No major effect of dopamine receptor 1/5 antagonist SCH-23390 on epileptic activity in the Tg2576 mouse model of amyloidosis.

The excitation-inhibition imbalance manifesting as epileptic activities in Alzheimer's disease is gaining more and more attention, and several potentially involved cellular and molecular pathways are currently under investigation. Based on in vitro studies, dopamine D1-type receptors in the anterior cingulate cortex and the hippocampus have been proposed to participate in this peculiar co-morbidity in mouse models of amyloidosis. Here, we tested the implication of dopaminergic transmission in vivo in the Tg2576 mouse model of Alzheimer's disease by monitoring epileptic activities via intracranial EEG before and after treatment with dopamine antagonists. Our results show that neither the D1-like dopamine receptor antagonist SCH23390 nor the D2-like dopamine receptor antagonist haloperidol reduces the frequency of epileptic activities. While requiring further investigation, our results indicate that on a systemic level, dopamine receptors are not significantly contributing to epilepsy observed in vivo in this mouse model of Alzheimer's disease.

Smoking Cessation Pharmacotherapy Efficacy in Comorbid Medical Populations: Secondary Analysis of the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) Randomized Clinical Trial.

INTRODUCTION: This study sought to compare medication efficacy in participants with medical comorbidities who smoke in the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) trial, a double-blind, triple-dummy, placebo- and active-controlled randomized controlled trial. AIMS AND METHODS: Participants were from the U.S. cohort of the main trial and randomized (1:1:1:1) to varenicline, bupropion, nicotine replacement therapy (NRT) patch, or placebo for 12 weeks with follow-up through week 24. Medical comorbidity data were derived from the baseline medical screening questionnaire and categorized into four subgroups (cardiac, respiratory, vascular, and diabetes). Within each comorbidity, generalized linear mixed models were used to assess the association between treatment and continuous abstinence rates from weeks 9-12 to 9-24. Similar models were used to test the effect of number of comorbidities on abstinence. RESULTS: Varenicline resulted in the highest week 12 abstinence rates across all pharmacotherapies and compared to placebo in all comorbidity subgroups: Cardiac (40.0% vs. 3.6%; odds ratios [OR] = 23.3 [5.1-107.1]), respiratory (24.7% vs. 12.8%; OR = 2.2 [1.3-3.8]), vascular (29.1% vs. 10.4%; OR = 3.6 [2.3-5.7]), and diabetes (30.9% vs. 8.3%; OR = 6.5 [2.3-19.0]). This was maintained at week 24 for those with cardiac (23.3% vs. 1.8%; OR = 21.7 [2.7-178.2]), vascular (18.9% vs. 7.1%; OR = 3.1 [1.8-5.3]), and diabetes (20.6% vs. 4.2%; OR = 8.4 [2.1-33.7]) comorbidities. Treatment contrasts within some comorbidity subgroups revealed superior efficacy of varenicline over other pharmacotherapies. All pharmacotherapies increased the odds of abstinence regardless of number of comorbidities. CONCLUSIONS: Varenicline is the most efficacious option for patients with manageable cardiac, respiratory, vascular, and diabetes conditions to quit smoking, supporting recent clinical practice guidelines that recommend varenicline as first-line pharmacotherapy. Bupropion and NRT demonstrated efficacy for some comorbidity subgroups. IMPLICATIONS: This secondary analysis of the EAGLES trial demonstrated that varenicline is the most efficacious option for patients with cardiac, respiratory, vascular, and diabetes diagnoses to quit smoking. This demonstration of varenicline efficacy among individuals with comorbid medical conditions supports recent clinical practice guidelines that recommend varenicline as a first-line pharmacotherapy for smoking cessation.

Lorcaserin: Worthy of Further Insights? Results from Recent Research.

