OXM-104, a potential candidate for the treatment of obesity, NASH and type 2 diabetes.

OBJECTIVE: Dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonists are therapeutic agents with an interesting liver-specific mode of action suitable for metabolic complications. In this study, dual GLP-1 and glucagon receptor agonist OXM-104 is compared head-to-head with the once-daily dual GLP-1 and glucagon receptor agonist cotadutide and GLP-1 receptor agonist semaglutide to explore the metabolic efficacy of OXM-104. METHODS: The in vitro potencies of OXM-104, cotadutide and semaglutide were assessed using reporter assays. In addition, in vivo efficacy was investigated using mouse models of diet-induced obesity (DIO mice), diabetes (db/db mice) and diet-induced NASH mice (MS-NASH). RESULTS: OXM-104 was found to only activate the GLP-1 and glucagon with no cross-reactivity at the (GIP) receptor. Cotadutide was also found to activate the GLP-1 and glucagon receptors, whereas semaglutide only showed activity at the GLP-1 receptor. OXM-104, cotadutide, and semaglutide elicited marked reductions in body weight and improved glucose control. In contrast, hepatoprotective effects, i.e., reductions in steatosis and fibrosis, as well as liver fibrotic biomarkers, were more prominent with OXM-104 and cotadutide than those seen with semaglutide, demonstrated by an improved NAFLD activity score (NAS) by OXM-104 and cotadutide, underlining the importance of the glucagon receptor. CONCLUSION: These results show that dual GLP-1 and glucagon receptor agonism is superior to GLP-1 alone. OXM-104 was found to be a promising therapeutic candidate for the treatment of metabolic complications such as obesity, type 2 diabetes and NASH.

Haemophilus influenzae septicaemia and urinary tract infection associated with nefrocalcinosis: case report.

Haemophilus influenzae is an uncommon uropathogen with fastidious growth requirements, which must be taken into consideration in the diagnostic process. We present a rare case of urosepsis with H. influenzae in a young patient with nefrocalcinosis.

Kidney stone disease.

Kidney stone disease is rapidly increasing with a strong relationship to metabolic syndrome. This review gives a brief overview of the current state and current treatment modalities. Increasing use of CT and ultrasound scans leads to increased diagnosis of asymptomatic kidney stones, which rarely require treatment. The trend in stone treatment goes towards endoscopic lithotripsy which together with ESWL enables a personalised approach. Obstructive stones with infection require urgent intervention to reduce mortality. Increased fluid intake, dietary changes as well as potassium citrate supplements are the most important elements in stone prevention in the common idiopathic stone disease.

The Effects of Dual GLP-1/Glucagon Receptor Agonists with Different Receptor Selectivity in Mouse Models of Obesity and Nonalcoholic Steatohepatitis.

There is an unmet need for nonalcoholic steatohepatitis (NASH) therapeutics, considering the increase in global obesity. Dual GLP-1/glucagon (GCG) receptor agonists have shown beneficial effects in circumventing the pathophysiology linked to NASH. However, dual GLP-1/GCG receptor agonists as a treatment of metabolic diseases need delicate optimization to maximize metabolism effects. The impacts of increased relative GLP-1/GCG receptor activity in NASH settings must be addressed to unleash the full potential. In this study, we investigated the potential of OXM-104 and OXM-101, two dual GLP-1/GCG receptor agonists with different receptor selectivity in the setting of NASH, to establish the relative receptor activities leading to the best metabolic outcome efficacies to reduce the gap between surgery and pharmacological interventions. We developed dual GLP-1/GCG receptor agonists with selective agonism. Despite the improved metabolic effects of OXM-101, we explored a hyperglycemic risk attached to increased relative GCG receptor agonism. Thirty-eight days of treatment with a dual GLP-1/GCG receptor agonist, OXM-104, with increased GLP-1 receptor agonism in obese NASH mice was found to ameliorate the development of NASH by lowering body weight, improving liver and lipid profiles, reducing the levels of the fibrosis marker PRO-C4, and improving glucose control. Similarly, dual GLP-1/GCG receptor agonist OXM-101 with increased relative GCG receptor agonism ameliorated NASH by eliciting dramatic body weight reductions to OXM-104, reflected in the improvement of liver and lipid enzymes and reduced PRO-C4 levels. Optimizing dual GLP-1/GCG agonists with increased relative GCG receptor agonism can provide the setting for future agonists to treat obesity, type 2 diabetes, and NASH without having a hyperglycemic risk. SIGNIFICANT STATEMENT: There is an unmet need for nonalcoholic steatohepatitis (NASH) therapeutics, considering the increase in global obesity. Dual GLP-1/glucagon (GCG) receptor agonists have shown beneficial effects in circumventing the pathophysiology linked to NASH. Therefore, this study has examined OXM-104 and OXM-101, two dual GLP-1/GCG receptor agonists in the setting of NASH, to establish the relative receptor activities leading to the best metabolic outcome efficacies to reduce the gap between surgery and pharmacological interventions.

