Efficacy and Safety of Evolocumab in Chinese Patients with Primary Hypercholesterolemia and Mixed Dyslipidemia: 12-Week Primary Results of the HUA TUO Randomized Clinical Trial.

INTRODUCTION: Evolocumab, a fully human proprotein convertase/subtilisin kexin type 9 inhibitor antibody, significantly lowers low-density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes mellitus and hyperlipidemia and mixed dyslipidemia. This 12-week study evaluated the efficacy and safety of evolocumab in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia at different levels of cardiovascular disease risk. METHODS: HUA TUO was a 12-week randomized, double-blind, placebo-controlled study. Chinese patients aged 18 years or older on stable optimized statin therapy were randomized 2:2:1:1 to receive evolocumab 140 mg every 2 weeks (Q2W), evolocumab 420 mg monthly (QM), or a matching placebo. The coprimary endpoints were percent change from baseline in LDL-C at the mean of weeks 10 and 12 and at week 12. RESULTS: Overall, 241 randomized patients (mean [standard deviation] age, 60.2 [10.3] years) received evolocumab 140 mg Q2W (n = 79), evolocumab 420 mg QM (n = 80), placebo Q2W (n = 41), or placebo QM (n = 41). At weeks 10 and 12, the placebo-adjusted least-squares mean percent change from baseline in LDL-C for the evolocumab 140 mg Q2W group was - 70.7% (95% CI - 78.0% to - 63.5%); - 69.7% (95% CI - 76.5% to - 63.0%) for the evolocumab 420 mg QM group. Significant improvements in all other lipid parameters were observed with evolocumab. The patient incidence of treatment-emergent adverse events was similar between the treatment groups and across dosing regimens. CONCLUSION: In Chinese patients with primary hypercholesterolemia and mixed dyslipidemia, 12-week treatment with evolocumab significantly lowered LDL-C and other lipids, and was safe and well tolerated (NCT03433755).

Ceftriaxone inhibits stress-induced bladder hyperalgesia and alters cerebral micturition and nociceptive circuits in the rat: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome research network study.

AIMS: Emotional stress plays a role in the exacerbation and development of interstitial cystitis/bladder pain syndrome (IC/BPS). Given the significant overlap of brain circuits involved in stress, anxiety, and micturition, and the documented role of glutamate in their regulation, we examined the effects of an increase in glutamate transport on central amplification of stress-induced bladder hyperalgesia, a core feature of IC/BPS. METHODS: Wistar-Kyoto rats were exposed to water avoidance stress (WAS, 1 hour/day x 10 days) or sham stress, with subgroups receiving daily administration of ceftriaxone (CTX), an activator of glutamate transport. Thereafter, cystometrograms were obtained during bladder infusion with visceromotor responses (VMR) recorded simultaneously. Cerebral blood flow (CBF) mapping was performed by intravenous injection of [14 C]-iodoantipyrine during passive bladder distension. Regional CBF was quantified in autoradiographs of brain slices and analyzed in three dimensional reconstructed brains with statistical parametric mapping. RESULTS: WAS elicited visceral hypersensitivity during bladder filling as demonstrated by a decreased pressure threshold and VMR threshold triggering the voiding phase. Brain maps revealed stress effects in regions noted to be responsive to bladder filling. CTX diminished visceral hypersensitivity and attenuated many stress-related cerebral activations within the supraspinal micturition circuit and in overlapping limbic and nociceptive regions, including the posterior midline cortex (posterior cingulate/anterior retrosplenium), somatosensory cortex, and anterior thalamus. CONCLUSIONS: CTX diminished bladder hyspersensitivity and attenuated regions of the brain that contribute to nociceptive and micturition circuits, show stress effects, and have been reported to demonstrated altered functionality in patients with IC/BPS. Glutamatergic pharmacologic strategies modulating stress-related bladder dysfunction may be a novel approach to the treatment of IC/BPS.

Voluntary exercise improves voiding function and bladder hyperalgesia in an animal model of stress-induced visceral hypersensitivity: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome research network study.

OBJECTIVE: The underlying mechanism of interstitial cystitis/bladder pain syndrome (IC/BPS) is not well understood and evaluation of current therapeutic interventions has not identified any generally effective treatments. Physical activity has shown beneficial effects on individuals suffering from chronic pain. Anxiety-prone rats exposed to water avoidance stress (WAS) develop urinary frequency and lower bladder sensory thresholds with high face and construct validity for the study of IC/BPS. The aim of this study was to evaluate the role of chronic voluntary exercise on urinary frequency, voiding function, and hyperalgesia in animals exposed to WAS. MATERIALS AND METHODS: Twenty-six female Wistar-Kyoto rats were exposed to WAS and thereafter randomized to either voluntary exercise for 3 weeks or sedentary groups. Voiding parameters were assessed at baseline, post-WAS, and weekly for 3 weeks. Before euthanasia, the animals underwent cystometrogram (CMG), external urinary sphincter electromyography, and assessment of visceromotor response (VMR) to isotonic bladder distension (IBD). RESULTS: WAS exposure resulted in adverse changes in voiding parameters. Compared with sedentary animals, animals in the voluntary exercise group had improved voiding parameters during metabolic cage and CMG testing, as well as improved bladder sensory thresholds as determined by VMR during IBD. CONCLUSION: Voluntary exercise in an animal model of chronic stress leads to improvement in voiding function and visceral bladder hyperalgesia.

