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Salivary hypofunction: An update on therapeutic strategies.
Salum, FG, Medella-Junior, FAC, Figueiredo, MAZ, Cherubini, K
Gerodontology. 2018;(4):305-316
Abstract
OBJECTIVE To perform a literature review addressing the therapeutic strategies for salivary hypofunction. BACKGROUND Qualitative and quantitative salivary dysfunctions predispose to changes in the oral mucosa and teeth, cause impairment to oral functions and negative impact on quality of life. MATERIALS AND METHODS A MEDLINE/PubMed search was conducted using the terms "Xerostomia" AND, "Saliva Artificial" OR, "Citric Acid," "Malic Acid," "Chewing Gum," "Acupuncture" OR, "Pilocarpine" OR, "Bethanechol" OR, "Cevimeline" OR, "Hyperbaric Oxygen Therapy" OR, "Stem Cell Therapy" OR "Genetic Therapy" and their Mesh Terms. RESULTS We selected 25 clinical trials investigating the effects of salivary substitutes, chewing gum, malic and citric acids, pilocarpine, cevimeline, bethanechol, acupuncture, hyperbaric oxygen therapy and regenerative therapies on salivary hypofunction. In most studies, the number of participants was low and the follow-up times short. The therapeutic modalities were classified according to the level of evidence on salivary dysfunction. CONCLUSIONS Pilocarpine and cevimeline had the strongest evidence of beneficial effect on salivary hypofunction. Citric and malic acids increase salivary flow but also increase the risk of erosion and dental caries. There are no controlled clinical trials supporting the efficacy of acupuncture, stem cell therapy and gene therapy on salivary dysfunction, although clinical observations suggest a promising effect. There is no evidence supporting salivary substitutes, chewing gum, bethanechol or hyperbaric oxygen on the treatment of salivary hypofunction.
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Comparative study of the effects of ipragliflozin and sitagliptin on multiple metabolic variables in Japanese patients with type 2 diabetes: A multicentre, randomized, prospective, open-label, active-controlled study.
Tsurutani, Y, Nakai, K, Inoue, K, Azuma, K, Mukai, S, Maruyama, S, Iizuka, T, Matsuzawa, Y, Saito, J, Omura, M, et al
Diabetes, obesity & metabolism. 2018;(11):2675-2679
Abstract
In the present randomized study, we assessed the efficacy of ipragliflozin compared with sitagliptin in 124 Japanese patients with type 2 diabetes. Sodium-glucose co-transporter-2 inhibitor-naïve and incretin-related agent-naïve patients were randomly assigned to receive additional 50 mg ipragliflozin or sitagliptin. The primary endpoint was the proportion of participants with >0.5% decrease in glycated haemoglobin (HbA1c) without body weight gain at 12 weeks. For secondary endpoints, we measured several biomarkers related to metabolic changes. After 12 weeks, 53.9% of participants in the ipragliflozin and 42.9% in the sitagliptin group reached the primary endpoint (P = 0.32). Decreases in homeostatic model assessment of insulin resistance, body fat percentage and skeletal muscle mass index, and increases in free fatty acids, ketone body concentration and HDL cholesterol levels were greater in the ipragliflozin group. Increases in homeostatic model assessment of β-cell function and decreases in proinsulin-to-insulin ratio were greater in the sitagliptin group. No serious adverse events occurred in either group. In conclusion, ipragliflozin had beneficial effects on fat reduction, insulin resistance and lipid metabolism, while sitagliptin had beneficial effects on β-cell function.
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G protein-coupled receptors as anabolic drug targets in osteoporosis.
Diepenhorst, N, Rueda, P, Cook, AE, Pastoureau, P, Sabatini, M, Langmead, CJ
Pharmacology & therapeutics. 2018;:1-12
Abstract
Osteoporosis is a progressive bone disorder characterised by imbalance between bone building (anabolism) and resorption (catabolism). Most therapeutics target inhibition of osteoclast-mediated bone resorption, but more recent attention in early drug discovery has focussed on anabolic targets in osteoblasts or their precursors. Two marketed agents that display anabolic properties, strontium ranelate and teriparatide, mediate their actions via the G protein-coupled calcium-sensing and parathyroid hormone-1 receptors, respectively. This review explores their activity, the potential for improved therapeutics targeting these receptors and other putative anabolic GPCR targets, including Smoothened, Wnt/Frizzled, relaxin family peptide, adenosine, cannabinoid, prostaglandin and sphingosine-1-phosphate receptors.
