Clinical efficacy and tolerability of zonisamide monotherapy in dogs with newly diagnosed idiopathic epilepsy: Prospective open-label uncontrolled multicenter trial.

BACKGROUND: Zonisamide (ZNS) is a newer generation antiseizure medication (ASM) used to treat epilepsy in dogs and cats. However, scientific and clinical information, particularly regarding monotherapy, is limited. OBJECTIVES: To evaluate the antiseizure efficacy and tolerability of ZNS monotherapy in dogs with newly diagnosed idiopathic epilepsy (IE). ANIMALS: Study included 56 client-owned dogs newly diagnosed with IE. METHODS: This was a prospective multicenter, open-label, uncontrolled study. All dogs were ASM-naïve and had ≥2 seizures within 12 weeks. Dogs were administered 2.7-14.4 mg/kg ZNS PO q12h and followed up for ≥12 weeks. Data from the 12-week maintenance treatment period were compared with those from the 4- to 12-week pretreatment period for efficacy evaluation. Data from the entire ZNS administration period were used to assess tolerability. RESULTS: Fifty-six dogs were included in our study. Of the dogs, 53 were assessed for efficacy; 40 (76%) had a ≥ 50% reduction in seizure frequency, and 29 (55%) achieved seizure freedom. For 90% of the dogs with ≥50% reduction in seizure frequency, the mean ZNS dose was 4.8 (range, 2.7-8.6) mg/kg q12h and the mean trough plasma ZNS concentration was 18.9 (range, 8.0-48.0) µg/mL. In 7 of the 56 dogs (13%), reduced activity, decreased appetite, vomiting, hindlimb weakness, soft stools, or constipation was observed, albeit mild and temporary. Laboratory tests revealed no relevant changes. CONCLUSIONS AND CLINICAL IMPORTANCE: Our study suggests that ZNS monotherapy is effective and well-tolerated in dogs with newly diagnosed IE.

Comparative evaluation of clinical glycemic control markers treated with imeglimin and its effect on erythrocytes in patients with type 2 diabetes mellitus: study protocol of a single-arm, open-label, prospective, exploratory trial.

Background: Imeglimin is a novel type 2 diabetes (T2D) drug that is expected to improve mitochondrial function. In its phase 3 clinical trials in Japanese patients with T2D, the hemoglobin A1c (HbA1c) decrease following imeglimin administration was slow, reaching a plateau after 20-24 weeks of treatment. In general, the erythrocyte lifespan may be a factor when HbA1c shows an abnormal value. Therefore, this study will comparatively evaluate HbA1c and other markers of glycemic control in patients with T2D after imeglimin administration and also examine the effects of imeglimin on erythrocytes. Methods: This single-arm, open-label, prospective, exploratory study is designed to evaluate the divergence between HbA1c and glycoalbumin (GA) or 1,5-anhydroglucitol (1,5-AG) and the glycemic reduction rate in 30 patients with T2D with inadequate glycemic control when imeglimin 2,000 mg is administered for 6 months. In addition, we will examine the effect on erythrocytes, the presumed cause of this divergence. We will measure sustained glycemic variability using flash glucose monitoring and examine the relationship between changes in these indices and HbA1c. Moreover, because prolonged erythrocyte lifespan is a possible cause of falsely high HbA1c levels, erythrocyte lifespan, erythrocyte deformability, and hemoglobin concentration will be evaluated as effects of imeglimin on erythrocytes. Furthermore, if imeglimin has an ameliorative effect on erythrocyte deformability, it may improve peripheral arterial disease; thus, we will also evaluate the toe-brachial pressure index, a measure of this effect. Discussion: In this study, if imeglimin administration results in diverging rates of hypoglycemic effect between HbA1c and GA or 1,5-AG and prolongs erythrocyte lifespan, GA and 1,5-AG, rather than HbA1c, will be considered appropriate measures of the hypoglycemic effect in the early stages of imeglimin administration. If imeglimin improves erythrocyte deformability, it may also be a new treatment strategy for peripheral arterial disease, a chronic complication of T2D. Ethics and dissemination: The study protocol was scientifically and ethically reviewed and approved by the Certified Clinical Research Review Board of Toho University (approval number: THU22002). The study protocol was registered in the Japan Registry of Clinical Trials (jRCT) in December 2022 (jRCTs031220489).