Lorcaserin is a 3-benzazepine that binds 5-HT2C serotonin receptors in the hypothalamus, where it mediates lack of hunger and/or satiety, and in the ventral tegmental area, the site of origin of the mesolimbic and mesocortical dopaminergic projections, which mediate pleasure and reward. The drug has been first developed for the treatment of obesity, where it has shown efficacy, and subsequently trialed to counter substance use (mostly cocaine, cannabis, opioids, and nicotine) and craving, but showed inconsistent effects. Since 2020, the US Food and Drug Administration obtained that the drug was voluntarily withdrawn from the US market on the grounds that its long-term use was found to be associated with a greater incidence of some types of cancer. Provided it can show to be free from cancerogenic effects, ongoing research suggests that lorcaserin may have therapeutic potential for a variety of disorders and conditions beyond obesity. Since 5-HT2C receptors are involved in many diversified physiological functions (mood, feeding, reproductive behavior, neuronal processes related to impulsiveness, and modulating reward-related mechanisms) this drug has the potential to treat different central nervous system conditions, such as depression and schizophrenia.

Effects of door-to-tolvaptan time on short-term clinical outcome in patients with acute heart failure.

AIMS: We investigated the effects of door-to-tolvaptan (D2T) time on short-term urine volume and in-hospital clinical outcomes in patients with acute heart failure (AHF). METHODS AND RESULTS: Patients with AHF, treated with tolvaptan at two hospitals, were enrolled in this retrospective observational study. The D2T time was defined as the time elapsed from the arrival of a patient at a participating hospital to the first administration of tolvaptan. The group with the D2T time within 6 h was defined as the 'early group'. The primary outcome was 48-h urine volume. The secondary outcomes were in-hospital death, length of hospital stay, and worsening renal function (WRF) incidence. A restricted cubic spline model was used to evaluate the presence of a nonlinear association between the D2T time and 48-h urine volume and the odds ratio of WRF incidence. Our study included a total of 138 patients with AHF who were started on tolvaptan after hospitalization. The median D2T time was 5.3 h (interquartile range: 3.0-31.9 h). Seventy-four patients (53.6%) were classified to be in the early group. Baseline characteristics were similar in the two groups: mean age (85.4 ± 9.6 years vs. 84.5 ± 9.5 years; P = 0.59) and male sex (n = 22 [33.3%] vs. n = 29 [46%]; P = 0.16), except that patients in the early group had higher systolic blood pressure than those in the delayed group (138.2 ± 22.9 vs. 125.7 ± 21.7; P = 0.001). The initial tolvaptan dose in the delayed group was much lower than that in the early group (7.5 [7.5, 7.5] vs. 7.5 [5.6, 7.5] mg; P = 0.01). Total urine volume in 48 h did not differ in the early and delayed groups (4113 ± 1758 mL vs. 4201 ± 1893 mL; P = 0.80). The relationship between D2T time and total urine volume within 48 h increased slightly, with a peak at a D2T time of 15 h, and gradually decreased, thereafter. In-hospital death and the length of hospital stay did not differ significantly between the two groups (n = 1, 1.3% vs. n = 4, 6.3%; P = 0.18, and 5.0 [12.0, 30.0] vs. 22.0 [14.5, 30.0] days; P = 0.17, respectively). Notably, the restricted cubic spline model for the odds ratio of WRF incidence increased as the D2T time was delayed (P for effect<0.01). CONCLUSIONS: The shorter D2T time did not affect the short-term urine volume and in-hospital outcomes but reduced the risk of WRF incidence in patients with AHF.

Pelabresib (CPI-0610): An Exciting Novel Drug for the Treatment of Myelofibrosis.