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Changes in metabolic parameters and body weight in brexpiprazole-treated patients with acute schizophrenia: pooled analyses of phase 3 clinical studies.
Newcomer, JW, Eriksson, H, Zhang, P, Weiller, E, Weiss, C
Current medical research and opinion. 2018;(12):2197-2205
Abstract
OBJECTIVE To analyze the effect of brexpiprazole on metabolic parameters and body weight in adults with schizophrenia, including clinically relevant sub-groups of patients, based on data from two pivotal phase 3 studies (NCT01393613; NCT01396421) and a long-term extension study (NCT01397786). METHODS The short-term studies were randomized, double-blind, placebo-controlled, fixed-dose (2 and 4 mg/day), 6-week phase 3 studies. The long-term study was an open-label 52-week study, recruiting de novo patients and those completing either short-term study. Maximum exposure to brexpiprazole was 58 weeks. Fasting metabolic parameters and weight were measured throughout the studies. Metabolic values were characterized as normal, borderline, or high (cholesterol, triglycerides, and glucose) and low or normal (HDL), using commonly reported thresholds. The incidences of all possible shifts in metabolic parameters were measured from baseline to any time post-baseline during the first 6 weeks, first 6 months, and last 6 months of treatment. RESULTS In short-term studies, the proportion of brexpiprazole-treated patients with unfavorable shifts in metabolic parameters was low and like that of placebo-treated patients; the incidence of these shifts was not dose-dependent. During both short- and long-term treatment, the incidence of unfavorable shifts with brexpiprazole was lower than that of favorable shifts. During short-term studies, the mean increase in body weight was 1.2 kg with brexpiprazole treatment and 0.2 kg with placebo. The mean increase in body weight during long-term treatment was 3.2 kg at week 58. CONCLUSIONS Brexpiprazole treatment was associated with moderate weight gain and small changes in metabolic parameters during both short- and long-term treatment.
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Improved cardiometabolic risk factors in Japanese patients with type 2 diabetes treated with ipragliflozin: a pooled analysis of six randomized, placebo-controlled trials.
Kashiwagi, A, Sakatani, T, Nakamura, I, Akiyama, N, Kazuta, K, Ueyama, E, Takahashi, H, Kosakai, Y
Endocrine journal. 2018;(7):693-705
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Abstract
To examine differential improvements among cardiovascular risk factors in response to treatment with ipragliflozin in Japanese type 2 diabetes mellitus (T2DM) patients, we conducted a pooled analysis of six randomized, double-blind trials of Japanese T2DM patients who received ipragliflozin 50 mg/day or placebo and had patient-level data for cardiometabolic risk parameters. Risk factors included glycated hemoglobin (HbA1c), body weight, homeostatic model assessment for insulin resistance and beta-cell function (HOMA-R and HOMA-beta, respectively), systolic blood pressure, fasting serum insulin concentrations, and the concentration of uric acid, lipids, and liver enzymes from baseline to end of treatment (EOT; 12-24 weeks). The primary endpoint of each trial was the change in HbA1c from baseline to EOT. Changes in risk factors from baseline to EOT were compared between ipragliflozin-treated and placebo groups, and between two subgroups (high- and low-risk groups for each parameter). All parameters, except low-density lipoprotein cholesterol (LDL-C) and non high-density lipoprotein cholesterol (non HDL-C), improved significantly in the ipragliflozin group. Subgroup analysis revealed a significantly greater improvement in the high-risk group versus low-risk group in HbA1c, HOMA-R, HOMA-beta, aspartate transaminase, alanine transaminase, and gamma-glutamyltransferase, but not in any of the lipid parameters or blood pressure. Liver function improvement in the ipragliflozin group was significantly correlated with changes in body weight, HbA1c, HOMA-beta, and HOMA-R. This analysis demonstrated that, in Japanese T2DM patients, ipragliflozin 50 mg/day was associated with improvements in cardiometabolic risk factors, except for LDL-C and non HDL-C.