Dapagliflozin Improves Erythropoiesis and Iron Metabolism in Type 2 Diabetic Patients with Renal Anemia.

Purpose: In this study, we examined the effects of dapagliflozin on changes in hematopoiesis, iron metabolism, and body composition indices in elderly type 2 diabetic patients with renal impairment and investigated the potential of dapagliflozin to treat renal anemia. Patients and Methods: The participants were elderly type 2 diabetics with renal impairment, and the indices of diabetes management, hematopoiesis, iron metabolism, and body composition were compared before and after dapagliflozin treatment. Results: Fourteen subjects were given dapagliflozin 5 mg once daily for 12 weeks, three of whom had eligibility criteria deviations, such as serum ferritin <50 ng/mL. For this purpose, 14 subjects were analyzed as full analysis set (FAS) and 11 as per-protocol set (PPS). FAS analysis revealed that dapagliflozin had no effect on hemoglobin A1c after 12 weeks but significantly decreased body mass index, significantly increased hemoglobin, hematocrit, and red blood cell count, significantly decreased log ferritin level only of iron metabolism index, and no important change in body water content. PPS analysis, on the other hand, revealed that dapagliflozin 12-week treatment showed a significant decrease in log hepcidin, serum iron, and transferrin saturation. Conclusion: These findings suggest that a 12-week course of dapagliflozin causes an increase in hemoglobin levels due to its hematopoietic effects in elderly type 2 diabetics with renal impairment, but that these effects may be independent of body water loss and iron metabolism improvement.

Clinical characterization of epileptic seizures in Pomeranians with idiopathic epilepsy or epilepsy of unknown cause.

BACKGROUND: Focal epileptic motor seizures manifested by limb contraction have been recognized anecdotally in Pomeranians. OBJECTIVES: To investigate clinical features of idiopathic epilepsy (IE) and epilepsy of unknown cause (EUC) in Pomeranians as well as the ADAM23 haplotype frequency previously reported as a common risk haplotype for epilepsy in several breeds of dogs. ANIMALS: Twenty-eight Pomeranians, including 15 with IE and 13 with EUC. Nine Pomeranians with epilepsy and 8 control Pomeranians were used for ADAM23 risk haplotype analysis. METHODS: Case series study including both retrospectively and prospectively collected cases. The ADAM23 haplotype was determined by direct sequencing of PCR amplicons. Data were analyzed descriptively. RESULTS: Focal epileptic seizures (FS) were the predominant type of seizure in 22 of 28 dogs (78.6%). Among these, 12 of the IE dogs (80.0%) and 10 of the EUC dogs (76.9%) showed FS. Notably, 21 of 22 Pomeranians with FS (95.5%) showed limb contraction during ictal periods. Some dogs with FS also showed immobility, generalized tremors, difficulty walking or moving, autonomic signs, orofacial automatisms or some combination during ictal events. Ten dogs with FS and limb contraction had electroencephalography (EEG) performed, and interictal epileptiform discharges were identified in 9 dogs. The haplotype frequency of ADAM23 in cases was lower (27.8%) than that of the controls (56.3%). CONCLUSIONS AND CLINICAL IMPORTANCE: In our study, FS was the predominant type of seizure in Pomeranians, and almost all cases with FS showed limb contraction, regardless of whether having IE or EUC.

The Potential of Bemegride as an Activation Agent in Electroencephalography in Dogs.

The present study investigated the potential of bemegride as a pharmacological activation agent that elicits epileptiform discharges (EDs) in interictal electroencephalogram (EEG) recordings in dogs. Four laboratory dogs with idiopathic epilepsy and four without epilepsy were included. The dogs were anesthetized using sevoflurane during EEG recordings. Bemegride was administered intravenously and repeatedly until EDs were enhanced or induced, or until the maximum dose (20 mg/kg) had been administered. Bemegride activated EDs in all dogs with epilepsy. These EDs predominantly occurred in each dog's spontaneous irritative zones, which were identified without the administration of bemegride. EDs occurred after the administration of bemegride in 50% of dogs without epilepsy. The dose required for activation was significantly lower in dogs with epilepsy (median; 7.3 mg/kg) than in those without (median; 19.7 mg/kg) (p = 0.0294). The only suspected adverse effect associated with the administration of bemegride was vomiting in two dogs after awakening from anesthesia. There were no other adverse effects, including seizures. The present results demonstrated the potential of bemegride as a safe and effective pharmacological activation agent of EDs in anesthetized dogs with epilepsy and provided more options for the diagnosis and therapeutic planning of epilepsy, including presurgical evaluations, in dogs.

