Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission.

Inhibitory GABA-ergic neurotransmission is fundamental for the adult vertebrate central nervous system and requires low chloride concentration in neurons, maintained by KCC2, a neuroprotective ion transporter that extrudes intracellular neuronal chloride. To identify Kcc2 gene expression­enhancing compounds, we screened 1057 cell growth-regulating compounds in cultured primary cortical neurons. We identified kenpaullone (KP), which enhanced Kcc2/KCC2 expression and function in cultured rodent and human neurons by inhibiting GSK3ß. KP effectively reduced pathologic pain-like behavior in mouse models of nerve injury and bone cancer. In a nerve-injury pain model, KP restored Kcc2 expression and GABA-evoked chloride reversal potential in the spinal cord dorsal horn. Delta-catenin, a phosphorylation-target of GSK3ß in neurons, activated the Kcc2 promoter via KAISO transcription factor. Transient spinal over-expression of delta-catenin mimicked KP analgesia. Our findings of a newly repurposed compound and a novel, genetically-encoded mechanism that each enhance Kcc2 gene expression enable us to re-normalize disrupted inhibitory neurotransmission through genetic re-programming.

The 5-HT2C receptor as a therapeutic target for alcohol and methamphetamine use disorders: A pilot study in treatment-seeking individuals.

Alcohol use disorder (AUD) and methamphetamine use disorder (MUD) are prevalent and have high adverse impacts on both the individual and society. Current treatment strategies for these disorders are ineffective at a population level. Lorcaserin, a 5-HT2C receptor agonist, has shown potential at reducing the symptoms of substance use disorder. This pilot study (initiated prior to market withdrawal) examined feasibility and safety of lorcaserin treatment in people undergoing residential detoxification and treatment for AUD and MUD. This was an open label pilot study of lorcaserin where participants (n = 10 AUD; n = 8 MUD) received 10-mg lorcaserin daily for 4 days then twice daily for 1 month. Primary outcome measures included recruitment and retention rate, incidence of treatment-emergent events, incidence of methamphetamine or alcohol withdrawal-related events, heart rate, and blood pressure. Secondary measures included pharmacokinetic data and self-reported alcohol or methamphetamine use, craving, and psychological distress. AUD participants were recruited faster and had a greater retention rate compared with MUD participants. Lorcaserin did not alter vital signs, was well tolerated, and had a similar pharmacokinetic profile to individuals with obesity. Lorcaserin reduced self-reported alcohol and amphetamine-type substance use and craving in AUD and MUD participants, respectively. Self-reported psychological health also improved over the treatment period for all participants. Despite the pilot nature of this study, our data support the notion of 5-HT2C receptors as a therapeutic target for drug and alcohol abuse.

5HT-2C agonist lorcaserin decreases cannabis self-administration in daily cannabis smokers.

There are no FDA-approved treatments for cannabis use disorder (CUD). Preclinical research has shown that the 5HT-2C agonist lorcaserin attenuates cue-induced reinstatement of THC seeking and self-administration. The goal of this placebo-controlled, counterbalanced, within-subject human laboratory study was to examine lorcaserin's effects on cannabis intoxication and self-administration. Lorcaserin (10 mg BID) was administered during one of two 13-day inpatient phases and placebo during the other; each phase was separated by ≥7 days of washout. Inpatient phases comprised (1) standardized cannabis administration (7.0% THC) at no financial cost (intoxication), counterbalanced with (2) the option to self-administer cannabis following either 0 or 3 days of abstinence. Cognitive task performance, food intake, subjective ratings of drug effects, objective/subjective sleep measures, and tobacco cigarette use were also assessed. Fifteen normal-weight, daily cannabis users (4F, 11M) not seeking treatment for CUD completed the study. Lorcaserin significantly reduced cannabis self-administration following 0 and 3 days of cannabis abstinence and also reduced craving for cannabis during abstinence. Lorcaserin produced small but significant increases in positive cannabis ratings and body weight relative to placebo. Lorcaserin also reduced tobacco cigarette smoking on days of cannabis administration relative to placebo. During abstinence, subjective but not objective measures of sleep quality worsened during lorcaserin maintenance. Overall, lorcaserin's ability to decrease drug taking and cannabis craving in nontreatment-seeking cannabis users supports further investigation of 5HT-2C agonists as potential pharmacotherapies for CUD.