Virtual reality simulator metrics cannot be used to assess competence in ureteronephroscopy and stone removal - a validation study.

OBJECTIVE: The growing use of simulation-based training makes it necessary to develop efficient training programs in order to ensure optimal use of time and resources. Our aim was to develop and gather validity evidence for a simulation-based test in ureteronephroscopy and set a pass/fail standard for the test that will allow future mastery learning. DESIGN: This study is a validation study. A test in ureteronephroscopy and stone removal on the URO Mentor™ virtual reality simulator (3D Systems, USA) was developed by two experienced urologists in order to ensure content. Participants with different experience completed three standardized tasks on the simulator and simulator-generated metrics were used as outcome parameters to minimize bias and ensure a fair response process. RESULTS: Twenty novices, 15 intermediates, and 8 experienced urologists were included in the study. Validity evidence for internal structure and relationship to other variables was questionable with weak and mostly insignificant correlations across all four metrics (Cronbach's alpha = 0.14, p = 0.15) and across the three modules (Cronbach's alpha = 0.41 (p = 0.02), 0.35 (p = 0.06), 0.10 (p = 0.35), and 0.30 (p = 0.09) for each metric, respectively). It was not possible to establish a pass/fail score for the simulation test with meaningful consequences. CONCLUSION: Our study showed that automatically generated simulator metrics cannot be used as a valid way of assessing competence in ureteronephroscopy. Virtual-reality simulator training could still be a valuable and patient-safe way to practice these skills, but an experienced supervisor is needed to determine when the trainee is ready to continue to supervised practice on patients.

Consultation on kidney stones, Copenhagen 2019: aspects of intracorporeal lithotripsy in flexible ureterorenoscopy.

PURPOSE: To summarize current knowledge on intracorporeal laser lithotripsy in flexible ureterorenoscopy (fURS), regarding basics of laser lithotripsy, technical aspects, stone clearance, lithotripsy strategies, laser technologies, endoscopes, and safety. METHODS: A scoping review approach was applied to search literature in PubMed, EMBASE, and Web of Science. Consensus was reached through discussions at the Consultation on Kidney Stones held in September 2019 in Copenhagen, Denmark. RESULTS AND CONCLUSIONS: Lasers are widely used for lithotripsy during fURS. The Holmium laser is still the predominant technology, and specific settings for dusting and fragmenting have evolved, which has expanded the role of fURS in stone management. Pulse modulation can increase stone ablation efficacy, possibly by minimizing stone retropulsion. Thulium fibre laser was recently introduced, and this technology may improve laser lithotripsy efficiency. Small fibres give better irrigation, accessibility, and efficiency. To achieve optimal results, laser settings should be adjusted for the individual stone. There is no consensus whether the fragmentation and basketing strategy is preferable to the dusting strategy for increasing stone-free rate. On the contrary, different stone scenarios call for different lithotripsy approaches. Furthermore, for large stone burdens, all laser settings and lithotripsy strategies must be applied to achieve optimal results. Technology for removing dust from the kidney should be in focus in future research and development. Safety concerns about fURS laser lithotripsy include high intrarenal pressures and temperatures, and measures to reduce both those aspects must be taken to avoid complications. Technology to control these parameters should be targeted in further studies.