Neurosurgery in canine epilepsy.

Epilepsy surgery is functional neurosurgery applied to drug-resistant epilepsy. Although epilepsy surgery has been established and achieves fair to good outcomes in human medicine, it is still an underdeveloped area in veterinary medicine. With the spread of advanced imaging and neurosurgical modalities, intracranial surgery has become commonplace in the veterinary field, and, therefore, it is natural that expectations for epilepsy surgery increase. This review summarizes current standards of intracranial epilepsy surgery in human medicine and describes its current status and expectation in veterinary medicine. Intracranial epilepsy surgery is classified generally into resection surgery, represented by cortical resection, lobectomy, and lesionectomy, and disconnection surgery, such as corpus callosotomy and multiple subpial transection. In dogs with drug-resistant epilepsy, corpus callosotomy is available as a disconnection surgery for generalized epilepsy. However, other types of disconnection and resection surgeries for focal epilepsy are limited to experimental studies in laboratory dogs and/or anecdotal case reports of lesionectomy, such as tumor or encephalocele removal, without epileptogenic evidence. Veterinary epilepsy surgery is a new and challenging neurosurgery field; with the development of presurgical evaluations such as advanced electroencephalography and neuroimaging, it may become more readily practiced.

Detection of Generalized Tonic-Clonic Seizures in Dogs With a Seizure Detection System Established Using Acceleration Data and the Mahalanobis Distance: A Preliminary Study.

Caregivers of dogs with epilepsy experience severe stress due to unpredictable seizures. Hence, they feel the need for a better management strategy. A seizure detection system (SDS), which can identify seizures and provide notifications to caregivers immediately, is required to address this issue. The current study aimed to establish a wearable automatic SDS using acceleration data and the Mahalanobis distance and to preliminarily investigate its feasibility among dogs. A generalized tonic-clonic seizure (GTCS) was targeted because it is the most common type of seizure and can have serious consequences (i.e., status epilepticus). This study comprised three phases. First, the reference datasets of epileptic and non-epileptic activities were established using acceleration data of GTCSs in 3 dogs and daily activities in 27 dogs. Second, the GTCS-detecting algorithm was created using the reference datasets and was validated using other acceleration data of GTCSs in 4 epileptic dogs and daily activities in 27 dogs. Third, a feasibility test of the SDS prototype was performed in three dogs with epilepsy. The algorithm was effective in identifying all acceleration data of GTCSs as seizures and all acceleration data of daily activities as non-seizure activities. Dogs with epilepsy were monitored with the prototype for 48-72 h, and three GTCSs were identified. The prototype detected all GTCSs accurately. A false positive finding was not obtained unless the accelerometer was displaced. Hence, a method that can detect epileptic seizures, particularly GTCSs, was established. Nevertheless, further large-scale studies must be conducted before the method can be commercialized.

Efficacy and safety of switching from febuxostat to dotinurad, a novel selective urate reabsorption inhibitor, in hyperuricemic patients with type 2 diabetic kidney disease: Protocol for a single-arm, open-label, prospective, exploratory study.