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Amelioration of fatty liver index in patients with type 2 diabetes on ipragliflozin: an association with glucose-lowering effects.
Takase, T, Nakamura, A, Miyoshi, H, Yamamoto, C, Atsumi, T
Endocrine journal. 2017;(3):363-367
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Abstract
In this study, we investigated the ameliorating effects of ipragliflozin on fatty liver in patients with type 2 diabetes. The factors that influenced the amelioration of fatty liver were also examined. Analysis included data of 21 Japanese patients with type 2 diabetes obtained from our prospective observational study. After obtaining patients' informed consent, once-daily ipragliflozin (50 mg/day) was given for 16 weeks. In addition to several clinical parameters, body composition was also compared before and after 16 weeks of treatment. The extent of fatty liver was estimated using a fatty liver index (FLI). After 16 weeks, FLI significantly decreased, from 70.1 ± 19.4 to 60.3 ± 25.5 (p = 0.0009) as well as levels of fasting plasma glucose (FPG), HbA1c, body weight, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and fat mass. To reveal the factors influencing the FLI changes observed on ipragliflozin treatment, correlations between changes in FLI and several other measured parameters were examined. Changes in FPG (correlation coefficient = 0.4683, p = 0.0323) and HbA1c (correlation coefficient = 0.4383, p = 0.0469) showed significant positive correlations with changes in FLI. On the other hand, no correlations of changes in FLI were observed with body weight, VAT, SAT nor fat mass. In conclusion, ipragliflozin ameliorated FLI in Japanese patients with type 2 diabetes. Improvement in FLI was associated with that of glucose intolerance.
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Preventive effect of ipragliflozin on nocturnal hypoglycemia in patients with type 2 diabetes treated with basal-bolus insulin therapy: An open-label, single-center, parallel, randomized control study.
Okajima, F, Nagamine, T, Nakamura, Y, Hattori, N, Sugihara, H, Emoto, N
Journal of diabetes investigation. 2017;(3):341-345
Abstract
The efficacy of the administration of sodium-glucose co-transporter 2 inhibitor or the co-administration of sodium-glucose co-transporter 2 inhibitor and dipeptidyl peptidase-4 inhibitor to insulin therapy is not well known. A total of 58 patients with type 2 diabetes, admitted for glycemic control, were randomized to basal-bolus insulin therapy (BBT) alone or BBT plus 50 mg ipragliflozin and/or 20 mg teneligliptin. Insulin doses were adjusted to maintain normal blood glucose levels. Plasma glucose profiles were estimated by continuous glucose monitoring before discharge. Required insulin doses were not significantly different among the treatment groups. The frequency of nocturnal hypoglycemia was significantly lower in the groups treated with ipragliflozin (6.5 ± 10.6%) and ipragliflozin plus teneligliptin (6.9 ± 14.3%) than in the group treated with BBT alone (42 ± 43.6%). The administration of sodium-glucose co-transporter 2 inhibitor with or without dipeptidyl peptidase-4 inhibitor prevented nocturnal hypoglycemia in type 2 diabetes patients with BBT.
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Effect of 24-week treatment with ipragliflozin on proinsulin/C-peptide ratio in Japanese patients with type 2 diabetes.