The Calcitonin Receptor Plays a Major Role in Glucose Regulation as a Function of Dual Amylin and Calcitonin Receptor Agonist Therapy.

Amylin treatment improves body weight and glucose control, although it is limited by a short action and need for high doses. Dual amylin and calcitonin receptor agonists (DACRAs) are dual amylin and calcitonin receptor agonists with beneficial effects beyond those of amylin. However, to what extent the additional benefits reside in their higher potency or their targeting of the calcitonin receptor remains unclear. Here we deconstruct the receptors involved in the effects of a DACRA, KBP-088, by comparing it to rat amylin (rAMY), rat calcitonin (rCT), and their combination in obese high-fat diet (HFD) and diabetic Zucker diabetic fatty (ZDF) rats. HFD-fed Sprague-Dawley rats and ZDF rats were treated for 4 weeks with KBP-088 (5 µg/kg per day), rAMY (300 µg/kg per day), rCT (300 µg/kg per day), and the combination of rAMY and rCT (300+300 µg/kg per day) using infusion pumps. Body weight, food intake, fasting glycemia, glycated hemoglobin type A1c levels, and glucose tolerance were assessed. In obese HFD-fed rats, KBP-088, rAMY, and the combination of rAMY and rCT significantly reduced body weight and improved glucose tolerance, whereas rCT alone had no effect. In diabetic ZDF rats, rCT was efficient in lowering fasting glycemia similar to rAMY, whereas dual activation by KBP-088 and the combination of rAMY and rCT were superior to activating either receptor alone. In conclusion, calcitonin therapy regulates fasting blood glucose in a diabetic rat model, thereby underscoring the importance of calcitonin receptor activation as well as the known role of amylin receptor agonism in the potent metabolic benefits of this group of peptides. SIGNIFICANCE STATEMENT: We deconstruct the receptors activated by dual amylin and calcitonin receptor agonist (DACRA) therapy to elucidate through which receptor the beneficial metabolic effects of the DACRAs are mediated. We show that calcitonin receptor activation is important for blood glucose regulation in diabetes. This is in addition to the known metabolic beneficial role of amylin receptor activation. These data help in understanding the potent metabolic benefits of the DACRAs and underline the potential of DACRAs as treatment for diabetes and obesity.

Dose Frequency Optimization of the Dual Amylin and Calcitonin Receptor Agonist KBP-088: Long-Lasting Improvement in Food Preference and Body Weight Loss.

Dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of type 2 diabetes and obesity because of their beneficial effects on body weight, blood glucose, insulin sensitivity, and food preference, at least short-term. DACRAs activate the receptors for a prolonged time period, resulting in metabolic effects superior to those of amylin. Because of the prolonged receptor activation, different dosing intervals and, hence, less frequent receptor activation might change the efficacy of DACRA treatment in terms of weight loss and food preference. In this study, we compared daily dosing to dosing every other day with the aim of understanding the optimal balance between efficacy and tolerability. Obese and lean male Sprague-Dawley rats were treated with the DACRA KBP-088, applying two different dosing intervals (1.5 nmol/kg once daily and 3 nmol/kg every other day) to assess the effect on body weight, food intake, glucose tolerance, and food preference when given the choice between chow (13% fat) and a high-fat diet (60% fat). Treatment with KBP-088 induced significant weight loss, reduction in adiposity, improvement in glucose control, and altered food preference toward food that is less calorie-dense. KBP-088 dosed every other day (3 nmol/kg) was superior to KBP-088 once daily (1.5 nmol/kg) in terms of weight loss and improvement of food preference. The beneficial effects were evident in both lean and obese rats. Hence, dosing KBP-088 every other day positively affects overall efficacy on metabolic parameters regardless of the lean/obese state, suggesting that less-frequent dosing with KBP-088 could be feasible. SIGNIFICANCE STATEMENT: Here, we show that food preference can be altered chronically toward choices that are less calorie-dense by pharmacological treatment. Further, pharmacological dosing regimens affect the efficacy differently, as dosing every other day improved body weight loss and alterations in food preference compared with daily dosing. This suggest that alterations of the dosing regimens could be feasible in the treatment of obesity.