Background: Dotinurad is a novel uricosuric drug in Japan with selective and potent urate transporter 1 (URAT1) inhibitory activity. This study aims to evaluate the efficacy and safety of dotinurad in hyperuricemic patients with type 2 diabetic kidney disease by comparing serum levels of urate and plasma and urinary levels of indoxyl sulfate excreted via the urate excretion transporter ATP binding cassette subfamily G member 2 (ABCG2), as indices, with baseline levels after switching from febuxostat to dotinurad. Methods: This single-center, single-arm, open-label, prospective, exploratory study aims to evaluate the effect of switching from febuxostat to dotinurad on serum urate levels and its background factors. The study will include 50 hyperuricemic patients with type 2 diabetic kidney disease and urate levels exceeding 6 mg/dL despite administration of febuxostat 20 mg/day for at least 3 months. The primary outcome is the achievement rate of serum urate levels of ≤6 mg/dL after 24 weeks of treatment with dotinurad at 0.5 mg to a maximum of 4 mg once daily. Secondary outcomes include the changes in serum urate levels, plasma and urinary indoxyl sulfate levels, and renal injury-related markers from baseline to observation points at weeks 4, 12, and 24. Discussion: The study hypothesizes that switching to dotinurad may reduce the plasma levels of indoxyl sulfate and increase its urinary levels in patients with hyperuricemia. These suggest that dotinurad can potently lower the serum urate level by inhibiting URAT1 without adversely affecting ABCG2. Thus, findings of this study are expected to provide useful insights into the treatment of hyperuricemia associated with type 2 diabetic kidney disease and the discovery of new possibilities for dotinurad. Ethics and Dissemination: Prior to the study, its study protocol was scientifically and ethically reviewed and approved by the Japan Physicians Association Clinical Research Review Board (approval number: JPA007-2204-02). In addition, patients who provide written informed consent will participate in the study. The results of this study will be published through submission to a peer-reviewed scientific journal. Clinical trial registration: https://jrct.niph.go.jp/en-latest-detail/jRCTs031220080, identifier jRCTs031220080.

Case Report: 1-Year Follow-Up of Vagus Nerve Stimulation in a Dog With Drug-Resistant Epilepsy.

A vagus nerve stimulation (VNS) system was surgically implanted to treat drug-resistant epilepsy in a 5-year-old male Shetland Sheepdog. At regular visits during a 1-year follow-up, treatment efficacy and adverse effects were assessed, and programmable stimulation parameters were adjusted to optimize stimulation intensity while avoiding adverse effects. The frequency of generalized tonic-clonic seizures was reduced by 87% after the initiation of VNS. The owner reported that the dog regained his personality, and the quality of life of both the dog and owner improved. The only adverse effect of VNS was a cough that was controlled by adjusting stimulation parameters. There were no surgical complications or other issues with the VNS device. This is the first long-term evaluation of VNS therapy in a dog, and the results obtained suggest that gradual adjustments of VNS parameters facilitate optimum VNS dosing.

S100 Genes are Highly Expressed in Peripheral Leukocytes of Type 2 Diabetes Mellitus Patients Treated with Dietary Therapy.

BACKGROUND AND OBJECTIVES: We demonstrated that the mRNA induction of S100s in rat peripheral leukocytes by severe hyperglycemia was reduced by inhibiting postprandial hyperglycemia. Here, we compared inflammatory gene expression in peripheral leukocytes between type 2 diabetes mellitus (T2DM) patients undergoing dietary therapy alone and healthy volunteers, and between T2DM patients undergoing dietary therapy alone and those undergoing such therapy in combination with drug therapy using the α-glucosidase inhibitor miglitol. METHODS: T2DM patients who had undertaken dietary therapy alone or in combination with drug therapy using miglitol for ≥ 8 weeks and healthy volunteers were subjected to a meal tolerance test and glucose concentration, neutrophil elastase concentration, and mRNA expression analyses of peripheral leukocytes by microarray and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) immediately before and 180 min after a meal. RESULTS: Blood glucose concentrations 60 min after a meal were lower in T2DM patients with dietary + miglitol therapy than in those with dietary therapy alone. Neutrophil elastase concentrations at 60 and 120 min after a meal were lower in T2DM patients with dietary + miglitol therapy than in those with dietary therapy alone. Expression levels of S100A8 in a fasting state and S100A6, S100A8, and S100A9 180 min after a meal were higher in T2DM patients with dietary therapy alone than in healthy volunteers. Expression levels of S100A12 in a fasting state and 180 min after a meal were higher in T2DM patients with dietary therapy alone than in T2DM patients with dietary + miglitol therapy. CONCLUSIONS: S100 genes were more highly expressed in T2DM patients with dietary therapy than in healthy volunteers.