The Multicomponent, Multitarget Therapy SUC in Cats with Chronic Kidney Disease: A Multicenter, Prospective, Observational, Nonrandomized Cohort Study.

BACKGROUND: We compared the natural multicomponent, multitarget therapy SUC (Solidago compositum ad us. vet., Ubichinon compositum and Coenzyme compositum, Heel GmbH, Baden-Baden, Germany) to the well-known angiotensin-converting enzyme inhibitor benazepril in a prospective, observational, nonrandomized, two-arm cohort study of cats with chronic kidney disease (CKD). The objective was to assess the tolerability and the effectiveness of SUC in cats with CKD. MATERIAL AND METHODS: One hundred thirty-six cats were screened for CKD, and 70 cats were eligible for the study. Thirty-three cats were assigned to the SUC treatment, and 35 cats received benazepril. All cats were diagnosed with CKD. The follow-up period was 168 days. Response was assessed as an improved or stable serum creatinine from baseline to the end of the study. Additionally, a clinical summary score, as measure of quality of life, was evaluated. RESULTS: Serum creatinine remained close to baseline in both study groups with slightly improved values in the SUC group. The clinical summary score improved significantly in the SUC group on days 3, 7, 28, 56 and 112, but not on day 168. CONCLUSIONS: Within the limitations of the study, the results carry implications for the usefulness of SUC as an interesting new treatment option for feline CKD. The results indicate that SUC might be more effective if given at least twice weekly.

Dopamine receptor D2, but not D1, mediates descending dopaminergic pathway-produced analgesic effect in a trigeminal neuropathic pain mouse model.

Neuropathic pain represents a challenge to clinicians because it is resistant to commonly prescribed analgesics due to its largely unknown mechanisms. Here, we investigated a descending dopaminergic pathway-mediated modulation of trigeminal neuropathic pain. We performed chronic constriction injury of the infraorbital nerve from the maxillary branch of trigeminal nerve to induce trigeminal neuropathic pain in mice. Our retrograde tracing showed that the descending dopaminergic projection from hypothalamic A11 nucleus to spinal trigeminal nucleus caudalis is bilateral. Optogenetic/chemogenetic manipulation of dopamine receptors D1 and D2 in the spinal trigeminal nucleus caudalis produced opposite effects on the nerve injury-induced trigeminal neuropathic pain. Specific excitation of dopaminergic neurons in the A11 nucleus attenuated the trigeminal neuropathic pain through the activation of D2 receptors in the spinal trigeminal nucleus caudalis. Conversely, specific ablation of the A11 dopaminergic neurons exacerbated such pain. Our results suggest that the descending A11-spinal trigeminal nucleus caudalis dopaminergic projection is critical for the modulation of trigeminal neuropathic pain and could be manipulated to treat such pain.

Effect of tolvaptan on renal handling of water and sodium, GFR and central hemodynamics in autosomal dominant polycystic kidney disease during inhibition of the nitric oxide system: a randomized, placebo-controlled, double blind, crossover study.