The Dual Amylin and Calcitonin Receptor Agonist, KBP-066, Induces an Equally Potent Weight Loss Across a Broad Dose Range While Higher Doses May Further Improve Insulin Action.

Pharmacological treatment with dual amylin and calcitonin receptor agonists (DACRAs) cause significant weight loss and improvement of glucose homeostasis. In this study, the maximally efficacious dose of the novel DACRA, KeyBiosciencePeptide (KBP)-066, was investigated. Two different rat models were used: high-fat diet (HFD)-fed male Sprague-Dawley rats and male Zucker diabetic fatty (ZDF, fa/fa) rats to determine the maximum weight loss and glucose homeostatic effect, respectively. One acute study and one chronic study was performed in HFD rats. Two chronic studies were performed in ZDF rats: a preventive and an interventive. All studies covered a dose range of 5, 50, and 500 µg/kg KBP-066 delivered by subcutaneous injection. Treatment with KBP-066 resulted in a significant weight reduction of 13%-16% and improved glucose tolerance in HFD rats, which was independent of dose concentration. Dosing with 50 and 500 µg/kg led to a transient but significant increase in blood glucose, both in the acute and the chronic study in HFD rats. All doses of KBP-066 significantly improved glucose homeostasis in ZDF rats, both in the preventive and interventive study. Moreover, dosing with 50 and 500 µg/kg preserved insulin secretion to a greater extent than 5 µg/kg when compared with ZDF vehicle rats. Taken together, these results show that maximum weight loss is achieved with 5 µg/kg, which is within the range of previously reported DACRA dosing, whereas increasing dosing concentration to 50 and 500 µg/kg may further improve preservation of insulin secretion compared with 5 µg/kg in diabetic ZDF rats. SIGNIFICANCE STATEMENT: Here we show that KeyBiosciencePeptide (KBP)-066 induces an equally potent body weight loss across a broad dose range in obese rats. However, higher dosing of KBP-066 may improve insulin action in diabetic rats both as preventive and interventive treatment.

The Dual Amylin and Calcitonin Receptor Agonist KBP-088 Induces Weight Loss and Improves Insulin Sensitivity Superior to Chronic Amylin Therapy.

KBP-088 (KeyBiosciencePeptide 088) is a potent dual amylin and calcitonin receptor agonist (DACRA). DACRAs are known to elicit potent activity in terms of typical amylin-induced responses, such as reducing food intake and body weight. However, to what extent amylin infusion can mimic the effects of the dual agonist KBP-088 is unknown. We studied the effect of acute dosing with KBP-088 (5 µg/kg) and rat amylin (100, 300, and 1000 µg/kg) and subsequently compared the chronic effect of KBP-088 (5 µg/kg per day) to increasing doses of rat amylin (100, 300, and 1000 µg/kg per day) delivered by continuous subcutaneous infusion, in high-fat diet (HFD) fed Long-Evans rats. Furthermore, acute amylin sensitivity was investigated. Single dose KBP-088 (5 µg/kg) potently reduced acute food intake for a prolonged period compared with amylin (100, 300, and 1000 µg/kg), confirming the difference in potency. Independent of dose, chronic amylin administration (100, 300, and 1000 µg/kg per day) was less effective than KBP-088 (5 µg/kg per day) in inducing body weight loss (15% with KBP-088, and 5%, 9%, and 8% with amylin, vehicle corrected) and reducing overall adiposity in HFD rats. Moreover, KBP-088 improved oral glucose tolerance with significantly reduced insulin levels (80% reduction) that were better than all doses of amylin (68%, 53%, and 7% reduction). Acute amylin sensitivity was independent of the chronic treatment. Dual activation of amylin and calcitonin receptors by KBP-088 is superior to amylin in reducing body weight and improving glucose tolerance, indicating a role for the calcitonin receptor.