Lower intake of saturated fatty acids is associated with persistently higher arterial stiffness in patients with type 2 diabetes.

AIMS/INTRODUCTION: There are few studies to investigate the relationship between macronutrients and longitudinal changes in arterial stiffness in patients with type 2 diabetes mellitus. This exploratory study sought to determine whether macronutrients were correlated with increased arterial stiffness independently of conventional atherosclerotic risk factors. MATERIALS AND METHODS: The study participants comprised 733 type 2 diabetes outpatients who had no apparent history of cardiovascular diseases. The dietary schedule was assessed with a validated, brief, self-administered diet history questionnaire. At baseline and at years 2 and 5, brachial-ankle pulse wave velocity was measured. A multivariable linear mixed-effects model was used to determine the predictive values of macronutrients and atherosclerotic risk factors for longitudinal changes in brachial-ankle pulse wave velocity. RESULTS: There was a significant increase in brachial-ankle pulse wave velocity values over the 5-year follow-up period. In a multivariable linear mixed-effects model that adjusted for age and sex, lower saturated fatty acid intake was significantly correlated with persistently higher brachial-ankle pulse wave velocity, independently of other atherosclerotic risk factors. Lower intake of dairy products in particular showed this correlation. CONCLUSIONS: Our data showed that lower saturated fatty acids intake was correlated with persistently higher brachial-ankle pulse wave velocity in type 2 diabetes patients. Among food sources of saturated fatty acids, lower dairy products specifically were correlated with elevated brachial-ankle pulse wave velocity. This might be because the consumption of dairy products in Japan is much lower than in Western countries.

Add-On Therapy with DPP-4 Inhibitors May Improve Renal Function Decline in α-Glucosidase Inhibitor and Metformin Users: A Retrospective Observational Study.

PURPOSE: We retrospectively evaluated the long-term effect of dipeptidyl peptidase (DPP)-4 inhibitors on estimated glomerular filtration rate (eGFR) slopes, and then evaluated the beneficial interaction between DPP-4 inhibitor initiation and baseline use of α-glucosidase inhibitor and/or metformin in patients with diabetic kidney disease. PATIENTS AND METHODS: Altogether, 1512 patients with type 2 diabetes were receiving DPP-4 inhibitor therapy over 1 year and were followed up for a maximum of 2 years before and after 7 years of treatment. The decline in renal function was estimated as the slope of the individual linear regression line of eGFR over 2-year follow-up. Prescription data on medications before and after DPP-4 inhibitor treatment were examined. RESULTS: The mean length of DPP-4 inhibitor treatment was 5.3 ± 2.6 years. The baseline mean eGFR slope (mL/min/1.73m2/year) was -2.24 ± 6.05. After DPP-4 inhibitor treatment, mean eGFR slope was significantly improved (-1.53 ± 6.36, P < 0.01) in patients with type 2 diabetes. This effect appeared more pronounced for baseline use of α-glucosidase inhibitor and/or metformin in patients with diabetic kidney disease. These non-users showed a trend towards attenuation or no effects. CONCLUSION: In the present study, patients treated with DPP-4 inhibitors had a significantly slower annual loss of kidney function. The benefit appears pronounced in α-glucosidase inhibitor and metformin users with advanced renal dysfunction. These results suggest that the beneficial effects of DPP-4 inhibitors on kidney function may have occurred in the presence of an α-glucosidase inhibitor and/or metformin.

Liraglutide Improves Estimated Glomerular Filtration Rate Slopes in Patients with Chronic Kidney Disease and Type 2 Diabetes: A 7-Year Retrospective Analysis.