PURPOSE OF REVIEW: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis, megakaryocyte atypia, and inflammatory cytokine overproduction, resulting in progressive cytopenias, splenomegaly, and high symptom burden. Current backbone of care includes JAK inhibitor (JAKi) therapy, which offers limited benefits and significant discontinuation rates. Targeting the epigenetic modifiers bromodomain and extra-terminal domain (BET) proteins is a novel approach for harnessing the expression of genes involved in critical oncogenic signalling pathways implicated in MF and other malignancies. Here, we review preclinical and clinical data on Pelabresib (CPI-0610), an investigational oral small-molecule potent BET-inhibitor being explored in MF. RECENT FINDINGS: BET inhibition has been shown to target multiple MF driver mechanisms in preclinical studies, with synergistic results using combination therapy with JAKi. Pelabresib is currently being evaluated in the phase II MANIFEST study as monotherapy and in combination with ruxolitinib for MF. Interim data showed favourable responses in symptoms and spleen volume after 24 weeks of treatment, with correlated improvements in bone marrow fibrosis and mutant allele fraction reduction. Based on these encouraging results, the Phase III MANIFEST-2 study was initiated. Pelabresib offers a much-needed innovative treatment approach for patients with MF, either as monotherapy or in combination with the current standard of care.

Efficacy and safety of combination behavioral activation for smoking cessation and varenicline for treating tobacco dependence among individuals with current or past major depressive disorder: A 2 × 2 factorial, randomized, placebo-controlled trial.

BACKGROUND AND AIMS: Treatment of depression-related psychological factors related to smoking behavior may improve rates of cessation among adults with major depressive disorder (MDD). This study measured the efficacy and safety of 12 weeks of behavioral activation for smoking cessation (BASC), varenicline and their combination. DESIGN, SETTING, PARTICIPANTS: This study used a randomized, placebo-controlled, 2 × 2 factorial design comparing BASC versus standard behavioral treatment (ST) and varenicline versus placebo, taking place in research clinics at two urban universities in the United States. Participants comprised 300 hundred adult smokers with current or past MDD. INTERVENTIONS: BASC integrated behavioral activation therapy and ST to increase engagement in rewarding activities by reducing avoidance, withdrawal and inactivity associated with depression. ST was based on the 2008 PHS Clinical Practice Guideline. Both treatments consisted of eight 45-min sessions delivered between weeks 1 and 12. Varenicline and placebo were administered for 12 weeks between weeks 2 and 14. MEASUREMENTS: Primary outcomes were bioverified intent-to-treat (ITT) 7-day point-prevalence abstinence at 27 weeks and adverse events (AEs). FINDINGS: No significant interaction was detected between behavioral treatment and pharmacotherapy at 27 weeks (χ2 (1) = 0.19, P = 0.67). BASC and ST did not differ (χ2 (1) = 0.43, P = 0.51). Significant differences in ITT abstinence rates (χ2 (1) = 4.84, P = 0.03) emerged among pharmacotherapy arms (16.2% for varenicline, 7.5% for placebo), with results favoring varenicline over placebo (rate ratio = 2.16, 95% confidence interval = 1.08, 4.30). All significant differences in AE rates after start of medication were higher for placebo than varenicline. CONCLUSION: A randomized trial in smokers with major depressive disorder found that varenicline improved smoking abstinence versus placebo at 27 weeks without elevating rates of adverse events. Behavioral activation for smoking cessation did not outperform standard behavioral treatment, with or without adjunctive varenicline therapy.

[Smoking, heated tobacco products, alcohol and diabetes mellitus (update 2023)]. / Rauchen, erhitzte Tabakprodukte, Alkohol und Diabetes mellitus (Update 2023).

Smoking and second-hand smoke strongly increase incidence of diabetes and probability for its complications. Smoking cessation can lead to weight gain and increased diabetes risk; however, it decreases cardiovascular and total mortality. A basal diagnostics (Fagerström Test, exhaled CO) is the basis for successful smoking cessation. Supporting medication include Varenicline, Nicotine Replacement Therapy and Bupropion. Socio-economic as well as psychological factors play an important role for smoking and smoking cessation. Heated tobacco products (like the E­cigarette) are no healthy alternative to cigarettes and are associated with increased morbidity and mortality.Moderate consumption of alcohol possibly decreases risk for diabetes and cardiovascular diseases. Selection bias and underreporting in studies maybe contribute to a too optimistic view. On the other hand, alcohol increases in a dose dependant fashion excess morbidity and disability adjusted life years, especially by cancer, liver diseases and infections.