Combining naproxen and a dual amylin and calcitonin receptor agonist improves pain and structural outcomes in the collagen-induced arthritis rat model.

BACKGROUND: Pain is a debilitating symptom of rheumatoid arthritis (RA), caused by joint inflammation and cartilage and bone destruction. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat pain and inflammation in RA, but are not disease-modifying and do not prevent joint destruction when administered alone. KBPs (Key Bioscience peptides) are synthetic peptides based on salmon calcitonin and are expected to inhibit bone resorption and to be chondroprotective. In this study, we investigated if combining a standard of care NSAID (naproxen) with a KBP resulted in improvement in pain scores, as well as disease activity and structural damage in a rat model of RA. METHODS: Collagen-induced arthritis (CIA) was induced in 40 female Lewis rats by immunization with porcine type II collagen; 10 rats were given sham injections. CIA rats were treated with KBP and/or naproxen. Health scores and joint scores were evaluated daily. Mechanical and cold allodynia tests and burrowing tests were used to assess pain-like behaviors. Blood samples were collected for biomarker testing, and paws were collected for histology and microcomputed tomography. RESULTS: Naproxen monotherapy increased the time until humane endpoints was reached, and improved health score, pain assessments, and trabecular thickness, while KBP monotherapy did not result in improvements. Combination therapy had improved efficacy over naproxen monotherapy; combination therapy resulted in improved health scores, and importantly reduced mechanical and cold allodynia assessment. Furthermore, protection of articular cartilage structure and preservation of bone structure and bone volume were also observed. CONCLUSIONS: This study demonstrates that combining KBP and naproxen may be a relevant therapeutic strategy for RA, resulting in improvements to the overall health, pain, inflammation, and joint structure.

Endoscopic observations as a tool to define underlying pathology in kidney stone formers.

PURPOSE: Advancements in endoscopy offer the possibility of inspection of intrarenal anatomy and pathology. The aim of the study was to evaluate renal papillary appearance in kidney stone formers and to correlate papillary findings with stone type and patient metabolic data. MATERIALS AND METHODS: A consecutive cohort of 46 kidney stone formers undergoing retrograde intrarenal surgery was enrolled. During surgery, renal papillae were characterized in the domains of ductal Plugging (DP), surface Pitting, Loss of papillary contour, and Amount of Randall's plaque (RP, PPLA scoring). Stone material was analyzed using micro-CT and infrared spectroscopy, and blood and urine were collected for metabolic evaluation. RESULTS: In all patients, renal papillae had changes in at least one of the domains of the PPLA score. Examining the total population, it was evident that patients with predominantly plugging (DP > 0) all had very low RP scores. There were no significant trends between mean PPLA scores and urinary analytes for the total group. CONCLUSION: Efforts to prevent renal stone formation have so far been insufficient in majority of patients. Digital endoscopy reveals that kidney stone formers have different and distinct papillary morphologies that seem to be linked to specific stone-forming pathways. Since renal papillary abnormalities may be easily identified during endoscopy, this may in the future prove to be an important method for tailoring prevention strategies in kidney stone patients.

Evaluation of ureteral lesions in ureterorenoscopy: impact of access sheath use.