Background: Liraglutide was administered to patients with type 2 diabetes, and its effects on estimated glomerular filtration rate (eGFR) slopes and albuminuria were retrospectively evaluated. Methods: This study included 568 patients with type 2 diabetes who received liraglutide therapy (up to 0.9 mg/day) >1 year and were followed-up for a maximum of 2 years before and 7 years after treatment. The decline in renal function was estimated as the slope of the individual linear regression line of eGFR over the follow-up time. Spot urine samples were collected to measure albuminuria, which were calculated using creatinine levels. In addition, HbA1c, body weight, blood pressure, and heart rate were monitored. Results: The mean liraglutide treatment period was 3.1 ± 2.0 years. The mean baseline eGFR slope [mL/(min ·1.73 m2·year)] was -2.75 ± 6.04. After liraglutide treatment, the mean eGFR slope significantly improved (-1.42 ± 4.30, P < 0.01). This effect appeared more pronounced for baseline eGFRs <45 mL/(min ·1.73 m2). Albuminuria, HbA1c, body weight, and systolic blood pressure levels were significantly reduced after treatment with liraglutide for 1 year, whereas diastolic blood pressure and heart rates were increased. Conclusions: Patients treated with liraglutide experienced a significantly slower annual decline in kidney function. The benefit appeared more pronounced in patients with the development and progression of diabetic kidney disease. These results suggest that the benefits of liraglutide on kidney function identified in clinical trials appear to be well generalizable to clinical practice.

Breakfast skipping is associated with persistently increased arterial stiffness in patients with type 2 diabetes.

OBJECTIVE: While certain lifestyle habits may be associated with arterial stiffness, there is limited literature investigating the relationship between lifestyle habits and longitudinal changes in arterial stiffness in patients with type 2 diabetes mellitus (T2DM). This is an exploratory study to determine whether lifestyle habits, in addition to conventional atherosclerotic risk factors, are associated with increased arterial stiffness. RESEARCH DESIGN AND METHODS: The study participants comprised 734 Japanese outpatients with T2DM and no history of apparent cardiovascular diseases. Lifestyle habits were analyzed using self-reported questionnaires, and brachial-ankle pulse wave velocity (baPWV) was measured at baseline, and at years 2 and 5. A multivariable linear mixed-effects model was used to determine the predictive value of lifestyle habits and possible atherosclerotic risk factors for longitudinal change in baPWV. RESULTS: Over 5 years of follow-up, baPWV values significantly increased. In a multivariable linear mixed-effects model that adjusted for age and gender, a low frequency of breakfast intake was significantly associated with persistently high baPWV, independently of other lifestyle habits. Furthermore, in a multivariable linear mixed-effects model that included both lifestyle habits and possible atherosclerotic risk factors, a low frequency of breakfast intake remained the only independent predictive factor for persistently high baPWV. Subjects who ate breakfast less frequently tended to have additional unhealthy lifestyle habits and atherosclerotic risk factors. CONCLUSIONS: Our analyses suggest that breakfast skipping is an independent lifestyle habit that is associated with persistently increased arterial stiffness in patients with T2DM. TRIAL REGISTRATION NUMBER: UMIN000010932.

Relationship between interictal epileptiform discharges under medetomidine sedation and clinical seizures in canine idiopathic epilepsy.

BACKGROUND: Electroencephalography (EEG) is required for the diagnosis of canine idiopathic epilepsy as a highest confidence level of diagnosis by the International Veterinary Epilepsy Task Force; however, EEG is seldom used and a standardised assessment method has not been reported. METHODS: Interictal EEG was performed under medetomidine sedation in dogs with idiopathic epilepsy and in control dogs. Epileptiform discharge (ED) frequency was compared between dogs with more severe and less severe seizures during one month before EEG and control dogs. RESULTS: All 10 dogs with more severe seizures had ED, as had 7 of 11 with less severe seizures. All epileptic dogs without ED had good long-term outcomes. ED frequency (number of ED per five minutes) was significantly higher in dogs with more severe (median, 4.5) than with less severe seizure (median, 0.46) and in the control dogs (median, 0.15). An ED frequency greater than 0.8 was considered to indicate epilepsy. CONCLUSION: Interictal EEG in a light sleep state under medetomidine sedation had a high detection rate of ED, and ED frequency had a positive correlation with the recent severity of epileptic seizures. This allows interictal EEG recordings to be used as a simplified and objective test that may help to diagnose epilepsy and to assess the recent severity of the disease in dogs.

Canagliflozin Increases Postprandial Total Glucagon-Like Peptide 1 Levels in the Absence of α-Glucosidase Inhibitor Therapy in Patients with Type 2 Diabetes: A Single-Arm, Non-randomized, Open-Label Study.