Tolvaptan resistance is related with a short-term poor prognosis in patients with lung cancer and syndrome of inappropriate anti-diuresis.

Purpose: Tolvaptan (TVP), a vasopressin receptor antagonist, represents a therapeutic option in the syndrome of inappropriate anti-diuresis (SIAD). The aim of this study was to evaluate the effect of TVP to treat and solve hyponatremia in oncologic patients. Methods: 15 oncologic patients who developed SIAD have been enrolled. Patients receiving TVP belonged to group A, whereas group B was characterized by hyponatremic patients treated with hypertonic saline solutions and fluid restriction. Results: In group A, the correction of serum sodium was achieved after 3.7±2.8 days. In group B, the target levels were obtained more slowly, after 5.2±3.1 days (p: 0.01) than in group A. The hospital stay and incidence of re-hospitalization were higher in group B than in group A. In this latter, 37% of patients had hyponatremic relapses, notwithstanding the progressive increase of doses from 7.5 to 60 mg per day of TVP, revealing a complete lack of response to TVP. In these patients, a growth of tumor mass or new metastatic lesions has been revealed. Conclusion: TVP improved hyponatremia more efficiently and stably than hypertonic solutions and fluid restrictions. Positive consequences have been obtained about the rate of chemotherapeutical cycles concluded, hospital stay, rate of relapse of hyponatremia, and re-hospitalization. Our study also suggested potential prognostic information that could be deduced from TVP patients, in whom sudden and progressive hyponatremia occurred, despite TVP dosage increase. A re-staging of these patients to rule out tumor mass growth or new metastatic lesions is suggested.

Impact of urine cyclic AMP relative to plasma arginine vasopressin on response to tolvaptan in patients with chronic kidney disease and heart failure.

BACKGROUND: The clinical utility of tolvaptan in chronic kidney disease (CKD) patients with heart failure remains uncertain. The level of urine cyclic adenosine monophosphate (AMP) relative to plasma arginine vasopressin (AVP) indicates the residual function of the collecting ducts in response to AVP stimulation and might be a key to predicting response of tolvaptan. METHODS: CKD patients who were hospitalized to treat their congestive heart failure refractory to conventional loop diuretics were considered to receive tolvaptan and included in this prospective study. The impact of urine cyclic AMP/plasma AVP ratio for prediction of response to tolvaptan, which was defined as any increase in urine volume at day 7 from day 0, was investigated. RESULTS: A total of 30 patients (median 75 years old, 24 men, and median estimated glomerular filtration rate 14.4 mL/min/1.73 m2) were included. As compared to baseline, urine volume increased at day 7 in 17 responders, whereas urine volume decreased at day 7 in 13 non-responders. Baseline urine cyclic AMP/plasma AVP ratio distributed between 0.25 and 4.01 with median 1.90. The urine cyclic AMP/plasma AVP ratio was a significant predictor of response to tolvaptan, which was adjusted for 6 potential confounders with a cutoff of 1.24. CONCLUSIONS: Baseline urine cyclic AMP/plasma AVP ratio is an independent predictor of response to tolvaptan in advanced CKD patients with heart failure. CLINICAL TRIAL REGISTRATION: UMIN000022422.

Impact of Goreisan upon aquaporin-2-incorporated aquaresis system in patients with congestive heart failure.

We often encounter patients with congestive heart failure refractory to conventional diuretics therapy, and Kampo Goreisan is receiving great concern to mediate body water balance particularly for such a cohort. However, its detailed biological mechanism remains uncertain. We had two hospitalized patients with congestive heart failure receiving tolvaptan. Following the administration of Goreisan, both urine cyclic adenosine monophosphate concentration and urine aquaporin-2 concentration decreased, accompanied by incremental diluted urine volume. Although further studies are warranted to establish therapeutic strategy, Goreisan might be a promising therapeutic tool for those with congestive heart failure refractory to conventional diuretics including tolvaptan, via pleiotropic effects including suppression of aquaporin-incorporated water reabsorption system.

