misclassification. RESULTS: Among the subjects who were classified into the highest intake category for vitamin E with dietary intake plus non-dietary nutrient intake, 34.2 % were misclassified into lower category with dietary intake alone. Similarly, intake of vitamin B(1), vitamin C and calcium were misclassified 28.8%, 18.8 %, 6.2 %, respectively. CONCLUSIONS: Our data suggest that estimation of vitamin intake from dietary sources alone would yield a maximum misclassification of one-third, which would lead to misleading conclusions being drawn from epidemiologic studies. In contrast, the degree of misclassification for calcium may be relatively small.

Transcriptomic analysis indicates putative metabolic changes caused by manipulation of phosphorus availability in rice leaves.

Plants have developed several strategies for coping with phosphorus (P) deficiency. However, the details of the regulation of gene expression of adaptations to low P are still unclear. Using a cDNA microarray, transcriptomic analyses were carried out of the rice genes regulated by P deficiency and P re-supply to P-deficient plants. The OsPI1 gene, which was isolated as the most significant up-regulated gene under -P conditions, was also the most significant down-regulated gene following P re-supply. Many starch metabolism-related genes, as well as several genes for P(i)-liberating enzymes, were up-regulated by -P treatment, suggesting a homeostatic contribution to the P(i) concentration in leaf tissues. mRNAs for glucanases were also induced by P re-supply: these are suspected to play a role in loosening the cell wall compounds. Most of the genes up-regulated by -P treatment were down-regulated by P re-supply, suggesting that their responses were specific to -P conditions. Conversely, the number of genes up-regulated by P re-supply was also larger following P re-supply than in the -P condition. It is proposed that the genes up-regulated by P re-supply play an important role in P acquisition by P-deficient plants.

Health-related quality of life (HRQOL) in Japanese osteoporotic patients and its improvement by elcatonin treatment.

Health-related quality of life (HRQOL; "QOL" hereafter) was evaluated in Japanese osteoporotic patients using three questionnaires; the SF-36 (MOS 36-Item Short-Form Health Survey; generic, profile-type), the EQ-5D (Euro Qol-5 Dimensions; generic, preference-based), and the JOQOL (Japanese Osteoporosis Quality of Life 1999; disease-targeted). The eight subscales and two summary scores of the SF-36 were impaired in these patients even after correction for age and sex. The scores on the EQ-5D and JOQOL correlated well with the subscales of the SF-36 that represent the physical aspects of physical function and bodily pain, which suggests that physical aspects are important determinants of overall QOL status in osteoporotic patients. Although the QOL scores did not correlate with bone mineral density, they were markedly influenced by the presence of vertebral fractures. In particular, the presence of two or more vertebral fractures greatly decreased the QOL scores. We then evaluated the QOL scores before and after treatment. The patients were either given calcium supplementation alone or calcium plus once-weekly elcatonin (Elcitonin, Asahi Kasei Pharma, Tokyo, Japan) injection. Elcatonin treatment markedly improved diverse aspects of the QOL, whereas calcium alone did not. The current data suggest that osteoporosis, especially in the presence of vertebral fracture, is associated with compromised QOL, and therapeutic intervention for osteoporosis should be evaluated in terms of QOL, as well as in terms of increases in bone mineral density and fracture prevention.