INTRODUCTION: To investigate canagliflozin-induced changes in postprandial total glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels in patients with type 2 diabetes mellitus (T2DM). METHODS: Forty-five patients with T2DM who had inadequate glycemic control (glycated hemoglobin ≥ 6.5%) with diet and exercise alone (n = 15, drug naïve) and in combination with either a stable dose of the α-glucosidase inhibitor acarbose (n = 15) or metformin (n = 15) received canagliflozin, a sodium-glucose cotransporter 2 inhibitor, at 100 mg once daily for 12 weeks. The primary endpoint was the change from baseline to week 12 in postprandial glucose and plasma levels of total GLP-1 and GIP during a meal tolerance test (MTT). RESULTS: Canagliflozin significantly reduced postprandial blood glucose (mean difference - 40.2 mg/mL at 60 min) and increased postprandial total GLP-1 (mean difference 1.8 pg/mL at 60 min) during an MTT. A transient reduction in the postprandial GIP level at only 30 min (mean difference - 80.3 pg/mL) during an MTT was observed. No changes in postprandial GLP-1 or GIP levels were seen after canagliflozin treatment as an add-on to acarbose in patients with T2DM. Acarbose treatment significantly decreased postprandial total GIP levels (P < 0.05) and tended to increase postprandial total GLP-1 levels (P = 0.07) compared to the other two treatments prior to canagliflozin. CONCLUSION: Canagliflozin 100 mg increased postprandial total GLP-1 levels in the absence of acarbose, suggesting that it may upregulate GLP-1 secretion through delayed glucose absorption in the upper intestine, as with the α-glucosidase inhibitor. TRIAL REGISTRATION: University Hospital Medical Information Network, UMIN000018345. FUNDING: Mitsubishi Tanabe Pharma Corporation.

Effect of luseogliflozin on hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease: A prospective, single-arm trial (LEAD trial).

AIMS: No pharmacological therapies are approved for non-alcoholic fatty liver disease (NAFLD). Luseogliflozin, a sodium glucose cotransporter 2 inhibitor, has been developed for the treatment of adults with type 2 diabetes (T2DM). The aim of this prospective, single-arm study is to evaluate the efficacy of luseogliflozin on hepatic fat content and glycated hemoglobin (HbA1c) in T2DM patients with NAFLD. METHODS: Forty T2DM patients with NAFLD were treated with luseogliflozin 2.5 mg/day for 24 weeks. Primary end-points were changes in HbA1c and hepatic steatosis evaluated by magnetic resonance imaging-hepatic fat fraction from baseline. Secondary end-points were changes in metabolic and hepatic function-related parameters, including hepatic fibrosis markers (Fibrosis-4 index, NAFLD fibrosis score, type IV collagen 7S. and Wisteria floribunda agglutinin-positive Mac-2 binding protein). RESULTS: Not only HbA1c and transaminase activities but also hepatic fat content were significantly decreased after 24 weeks of therapy with luseogliflozin. The reduction of hepatic fat content was significantly correlated with the reduction of alanine aminotransferase. Although hepatic fibrosis markers were unchanged, serum ferritin levels reduced and serum albumin significantly increased after the treatment. CONCLUSION: Luseogliflozin can be a novel promising agent for the treatment of T2DM patients with NAFLD. Prospective randomized controlled trials are warranted to confirm this impact of luseogliflozin onT2DM with NAFLD.

Effects of three infusion fluids with different sodium chloride contents on steady-state serum concentrations of bromide in dogs.

Potassium bromide overdose (bromism) in the management of canine epilepsy has been known. However, a protocol to reduce bromide concentrations rapidly has not been previously established. The effects of three infusion fluids with different chloride contents on the steady-state serum concentrations of bromide in beagles were determined. After stabilization of the serum bromide concentrations, seven dogs were infused with saline (Na+ 154 mmol/L; Cl- 154 mmol/L), lactated Ringer's (Na+ 131 mmol/L; Cl- 110 mmol/L), or maintenance solutions (Na+ 35 mmol/L; Cl- 35 mmol/L) at a rate of 2 or 10 ml kg-1  hr-1 for 5 hr. Serum and urine were collected hourly, and the bromide concentrations were measured. When saline and lactated Ringer's solutions were infused at a rate of 10 ml kg-1  hr-1 for 5 hr, serum bromide concentrations were decreased by 14.24% and urine bromide concentrations by 17.63%, respectively. Of all compositions of infusion fluids, only sodium and chloride contents were associated with the decreased serum concentrations and the increased renal clearance of bromide. In summary, saline and lactated Ringer's solutions reduced serum bromide concentrations in a sodium chloride-dependent manner in dogs were found when infused at 10 ml kg-1  hr-1 for 5 hr.