BACKGROUND: Tolvaptan slows progression of autosomal dominant polycystic kidney disease (ADPKD) by antagonizing the vasopressin-cAMP axis. Nitric oxide (NO) stimulates natriuresis and diuresis, but its role is unknown during tolvaptan treatment in ADPKD. METHODS: Eighteen patients with ADPKD received tolvaptan 60 mg or placebo in a randomized, placebo-controlled, double blind, crossover study. L-NMMA (L-NG-monomethyl-arginine) was given as a bolus followed by continuous infusion during 60 min. We measured: GFR, urine output (UO), free water clearance (CH2O), fractional excretion of sodium (FENa), urinary excretion of aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCγ), plasma concentrations of vasopressin (p-AVP), renin (PRC), angiotensinII (p-AngII), aldosterone (p-Aldo), and central blood pressure (cBP). RESULTS: During tolvaptan with NO-inhibition, a more pronounced decrease was measured in UO, CH2O (61% vs 43%) and FENa (46% vs 41%) after placebo than after tolvaptan; GFR and u-AQP2 decreased to the same extent; p-AVP increased three fold, whereas u-ENaCγ, PRC, p-AngII, and p-Aldo remained unchanged. After NO-inhibition, GFR increased after placebo and remained unchanged after tolvaptan (5% vs -6%). Central diastolic BP (CDBP) increased to a higher level after placebo than tolvaptan. Body weight fell during tolvaptan treatment. CONCLUSIONS: During NO inhibition, tolvaptan antagonized both the antidiuretic and the antinatriuretic effect of L-NMMA, partly via an AVP-dependent mechanism. U-AQP2 was not changed by tolvaptan, presumeably due to a counteracting effect of elevated p-AVP. The reduced GFR during tolvaptan most likely is caused by the reduction in extracellular fluid volume and blood pressure. TRIAL REGISTRATION: Clinical Trial no: NCT02527863 . Registered 18 February 2015.

Dual Impact of Tolvaptan on Intracellular and Extracellular Water in Chronic Kidney Disease Patients with Fluid Retention.

Objective Tolvaptan, an oral selective V2-receptor antagonist, is a water diuretic that ameliorates fluid retention with a lower risk of a worsening renal function than conventional loop diuretics. Although loop diuretics predominantly decrease extracellular water (ECW) compared with intracellular water (ICW), the effect of tolvaptan on fluid distribution remains unclear. We therefore examined how tolvaptan changes ICW and ECW in accordance with the renal function. Methods Six advanced chronic kidney disease patients (stage 4 or 5) with fluid retention were enrolled in this study. Tolvaptan (7.5 mg/day) added to conventional diuretic treatment was administered to remove fluid retention. The fluid volume was measured using a bioimpedance analysis device before (day 0) and after (day 5 or 6) tolvaptan treatment. Results Body weight decreased by 2.6%±1.3% (64.4±6.5 vs. 62.8±6.3 kg, p=0.06), and urine volume increased by 54.8%±23.9% (1,215±169 vs. 1,709±137 mL/day, p=0.03) between before and after tolvaptan treatment. Tolvaptan significantly decreased ICW (6.5%±1.5%, p=0.01) and ECW (7.5%±1.4%, p=0.02), which had similar reduction rates (p=0.32). The estimated glomerular filtration rate remained unchanged during the treatment (14.6±2.8 vs. 14.9±2.7 mL/min/1.732 m, p=0.35). Conclusion Tolvaptan ameliorates body fluid retention, and induces an equivalent reduction rate of ICW and ECW without a worsening renal function. Tolvaptan is a novel water diuretic that has a different effect on fluid distribution compared with conventional loop diuretics.

Combination drug versus monotherapy for the treatment of autosomal dominant polycystic kidney disease.

INTRODUCTION: Despite progress in the understanding of pathogenetic mechanisms of organ cyst formation in autosomal dominant polycystic kidney disease, current treatment methods are insufficient. Experimental studies and clinical trials target at inhibition of cysts development and to slowing CKD progression. AREAS COVERED: The purpose of this analysis is to overview available literature regarding treatment of ADPKD. The most important recent events concerning ADPKD treatment are: the results of TEMPO 3/4 study and the registration of tolvaptan in the treatment of patients with CKD stage I-III and rapidly progressive ADPKD by EMA. ERA-EDTA recommendations for use of tolvaptan in ADPKD of 2016 will be useful for the identification of patients with rapid progression of disease who will benefit most from treatment. Clinical trials concerning inhibitors of mTOR and SSAs have not delivered convincing evidence of their effectiveness. Usefulness of statins in ADPKD require confirmation in adults. The HALT-PKD study confirmed that inhibition of RAA system slows progression of ADPKD. EXPERT OPINION: Current treatment of ADPKD involves: the optimization of life style and combined pharmacological treatment with ACE inhibitors or angiotensin receptor blockers, statins (patients with lipid disorders and cardiovascular disease) and tolvaptan (patients with stage I-III CKD and rapidly progressive ADPKD).