The 2022 Ferno Award Address: CrEATE, an Efficient Crossover Evaluation of Addiction Treatment Efficacy.

Dozens of drugs have been evaluated in recent decades for initial evidence of efficacy to aid smoking cessation (i.e. "early Phase 2" testing, according to U.S. FDA terminology), with the vast majority failing to show efficacy. Even small randomized clinical trials (RCTs), the most common early Phase 2 tests, are costly undertakings, made more unappealing by their high likelihood of failure. At the same time, another early Phase 2 approach, acute tests of drug effects on surrogate endpoints such as withdrawal or craving severity, are more practical but have little predictive clinical validity. Described here is an innovative procedure that optimally combines the validity of clinical trials with the practical advantages of surrogate endpoint studies to more efficiently determine whether or not a novel drug warrants continued clinical development. This CrEATE procedure, or Crossover Evaluation of Addiction Treatment Efficacy, does so by assessing short-term quit success in smokers highly motivated to quit when briefly treated with active drug versus placebo in a crossover design, so that quit efficacy from both conditions is compared within participants. The program to develop and evaluate CrEATE demonstrates its sensitivity to efficacy from all three FDA-approved first-line cessation medications (NRT, varenicline, bupropion), tested here as model drugs, as well as specificity in identifying lack of efficacy with a drug known to be ineffective for cessation (modafinil). CrEATE has subsequently been used to evaluate a few novel interventions, concluding they lack efficacy in increasing quit success. Future directions for the potential utility of CrEATE are provided. Implications: The ability of CrEATE to reach a Go/No Go decision more quickly and with far less cost lowers the risk of failure, meaning widespread use of the procedure should encourage the evaluation of more novel candidate drugs. With its greater efficiency, failed tests, unfortunately the most likely outcome in early Phase 2 studies, will cause less waste of resources. At the same time, CrEATE tests that indicate a novel treatment has efficacy will justify the substantial time and expense of moving forward to evaluate the drug in late Phase 2 RCTs.

Tolvaptan in portal hypertension: real life experience.

Tolvaptan (TVP) is a selective antagonist of vasopressin receptors, approved for the treatment of hyponatremia in SIADH, congestive heart failure (CHF) and cirrhosis. We retrospectively reviewed all cases where TVP was used in a tertiary hospital (January 2012- January 2017). Our aim was to study the use of TVP in real life practice in patients with portal hypertension (PHT) (past history of non-malignant ascites or variceal bleed).

Effect of Extending the Duration of Prequit Treatment With Varenicline on Smoking Abstinence: A Randomized Clinical Trial.

Importance: Even with varenicline, the leading monotherapy for tobacco dependence, smoking abstinence rates remain low. Preliminary evidence suggests that extending the duration of varenicline treatment before quitting may increase abstinence. Objective: To test the hypotheses that, compared with standard run-in varenicline treatment (1 week before quitting), extended run-in varenicline treatment (4 weeks before quitting) reduces smoking exposure before the target quit date (TQD) and enhances abstinence, particularly among women. Design, Setting, and Participants: This double-blind, randomized, placebo-controlled clinical trial enrolled participants from October 2, 2017, to December 9, 2020, at a single-site research clinic in Buffalo, New York. Of 1385 people screened, 320 adults reporting smoking 5 or more cigarettes per day (CPD) were randomized and followed up for 28 weeks. Data were analyzed from August 2021 to June 2022. Interventions: In the pre-TQD period (weeks 1-4), the extended run-in group received 4 weeks of varenicline; the standard run-in group received 3 weeks of placebo followed by 1 week of varenicline. Both groups received open-label varenicline during weeks 5 to 15 and brief quit counseling at 6 clinic visits. Main Outcomes and Measures: The primary outcome consisted of cotinine-verified (at end of treatment [EOT]) self-reported continuous abstinence from smoking (in CPD) during the last 4 weeks of treatment. Secondary outcomes included bioverified self-report of continuous abstinence at the 6-month follow-up and percentage of reduction in self-reported smoking rate during the prequit period (week 1 vs week 4). Results: A total of 320 participants were randomized, including 179 women (55.9%) and 141 men (44.1%), with a mean (SD) age of 53.7 (10.1) years. Continuous abstinence during the final 4 weeks of treatment (weeks 12-15; EOT) was not greater in the extended run-in group (64 of 163 [39.3%]) compared with the standard run-in group (57 of 157 [36.3%]; odds ratio [OR], 1.13 [95% CI, 0.72-1.78]), nor was the hypothesized group × sex interaction significant (OR, 0.52 [95% CI, 0.21-1.28]). Similar nonsignificant results were obtained for continuous abstinence at the 6-month follow-up. The mean (SE) decrease in self-reported smoking rate during the prequit period was greater in the extended run-in group (-38.8% [2.8%]) compared with the standard run-in group (-17.5% [2.7%]). Conclusions and Relevance: Among adult daily smokers, extending the duration of prequit varenicline treatment beyond the standard 1-week run-in period reduced prequit smoking exposure but, more importantly, did not significantly improve continuous abstinence rates. Trial Registration: ClinicalTrials.gov Identifier: NCT03262662.