OBJECTIVE: The aim of this study was to evaluate the incidence of ureteral lesions in retrograde intrarenal surgery (RIRS) with and without the use of a 10/12 Fr ureteral access sheath (UAS). A further objective was to search for preoperative factors that could influence the risk of ureteral damage. MATERIALS AND METHODS: Data were collected from a clinical database on 180 consecutive adult patients undergoing RIRS for kidney stones with or without a 10/12 Fr UAS. The primary outcome measure was ureteral lesions endoscopically identified at the end of surgery using the Post-Ureteroscopic Lesion Scale (PULS) classification system. RESULTS: The use of 10/12 Fr UASs resulted in less severe lesions than reported previously with larger diameter UASs. There was a higher risk of superficial lesions in the UAS group, with a calculated crude odds ratio (OR) of 1.84 [95% confidence interval (CI) 1.00-3.37]. When adjusting for age and gender, the OR was 1.68 (95% CI 0.90-3.13; p = 0.10) and thus was not significant. The only factor that remained significant was age (OR =1.02/year, 95% CI 1.00-1.04). CONCLUSION: There was a trend towards a higher risk of ureteral lesions in RIRS with a 10/12 Fr UAS compared with an endoscope alone, but when adjusting for age and gender the incidence of ureteral lesions was comparable between RIRS with and without the use of a 10/12 Fr UAS.

Histopathological correlations to ureteral lesions visualized during ureteroscopy.

PURPOSE: To correlate ureteral lesions visualized during ureteroscopy with histopathological findings. MATERIALS AND METHODS: Ureteral access sheaths (UAS) sized 13/15 Fr. were inserted bilaterally in 22 laboratory pigs. During retraction of the UAS with a semirigid ureteroscope inside, ureteral lesions were evaluated and registered using the Post-ureteroscopic lesion scale (PULS). Ureters were excised in vivo between the uretero-pelvic junction and the uretero-vesical junction. Embedded in paraffin, 4-µm thick sections were step sectioned at 250-300 µm intervals and haematoxylin and eosin (HE) stained. Histopathological scoring of ureteral wall lesions was subsequently performed according to PULS. RESULTS: In 72.1% of ureters, the highest histopathological score was at least 1 grade higher than the highest endoscopic PULS score. For 12 (27.9%) lesions, the difference was 2 scores higher, and for 1 (2.3%), it was 3 scores higher. The histopathological PULS grade was higher than the endoscopical PULS grade at all minimum, quartile, and maximum scores. There was a significant difference in the distribution of highest lesional scores between the endoscopic and histopathological PULS (p = 0.002). The calculated mean of the highest scores was 1.49 for endoscopic PULS and 2.51 for histopathological PULS (p < 0.0001). CONCLUSION: Histopathological evaluation of ureteral wall lesions after UAS placement revealed a significantly higher degree of severity than observed endoscopically. Thus, endoscopy underestimated the histopathological extent of the lesion in the majority of cases.

The Dual Amylin- and Calcitonin-Receptor Agonist KBP-042 Works as Adjunct to Metformin on Fasting Hyperglycemia and HbA1c in a Rat Model of Type 2 Diabetes.

KBP-042 is a dual amylin and calcitonin receptor agonist that increases glucose tolerance and insulin action and reduces body weight in rat models of obesity and prediabetes. The objective of the present study was to 1) evaluate KBP-042 as a treatment of late-stage type 2 diabetes in a rat model and 2) assess the value of adding KBP-042 to the standard of care, metformin, to consider KBP-042 as a relevant drug for treating patients with type 2 diabetes. Two studies were included: an intervention study and a prevention study. In the intervention study, treatment with 5 µg/kg KBP-042 was initiated in 11-week-old Zucker diabetic fatty (ZDF) rats, in which glucose tolerance, fasting glycemia, and glycated hemoglobin were assessed after 4 weeks. In the prevention study, either metformin (400 mg/kg), KBP-042 (5 µg/kg), or a combination of both were administered to ZDF rats for a total of 9 weeks. Glycemia, glucose tolerance, and insulin tolerance were tested. Furthermore, fasting plasma insulin and glucagon levels were evaluated. Finally, pancreatic content of insulin was assessed as a surrogate marker of beta-cell mass. It was found that KBP-042 was efficient in lowering fasting plasma glucose as well as improving glucose tolerance, both as prevention and intervention of disease progression. Furthermore, KBP-042 was efficient in combination with metformin and had additional effects compared with either therapy alone. In conclusion, KBP-042 is a highly relevant therapeutic candidate against type 2 diabetes, effective both as an add-on therapy to metformin and as a stand-alone therapy.