Accumulation of Laforin and Other Related Proteins in Canine Lafora Disease With EPM2B Repeat Expansion.

Canine Lafora disease (LD) is an autosomal recessive genetic disorder causing nonfatal structural epilepsy, mainly affecting miniature wirehaired dachshunds. Repeat expansion in the EPM2B gene causes a functional impairment of the ubiquitin ligase malin which regulates glycogen metabolism. Abnormally structured glycogen accumulates and develop polyglucosan bodies predominantly in the central nervous system. The authors performed a comprehensive clinical, genetic, and pathological study of 4 LD cases affecting miniature wirehaired dachshund dogs with EPM2B repeat expansions, with systemic distribution of polyglucosan bodies and accumulation of laforin and other functionally associated proteins in the polyglucosan bodies. Myoclonic seizures first appeared at 7-9 years of age, and the dogs died at 14-16 years of age. Immunohistochemistry for calbindin revealed that the polyglucosan bodies were located in the cell bodies and dendritic processes of Purkinje cells. Polyglucosan bodies were also positive for laforin, hsp70, α/ß-synuclein, ubiquitin, LC3, and p62. Laforin-positive polyglucosan bodies were located in neurofilament-positive neurons but not in GFAP-positive astrocytes. In nonneural tissues, periodic acid-Schiff (PAS)-positive polyglucosan bodies were observed in the heart, skeletal muscle, liver, apocrine sweat gland, and smooth muscle layer of the urinary bladder. In the skeletal muscle, polyglucosan bodies were observed only in type 1 fibers and not in type 2 fibers. The results indicate that although the repeat expansion of the EPM2B gene is specific to dogs, the immunohistochemical properties of polyglucosan body in canine LD are comparable to human LD. However, important phenotypic variations exist between the 2 species including the affected skeletal muscle fiber type.

Efficacy of ipragliflozin as monotherapy or as add-on therapy with other oral antidiabetic medications for treating type 2 diabetes in Japanese patients with inadequate glycemic control: A subgroup analysis based on patient characteristics.

AIMS/INTRODUCTION: The aim of the present study was to evaluate the efficacy and safety of ipragliflozin in treating Japanese type 2 diabetes patients with inadequate glycemic control by investigating diurnal variations of blood glucose and body composition. MATERIALS AND METHODS: This was an investigator-initiated, multicenter, prospective study with a 6-month treatment period. The primary outcome investigated was change in hemoglobin A1c levels from baseline. Secondary outcomes included changes in fasting plasma glucose, insulin resistance, variations in 24-h glucose levels detected by continuous glucose monitoring, bodyweight, body composition, waist circumference and serum lipids. Adverse events were evaluated throughout the study. RESULTS: A total of 98 patients completed the study. Over the 6-month period, ipragliflozin-treated patients showed reduction in hemoglobin A1c levels by 0.3%, fasting plasma glucose levels by 13.0 mg/dL, bodyweight by 2.1 kg, body fat mass by 1.5 kg and extracellular water by 0.3 kg, as well as a decrease in systolic/diastolic blood pressures. Significant reductions from baseline in mean amplitude of glucose excursions and standard deviation, and the reduced frequency of hyperglycemia were confirmed. High-density lipoprotein cholesterol was also significantly improved. Notably, the subgroup analysis of hemoglobin A1c levels, bodyweight, waist circumference, and body composition based on age, sex and body mass index showed similar reductions within each subgroup. The incidences of adverse events and adverse drug reactions were 20.0% and 1.0%, respectively, over the 6-month period. CONCLUSIONS: Ipragliflozin is a useful oral antidiabetic medication for patients with a wide range of background characteristics.