Varenicline and related interventions on smoking cessation: A systematic review and network meta-analysis.

BACKGROUND: Based on randomized controlled trials, a network meta-analysis was conducted to compare treatment effects across varenicline and related smoking interventions. METHODS: English databases were screened for randomized controlled trials reporting the effect of varenicline as treatment for smoking. The risk of bias in included trials was assessed using the Cochrane Handbook tool. Stata 15.1 software was used to perform network meta-analysis, and the GRADE approach was used to assess the evidence credibility on the tobacco treatment effects of different interventions. RESULTS: Thirty-four studies involving 26,130 smokers were included in the network meta-analysis. Varenicline and 11 other interventions were reported, yielding 66 pairs of comparisons. Network meta-analysis showed that varenicline monotherapy or its combination with other interventions were superior in achieving smoking cessation compared to bupropion, nicotine replacement therapy, counselling, and placebo. Furthermore, compared to the varenicline, evident abstinence superiority was found in varenicline + bupropion (odds ratio = 1.49, 95% confidence interval [1.02, 2.18]). Finally, the surface under the cumulative ranking curve value indicated that varenicline + bupropion has the highest probability to become the best intervention. CONCLUSIONS: Varenicline monotherapy increased the odds of smoking cessation further than bupropion monotherapy, nicotine replacement therapy, counselling, and placebo, while varenicline combined with other interventions may even achieve a better abstinence effect. More credible evidence has been reported indicating that the combination of varenicline and bupropion is a superior treatment for smoking.

Effectiveness of Varenicline and Cytisine for Alcohol Use Reduction Among People With HIV and Substance Use: A Randomized Clinical Trial.