In-Hospital Diuretic Agent Use and Post-Discharge Clinical Outcomes in Patients Hospitalized for Worsening Heart Failure: Insights From the EVEREST Trial.

OBJECTIVES: The aim of this study was to characterize the association between decongestion therapy and 30-day outcomes in patients hospitalized for heart failure (HF). BACKGROUND: Loop diuretic agents are commonly prescribed for the treatment of symptomatic congestion in patients hospitalized for HF, but the association between loop diuretic agent dose response and post-discharge outcomes has not been well characterized. METHODS: Cox proportional hazards models were used to estimate the association among average loop diuretic agent dose, congestion status at discharge, and 30-day post-discharge all-cause mortality and HF rehospitalization in 3,037 subjects hospitalized with worsening HF enrolled in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) study. RESULTS: In univariate analysis, subjects exposed to high-dose diuretic agents (≥160 mg/day) had greater risk for the combined outcome than subjects exposed to low-dose diuretic agents (18.9% vs. 10.0%; hazard ratio: 2.00; 95% confidence interval: 1.64 to 2.46; p < 0.0001). After adjustment for pre-specified covariates of disease severity, the association between diuretic agent dose and outcomes was not significant (hazard ratio: 1.11; 95% confidence interval: 0.89 to 1.38; p = 0.35). Of the 3,011 subjects with clinical assessments of volume status, 2,063 (69%) had little or no congestion at hospital discharge. Congestion status at hospital discharge did not modify the association between diuretic agent exposure and the combined endpoint (p for interaction = 0.84). CONCLUSIONS: Short-term diuretic agent exposure during hospital treatment for worsening HF was not an independent predictor of 30-day all-cause mortality and HF rehospitalization in multivariate analysis. Congestion status at discharge did not modify the association between diuretic agent dose and clinical outcomes.

Heart Failure Update: Outpatient Management.

Outpatient management of heart failure (HF) is aimed at treating symptoms and preventing hospitalizations and readmissions. Management is initiated in a stepwise approach. Blockade of the renin-angiotensin system is a cornerstone of therapy and should be started, along with beta blockers, as soon as the diagnosis of HF is made. Other drugs, including diuretics, aldosterone antagonists, hydralazine, and nitrates, may be added based on symptoms and American College of Cardiology/American Heart Association stage. Despite a great interest in and theoretical benefit of naturoceutical products in the mitigation of oxidative stress and HF progression, none has been proven to be beneficial, and concerns exist regarding their interactions with standard HF drugs. Other nonpharmacologic interventions, including sodium restriction, regular exercise, and/or cardiac rehabilitation, should be initiated at diagnosis. HF often is progressive, and clinicians should be aware of late stage management options, including implantable devices, cardiac transplantation, and hospice care.

Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice.

Recently, the European Medicines Agency approved the use of the vasopressin V2 receptor antagonist tolvaptan to slow the progression of cyst development and renal insufficiency of autosomal dominant polycystic kidney disease (ADPKD) in adult patients with chronic kidney disease stages 1-3 at initiation of treatment with evidence of rapidly progressing disease. In this paper, on behalf of the ERA-EDTA Working Groups of Inherited Kidney Disorders and European Renal Best Practice, we aim to provide guidance for making the decision as to which ADPKD patients to treat with tolvaptan. The present position statement includes a series of recommendations resulting in a hierarchical decision algorithm that encompasses a sequence of risk-factor assessments in a descending order of reliability. By examining the best-validated markers first, we aim to identify ADPKD patients who have documented rapid disease progression or are likely to have rapid disease progression. We believe that this procedure offers the best opportunity to select patients who are most likely to benefit from tolvaptan, thus improving the benefit-to-risk ratio and cost-effectiveness of this treatment. It is important to emphasize that the decision to initiate treatment requires the consideration of many factors besides eligibility, such as contraindications, potential adverse events, as well as patient motivation and lifestyle factors, and requires shared decision-making with the patient.