Nagai, Y, Ohta, A, Sada, Y, Kato, H, Tanaka, Y
Expert opinion on pharmacotherapy. 2017;(1):13-17
Abstract
BACKGROUND Chronic hyperglycemia has an adverse influence on beta-cell function, which is known as 'glucotoxicity'. Sodium-glucose cotransporter-2 (SGLT2) inhibitors lower the blood glucose concentration by enhancing urinary glucose excretion. This study was performed to clarify the influence of the SGLT2 inhibitor ipragliflozin on beta-cell function assessed from the plasma intact proinsulin/C-peptide ratio in Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This was a 24-week, prospective, single-center, open-label, single-arm study. The subjects were 19 Japanese patients with type 2 diabetes. After a 4- to 8-week period of lifestyle modification, ipragliflozin (50 mg/d) was added to their existing treatment. At baseline and at 12 and 24 weeks after starting ipragliflozin treatment, a meal test was performed to evaluate the fasting and 2-hour proinsulin/C-peptide ratio. RESULTS After 24 weeks, the body mass index, fasting plasma glucose, and hemoglobin A1c were all decreased significantly. Both the fasting and 2-hour proinsulin/C-peptide ratio decreased significantly from 25.0 ± 18.9 × 10-3 to 14.3 ± 9.0 × 10-3 and from 23.2 ± 14.9 × 10-3 to 13.7 ± 5.4 × 10-3, respectively (both p < 0.01 vs. baseline). CONCLUSIONS These findings indicate that ipragliflozin might have a beneficial effect on beta-cells.
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Efficacy and safety of ipragliflozin and metformin for visceral fat reduction in patients with type 2 diabetes receiving treatment with dipeptidyl peptidase-4 inhibitors in Japan: a study protocol for a prospective, multicentre, blinded-endpoint phase IV randomised controlled trial (PRIME-V study).
Koshizaka, M, Ishikawa, K, Ishikawa, T, Kobayashi, K, Takemoto, M, Horikoshi, T, Shimofusa, R, Takahashi, S, Nagashima, K, Sato, Y, et al
BMJ open. 2017;(5):e015766
Abstract
INTRODUCTION In Japan, dipeptidyl peptidase-4 (DPP-4) inhibitors are frequently used as the treatment of choice for patients with type 2 diabetes. In some cases, however, poor glycaemic and body weight control issues persist despite treatment with DPP-4 inhibitors. Previous researchers have revealed that sodium-dependent glucose transporter-2 (SGLT-2) inhibitors reduce both plasma glucose levels and body weight in patients with type 2 diabetes. However, further investigation regarding the effects of SGLT-2 inhibitors on body composition, especially in the Asian population who tends to have relatively low-to-moderate body mass indices, is required. Therefore, we aim to determine the effects of treatment with SGLT-2 inhibitors or metformin for reducing visceral fat in 106 Asian patients with type 2 diabetes who were undergoing treatment with the DPP-4 inhibitor sitagliptin (50 mg daily) for poor glycaemic control. METHODS AND ANALYSIS A prospective, multicentre, blinded-endpoint phase IV randomised controlled study will be conducted to evaluate the safety and efficacy of a 24-week treatment with either an SGLT-2 inhibitor (ipragliflozin) or metformin for reducing visceral fat and plasma glucose levels in patients with type 2 diabetes. Patients who satisfy the eligibility criteria will be randomised (1:1) to receive ipragliflozin (50 mg daily) or metformin (1000 mg daily). The primary outcome is the rate of change in the total area of visceral fat for patients in both treatment groups, measured using CT, after 24 weeks of therapy. Two radiologists, blinded to the clinical information, will perform centralised analysis of the images in a unified measurement condition. ETHICS AND DISSEMINATION The protocol was approved by the institutional review board of each hospital. This study is ongoing and due to finish in April 2017. The findings of this study will be disseminated via peer-reviewed publications and conference presentations, and will also be disseminated to participants. TRIAL REGISTRATION NUMBER UMIN000015170, R000016861 (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000016861); Pre-results.
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First case of drug eruption due to ipragliflozin: Case report and review of the literature.
Saito-Sasaki, N, Sawada, Y, Nishio, D, Nakamura, M
The Australasian journal of dermatology. 2017;(3):236-238
Abstract
Ipragliflozin is a new drug for the treatment of diabetes mellitus. Its action of sodium-glucose cotransporter 2 (SGLT2) inhibition induces glucosuria and decreases blood glucose levels. We report the first case of ipragliflozin-related eczematous drug eruption and a review of the past literature on drug eruptions caused by SGLT2 inhibitors.