Optimization of tolerability and efficacy of the novel dual amylin and calcitonin receptor agonist KBP-089 through dose escalation and combination with a GLP-1 analog.

Amylin and GLP-1 agonism induce a well-known anorexic effect at dose initiation, which is managed by dose escalation. In this study we investigated how to optimize tolerability while maintaining efficacy of a novel, highly potent dual amylin and calcitonin receptor agonist (DACRA), KBP-089. Furthermore, we tested the GLP-1 add-on potential of KBP-089 in high-fat diet (HFD)-fed rats. KBP-089 potently activated both the amylin and calcitonin receptors in vitro and demonstrated a prolonged receptor activation as well as a potent reduction of acute food intake. HFD rats dosed every day or every second day obtained equal weight loss at study end, albeit with an uneven reduction in both food intake and body weight in rats dosed every second day. In a 4-fold dose escalation, KBP-089 induced a transient reduction in food intake at every escalation step, with reducing magnitude over time, and the following treatment with 2.5, 10, and 40 µg/kg resulted in an ~15% vehicle-corrected weight loss, a corresponding reduction in adipose tissue (AT), and, in all treatment groups, improved oral glucose tolerance (P < 0.01). Twofold and linear escalations suppressed body weight evenly with no significant reduction in food intake at either escalation step. KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) reduced 24-h food intake by 29% and 37% compared with vehicle, respectively; however, when they were combined, 24-h food intake was reduced by 87%. Chronically, KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) lowered body weight 8% and 2% in HFD rats, respectively, whereas the combination resulted in a 12% body weight reduction. Moreover, the combination improved glucose tolerance (P < 0.05). In conclusion, DACRAs act complementarily with GLP-1 on food intake and body weight. Furthermore, on escalation, KBP-089 was well tolerated and induced and sustained a significant weight loss and a reduction in AT in lean and HFD rats, underscoring the potential of KBP-089 as an anti-obesity agent.

A novel dual amylin and calcitonin receptor agonist, KBP-089, induces weight loss through a reduction in fat, but not lean mass, while improving food preference.

BACKGROUND AND PURPOSE: Obesity and associated co-morbidities, such as type 2 diabetes and non-alcoholic fatty liver disease, are major health challenges. Hence, there is an important need to develop weight loss therapies with the ability to reduce the co-morbidities. EXPERIMENTAL APPROACH: The effect of the dual amylin and calcitonin receptor agonist (DACRA), KBP-089, on body weight, glucose homeostasis and fatty acid accumulation in liver and muscle tissue and on food preference was investigated. Furthermore, we elucidated weight-independent effects of KBP-089 using a weight-matched group. KEY RESULTS: Rats fed a high-fat diet were treated, s.c., with KBP-089 0.625, 1.25, 2.5 µg·kg-1 or vehicle. KB-089 induced in a dose-dependent and sustained weight loss (~17% by 2.5 µg·kg-1 ). Moreover, KBP-089 reduced fat depot size and reduced lipid accumulation in muscle and liver. In Zucker Diabetic Fatty rats, KBP-089 improved glucose homeostasis through improved insulin action. To obtain a weight-matched group, significantly less food was offered (9% less than in the KBP-089 group). Weight matching led to improved glucose homeostasis by reducing plasma insulin; however, these effect were inferior compared to those of KBP-089. In the food preference test, rats fed a normal diet obtained 74% of their calories from chocolate. KBP-089 reduced total caloric intake and induced a relative increase in chow consumption while drastically reducing chocolate consumption compared with vehicle. CONCLUSIONS AND IMPLICATIONS: The novel DACRA, KBP-089, induces a sustained weight loss, leading to improved metabolic parameters including food preference, and these are beyond those observed simply by diet-induced weight loss.

First clinical evaluation of a new single-use flexible ureteroscope (LithoVue™): a European prospective multicentric feasibility study.