The Vasopressin 2 Receptor Antagonist Tolvaptan Improves Nutrition and Inflammatory States in Peritoneal Dialysis Patients with Diabetes Mellitus.

Previously, we reported that, in peritoneal dialysis (PD) patients, tolvaptan preserves residual renal function and ameliorates left ventricular hypertrophy. Here, we evaluated the effect of tolvaptan in terms of nutrition and inflammatory states. Of 24 incident PD patients with diabetes, 12 were assigned to a control group that did not receive tolvaptan, and 12, to a group that, 2 weeks after initiation of PD, received tolvaptan 15 mg daily for 12 months. At baseline and at 6 and 12 months after initiation of PD, we evaluated serum C-reactive protein (CRP), albumin, urine volume, peritoneal ultrafiltration (UF), phosphate elimination, protein uptake, left ventricular mass index (LVMI), and the diameter of the inferior vena cava (IVC). Compared with the control group, the tolvaptan group experienced preserved urine volume and UF, lower LVMI and IVC diameter, and higher protein uptake. The average protein uptake was significantly correlated with urine volume, albumin, and CRP; and serum CRP was significantly correlated with albumin. Our study results suggest that tolvaptan improves not only fluid management, but also nutrition state in PD patients.

Horizons in the Pharmacotherapy of Obesity.

Obesity drugs have had a chequered history. In the recent past, only the low efficacy, pancreatic lipase inhibitor orlistat was available worldwide and it was little used. The 5HT2C agonist, lorcaserin, and two combinations of old drugs have been approved in the United States but not in Europe. The diabetes drug liraglutide has been approved in both the US and Europe and seems likely to be most widely accepted. In view of regulators' caution in approving obesity drugs, some (like beloranib) may initially be progressed for niche obesity markets. New drug targets have been identified in brown adipose tissue with the aim of not only activating thermogenesis but also increasing the capacity for thermogenesis in this tissue. Attempts are being made to match the efficacy of bariatric surgery by mimicking multiple gut hormones. Unapproved pharmacotherapies are tempting for some patients. Others remain optimistic about more conventional routes to pharmacotherapy.

Late-Stage Cancer Patients Remain Highly Responsive to Immune Activation by the Selective TLR8 Agonist Motolimod (VTX-2337).

PURPOSE: Immunotherapy as a treatment for cancer holds the promise of complete and durable tumor remission, yet the immunosuppressive environment created by many tumors, advanced patient age, and previous treatments with cytotoxic agents may limit the approach. The activity of motolimod (VTX-2337), a potent and selective Toll-like receptor 8 (TLR8) agonist, was therefore assessed in the context of advanced, late-stage cancer patients. EXPERIMENTAL DESIGN: The repertoire of mediators induced from human peripheral blood mononuclear cells in response to motolimod was characterized. Translational studies in cynomolgus monkeys elucidated the activity of motolimod on an intact immune system, identified biomarkers of TLR8 activation, and defined the relationship between the pharmacokinetic and pharmacodynamic (PK/PD) response. The PK/PD relationship for motolimod in cancer patients was assessed, compared with preclinical findings, and contrasted with activity in healthy volunteers. RESULTS: In late-stage cancer patients, plasma levels of multiple biomarkers, including IL6, G-CSF, MCP-1, and MIP1-ß, increased with increasing motolimod dose. The magnitude and breadth of the biomarker response closely aligned with the response seen in preclinical studies, demonstrating that advanced cancer patients remained responsive to TLR8 activation. In addition, the PK/PD response in cancer patients closely aligned with the activity of motolimod seen in healthy volunteers. CONCLUSIONS: Late-stage cancer patients are highly sensitive to TLR8 activation by motolimod. Tumor burden, advanced age, and prior treatment history with cytotoxic agents did not moderate or modify the response predicted by nonclinical studies and confirmed in healthy volunteers. Clin Cancer Res; 21(24); 5445-52. ©2015 AACR.