Exercise modulates neuronal activation in the micturition circuit of chronically stressed rats: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study.

BACKGROUND: Rats exposed to water avoidance stress (WAS) show increased urinary frequency, increased somatosensory nociceptive reflex responses, as well as altered brain responses to bladder distension, analogous to similar observations made in patients with urologic chronic pelvic pain syndrome (UCPPS). Exercise has been proposed as a potential treatment option for patients with chronic urinary frequency and urgency. We examined the effects of exercise on urinary voiding parameters and functional brain activation during bladder distension in rats exposed to WAS. METHODS: Adult, female Wistar Kyoto rats were exposed to 10 days of WAS and thereafter randomized to either voluntary exercise for 3 weeks or sedentary groups. Voiding parameters were assessed at baseline, post-WAS, and weekly for 3 weeks. Thereafter, cerebral blood flow (CBF) mapping was performed during isotonic bladder distension (20 cm H2O) after intravenous bolus injection of [14C]-iodoantipyrine. Regional CBF was quantified in autoradiographs of brain slices and analyzed in 3-D reconstructed brains by statistical parametric mapping. Functional connectivity was examined between regions of the micturition circuit through interregional correlation analysis. RESULTS: WAS exposure in sedentary animals (WAS/no-EX) increased voiding frequency and decreased urinary volumes per void. Exercise exposure in WAS animals (WAS/EX) resulted in a progressive decline in voiding frequency back to the baseline, as well as increased urinary volumes per void. Within the micturition circuit, WAS/EX compared to WAS/no-EX demonstrated a significantly lower rCBF response to passive bladder distension in Barrington's nucleus that is part of the spinobulbospinal voiding reflex, as well as in the periaqueductal gray (PAG) which modulates this reflex. Greater rCBF was noted in WAS/EX animals broadly across corticolimbic structures, including the cingulate, medial prefrontal cortex (prelimbic, infralimbic areas), insula, amygdala, and hypothalamus, which provide a 'top-down' decision point where micturition could be inhibited or triggered. WAS/EX showed a significantly greater positive brain functional connectivities compared to WAS/no-EX animals within regions of the extended reflex loop (PAG, Barrington's nucleus, intermediodorsal thalamic nucleus, pons), as well as within regions of the corticolimbic decision-making loop of the micturition circuit, with a strikingly negative correlation between these pathways. Urinary frequency was positively correlated with rCBF in the pons, and negatively correlated with rCBF in the cingulate cortex. CONCLUSION: Our results suggest that chronic voluntary exercise may decrease urinary frequency at two points of control in the micturition circuit. During the urine storage phase, it may diminish the influence of the reflex micturition circuit itself, and/or it may increase corticolimbic control of voiding. Exercise may be an effective adjunct therapeutic intervention for modifying the urinary symptoms in patients with UCPPS.

Spinal cord stimulation ameliorates detrusor over-activity and visceromotor pain responses in rats with cystitis.

AIM: Interstitial cystitis/painful bladder syndrome/(IC/PBS) results in recurring pain in the bladder and surrounding pelvic region caused by abnormal excitability of micturition reflexes. Spinal cord stimulation (SCS) is currently clinically used for the attenuation of neuropathic and visceral pain. The present study examined whether SCS at upper lumbar segments modulates detrusor overactivity and visceral hyperalgesia associated with cystitis in a rat model of cyclophosphamide (CYP)-induced cystitis. METHODS: Cystitis was induced by intraperitoneal injection of CYP (200 mg/kg) in six adult female Sprague Dawley rats 48 h prior to urodynamic recordings. Another six rats served as-controls with saline injection. Cystometry and the external urethral sphincter (EUS) electromyography during bladder infusion were evaluated under urethane anesthesia. The visceromotor reflexes (VMR) obtained from the external abdominal oblique muscle were quantified during bladder infusion and isotonic bladder distension (IBD), respectively. After baseline recordings were taken, SCS was applied on the dorsal surface of L3 for 25 min. Urodynamic recordings and VMR during bladder infusion and IBD were repeated 2 h after SCS. RESULTS: CYP resulted in detrusor overactivity, stronger EUS tonic contractions, and increased VMR. SCS significantly reduced non-voiding contractions, prolonged EUS relaxation, and delayed VMR appearance during bladder infusion as well as significantly decreased VMR during IBD in cystitis rats. CONCLUSION: SCS improved bladder function and EUS relaxation during bladder infusion and significantly attenuated visceral nociceptive-related VMR during IBD in cystitis rats. SCS may have therapeutic potential for patients with hyperalgesia and IC/PBS.