Importance: Cigarette smoking and risky alcohol consumption co-occur and are undertreated. Nicotine receptor partial agonists and nicotine replacement therapy (NRT) treat smoking but are unproven for alcohol, and clinical trials rarely include individuals with HIV, substance use, and mental health conditions. Objective: To compare the effects on drinking and smoking of nicotinic acetylcholine receptor partial agonists varenicline and cytisine with those of NRT. Design, Setting, and Participants: This 4-group randomized, double-blinded, placebo-controlled clinical trial was conducted from July 2017 to December 2020 in St Petersburg, Russia. Included participants were 400 individuals with HIV who engaged in risky drinking (≥5 prior-month heavy-drinking days [HDDs]) and daily smoking; they were followed up for 12 months after enrollment. Data were analyzed from May 2021 through June 2022. Interventions: Participants received alcohol and tobacco counseling, 1 active medication, and 1 placebo in 1 of 4 groups: active varenicline and placebo NRT (group 1), placebo varenicline and active NRT (group 2), active cytisine and placebo NRT (group 3), or placebo cytisine and active NRT (group 4). Main Outcomes and Measures: The primary outcome was number of prior-month HDDs at 3 months. Secondary outcomes included biochemically validated abstinence from alcohol at 3 months and smoking at 6 months. Results: Among 400 participants (263 [65.8%] men; mean [SD] age, 39 [6] years), 97 individuals (24.3%) used opioids and 156 individuals (39.1%) had depressive symptoms. These individuals had a mean (SD) CD4 count of 391 (257) cells/mm3, smoked a mean (SD) of 21 [8] cigarettes/d, and reported a mean (SD) of 9.3 (5.8) HDDs in the prior 30 days. At 3 months, the mean (SD) number of HDDs was decreased vs baseline across all groups (group 1: 2.0 [3.8] HDDs vs. 9.5 [6.1] HDDs; group 2: 2.1 [4.3] HDDs vs 9.3 [5.7] HDDs; group 3: 1.5 [3.3] HDDs vs 8.9 [5.0] HDDs; group 4: 2.4 [5.2] HDDs vs 9.6 [6.3] HDDs). There were no significant differences at 3 months between groups in mean (SD) HDDs, including group 1 vs 2 (incident rate ratio [IRR], 0.94; 95% CI, 0.49-1.79), 3 vs 4 (IRR, 0.60; 95% CI, 0.30-1.18), and 1 vs 3 (IRR, 1.29; 95% CI, 0.65-2.55). There were no significant differences at 6 months between groups in smoking abstinence, including group 1 vs 2 (15 of 100 individuals [15.0%] vs 17 of 99 individuals [17.2%]; odds ratio [OR],0.89; 95% CI, 0.38-2.08), 3 vs 4 (19 of 100 individuals [19.0%] vs 19 of 101 individuals [18.8%]; OR, 1.00; 95% CI, 0.46-2.17), and 1 vs 3 (OR, 0.79; 95% CI, 0.35-1.78). Post hoc analyses suggested lower mean (SD) HDDs (eg, at 3 months: 0.7 [1.8] HDDs vs 2.3 [4.6] HDDs) and higher alcohol abstinence (eg, at 3 months: 30 of 85 individuals [35.3%] vs 54 of 315 individuals [17.1%]) among those who quit vs continued smoking. Conclusions and Relevance: This study found that among individuals with HIV who engaged in risky drinking and smoking, varenicline and cytisine were not more efficacious than NRT to treat risky drinking and smoking but that behavior change rates were high in all groups. Trial Registration: ClinicalTrials.gov Identifier: NCT02797587.

Evaluating Treatment Mechanisms of Varenicline: Mediation by Affect and Craving.

INTRODUCTION: Negative reinforcement models posit that relapse to cigarette smoking is driven in part by changes in affect and craving during the quit attempt. Varenicline may aid cessation by attenuating these changes; however, this mediational pathway has not been formally evaluated in placebo-controlled trials. Thus, trajectories of negative affect (NA), positive affect (PA), and craving were tested as mediators of the effect of varenicline on smoking cessation. AIMS AND METHODS: Secondary data analysis was conducted on 828 adults assigned to either varenicline or placebo in a randomized controlled trial for smoking cessation (NCT01314001). Self-reported NA, PA, and craving were assessed 1-week pre-quit, on the target quit day (TQD), and 1 and 4 weeks post-TQD. RESULTS: Across time, NA peaked 1-week post-quit, PA did not change, and craving declined. Less steep rises in NA (indirect effect 95% CI: .01 to .30) and lower mean craving at 1-week post-quit (CI: .06 to .50) were mediators of the relationship between varenicline and higher cessation rates at the end of treatment. PA was associated with cessation but was not a significant mediator. CONCLUSIONS: These results partially support the hypothesis that varenicline improves smoking cessation rates by attenuating changes in specific psychological processes and supported NA and craving as plausible treatment mechanisms of varenicline. IMPLICATIONS: The present research provides the first evidence from a placebo-controlled randomized clinical trial that varenicline's efficacy is due, in part, to post-quit attenuation of NA and craving. Reducing NA across the quit attempt and craving early into the attempt may be important treatment mechanisms for effective interventions. Furthermore, post-quit NA, PA, and craving were all associated with relapse and represent treatment targets for future intervention development.