INTRODUCTION: We evaluated a new digital single-use flexible ureteroscope, LithoVue™ with respect to deflection, image quality and maneuverability. METHODS: A prospective cohort study was conducted in eight tertiary reference centers in Europe in December 2015 and January 2016. All consecutive patients included underwent flexible ureteroscopy and were 18 years or older. Deflection and image quality pre- and post-use and maneuverability were rated with a Likert scale. RESULTS: A total of 40 procedures were performed (five per institution). The indication for FURS was treatment of renal stones in 92.5 % of the cases. Before LithoVue™ usage, the median measured upward and downward deflections were both 270°. Image quality was rated as "very good" in 65 % of cases and "good" in 30 %. Maneuverability was "very good" in 77.5 % and "good" in 17.5 %. At the final evaluation, median upward and downward deflections were both 270°. Image quality was still "very good" in 65 % of cases and "good" in 30 % with no significant difference compared with preoperative data (p = 1). Maneuverability was "very good" in 72.5 % and "good" in 17.5 %, with no significant difference compared with preoperative data (p = 0.92). Two LithoVue™ broke during surgery (5 %): one occurring in extreme deflection with acute infundibulopelvic angle and spontaneous loss of vision for the second one. CONCLUSION: The LithoVue™ displayed good image quality, active deflection and maneuverability. Further evaluation of surgical outcomes and cost analysis will help to present the best utility of this single-use FURS in current practice.

Ureteral Access Sheath Influence on the Ureteral Wall Evaluated by Cyclooxygenase-2 and Tumor Necrosis Factor-α in a Porcine Model.

OBJECTIVE: To examine the effect of ureteral access sheath (UAS) on the expression of the pro-inflammatory mediators cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α) in the ureteral wall. MATERIAL AND METHODS: In 22 pigs an UAS was inserted and removed after 2 minutes on one side and 2 hours on the contralateral side. Postoperatively ureters were excised in vivo, and tissue samples from the distal (2 minutes/2 hours) and proximal ureter (2 minutes/2 hours) were snap-frozen before quantitative polymerase chain reaction analysis of COX-2 and TNF-α. Five unmanipulated ureteral units from other pigs served as the control group. RESULTS: Compared to controls COX-2 mRNA was significantly upregulated in all UAS treated ureteral groups. Similarly, TNF-α mRNA was upregulated in all groups except the 2-minute proximal ureteral group. Both COX-2 and TNF-α expression were significantly higher in the distal than in the proximal ureter in the UAS treated ureters. After UAS insertion for 2 minutes, expression levels in the distal ureter were increased 6.5- and 8-fold for COX-2 and TNF-α, respectively; and after 2 hours of UAS placement COX-2 and TNF-α mRNA expression levels were increased 9- and 9.5-fold, respectively. CONCLUSION: The pro-inflammatory mediators COX-2 and TNF-α were significantly upregulated in the ureteral wall by the influence of UAS. These findings may have implications for postoperative pain, drainage, and complications.

Pharmacological Relaxation of the Ureter When Using Ureteral Access Sheaths during Ureterorenoscopy: A Randomized Feasibility Study in a Porcine Model.

Objective. High intraluminal pressure during ureterorenoscopy (URS) increases risk of infectious and haemorrhagic complications. Intrarenal pressure may be reduced by the use of ureteral access sheaths (UASs), which on the other hand may cause ureteral damage. We have previously shown that the ß-agonist isoproterenol (ISO), when administered topically in the irrigation fluid, is able to inhibit ureteral muscle tone and lower intrarenal pressure during URS. The aim of this study was to examine the effect of ISO on the success rate of UAS insertion in a porcine model. Materials and Methods. 22 pigs in which a UAS could not initially be placed were randomized to endoluminal irrigation with either ISO (0.1 µg/mL) or saline before a new insertion trial. Subsequently, it was registered whether the UAS could be passed without resistance. During extraction of the sheath, any ureteral lesions were characterized ureteroscopically using the PULS classification system. Surgeons were blinded to randomization. Results. In the ISO group, the observed effect of irrigation was 63% successful UAS insertions, compared to 27% in the saline group. No serious lesions (