Effects of ivabradine on cardiac electrophysiology in dogs with age-related atrial fibrillation.

BACKGROUND: Ivabradine is an inhibitor of mixed Na+-K+ current that could combine with HCN channels to reduce the transmembrane velocity of funny current (If), heart rate, and cardiac efficiency, and thus be used for the treatment of cardiovascular diseases such as chronic heart failure. As an ion channel blocker, Ivabradine is also a potential antiarrhythmic agent. MATERIAL/METHODS: Twelve aging dogs (8-10 years old) underwent rapid atrial pacing for 2 months to induce age-related AF in this study. The dogs were randomly divided into the Ivabradine group and aging-AF group. The effects of Ivabradine on the electrophysiological parameters, including the effective refractory period (ERP) of the pulmonary veins and atrium, duration of AF, and inducing rate of AF, were investigated. RESULTS: As compared to the aging-AF group, the ERPs of the left superior pulmonary vein (139.00±4.18 ms vs. 129.00±4.08 ms, P=0.005) and left auricle (135.00±3.53 ms vs. 122.00±4.47 ms, P=0.001) were significantly increased, while the duration of AF (46.60±5.07 s vs. 205.40±1.14 s, P=0.001) and inducing rate of AF (25% vs. 60%, P=0.001) were significantly decreased. CONCLUSIONS: Ivabradine could effectively reduce the inducing rate of AF, and thus be used as an upstream drug for the prevention of age-related AF.

A case of atrial tachycardia treated with ivabradine as bridge to ablation.

Ivabradine is indicated in cardiac failure and ischemia to reduce sinus rate by inhibition of the pacemaker I(f) current in sinoatrial node. We report a case of an 18-year-old woman with left atrial tachyarrhythmia resistant to several antiarrhythmic drugs and to electric cardioversion who responded only to ivabradine, which significantly reduced heart rate without abolishing the arrhythmia itself. An ectopic focus in the ostium of left pulmonary veins was found and the patient was successfully ablated. We suggest that ivabradine might be therefore useful in the treatment of supraventricular tachyarrhythmias due to an enhanced automaticity.

The Effect of Chinese rhubarb, Rheum officinale, with and without benazepril on the progression of naturally occurring chronic kidney disease in cats.

BACKGROUND: Renal fibrosis is common in progressive kidney disease. Transforming growth factors ß (TGF-ß) are important mediators of all types of fibrosis, including renal fibrosis. Chinese rhubarb has been shown to have antifibrotic properties in part because of inhibition of TGF-ß and has slowed the progression of kidney disease in rodent models. HYPOTHESIS: That administration of a Chinese rhubarb supplement will slow the progression of chronic kidney disease (CKD) in cats and the concurrent administration of Chinese rhubarb and benazepril will be more effective than either alone. ANIMALS: Twenty-nine client-owned cats with naturally occurring IRIS Stage 2 or early Stage 3 CKD and without comorbidity such as cancer, urinary tract obstruction, urinary tract infection, poorly controlled hyperthyroidism, or systemic hypertension were enrolled in the study. METHODS: A randomized, positive-controlled, prospective study was performed. Cats received Chinese rhubarb, benazepril, or both in addition to standard treatment for CKD. Repeated measures ANOVA was used to assess changes in serum creatinine concentration, body weight, hematocrit, urine protein: urine creatinine ratio (UPC), and systemic arterial blood pressure over time between and within treatment groups over an average of 22 months. RESULTS: No significant differences were detected in serum creatinine concentration, body weight, hematocrit, UPC, and systemic arterial pressure over time between or within treatment groups. CONCLUSIONS AND CLINICAL IMPORTANCE: This study failed to detect a significant difference in the progression of CKD in cats treated with Chinese rhubarb, benazepril, or both. Further study in specific subsets of cats with CKD is warranted.