[A case of SIADH due to pancreatic cancer was improved by tolvaptan].

We report the case of a 68-year-old man, who presented in emergency care with inarticulate speech. The patient was diagnosed with syndrome of inappropriate antidiuretic hormone (SIADH) associated with pancreatic cancer. All diagnostic criteria for SIADH were met, and cancer of the pancreatic tail was identified by computed tomography. Standard treatment for SIADH includes water restriction, oral NaCl, continuous intravenous infusion of 3% NaCl, and intravenous infusion of furosemide. However, these treatments have varying effectiveness and are difficult for both patients and medical staff. Furthermore, unless treatment of the underlying disease is successful, continued hospitalization is needed and the patient's quality of life is significantly impaired. In this case, hyponatremia improved with this standard treatment, but ascites and edema developed. We treated the patient with tolvaptan due to decreased cardiac function, and symptoms improved rapidly. Although surgery and chemotherapy could not be performed for pancreatic cancer, the SIADH was treated for 7 months without relapse. In summary, a case of SIADH complicated by pancreatic cancer was difficult to control with standard treatment, but responded rapidly to tolvaptan, and outpatient treatment could be continued for a long period. Tolvaptan is useful for the treatment of SIADH associated with cancer.

Lorcaserin for Dravet Syndrome: A Potential Advance Over Fenfluramine?

Lorcaserin, a selective serotonin 5-HT2C receptor agonist, was developed as an appetite suppressant with the rationale of minimizing the risk of cardiovascular toxicity associated with non-selective serotoninergic agents such as fenfluramine. Eight years after FDA approval, however, it was withdrawn from the market, when a large safety study suggested a potential cancer risk. Following in the fenfluramine footsteps and utilizing the repurposing approach coupled with the regulatory orphan drug designation, lorcaserin is currently in clinical development for the treatment of epilepsy. This potential novel indication builds on the evidence that 5-HT2C receptor stimulation can protect against seizures, and accounts at least in part for fenfluramine's antiseizure effects in Dravet syndrome models. In animal models, lorcaserin shows a narrower range of antiseizure activity than fenfluramine. In particular, lorcaserin is inactive in classical acute seizure tests such as maximal electroshock and subcutaneous pentylenetetrazole in mice and rats, and the 6-Hz stimulation model in mice. However, it is active in the GAERS absence seizure model, and in mutant zebrafish models of Dravet syndrome. Preliminary uncontrolled studies in patients with Dravet syndrome have yielded promising results, and a phase III, double-blind, placebo-controlled, parallel group trial is currently ongoing to assess its efficacy and safety in children and adults with Dravet syndrome.

A Phase Ib Dose Escalation Trial of RO4929097 (a γ-secretase inhibitor) in Combination with Exemestane in Patients with ER + Metastatic Breast Cancer (MBC).

PRECLINICAL STUDIES: have demonstrated a complex cross-talk between Notch and estrogen signaling in ERα-positive breast cancer. Gamma-secretase inhibitors (GSIs) are investigational agents that block the cleavage and activation of Notch receptors. In animal models of endocrine-resistant breast cancer, combinations of tamoxifen and GSIs produce additive or synergistic efficacy, while decreasing the intestinal toxicity of GSIs. However, results of a clinical trial of a GSI-endocrine therapy combination in the metastatic setting have not been published to date, nor had the safety of such combinations been investigated with longer term treatment. We conducted a phase 1b dose escalation trial (NCT01149356) of GSI RO4929097 with exemestane in patients with ERα+, metastatic breast cancer (MBC) STUDY OBJECTIVES: To determine the safety, tolerability and maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of RO4929097 when administered in combination with exemestane in patients with estrogen receptor positive metastatic breast cancer RESULTS: We enrolled 15 patients with MBC. Of 14 evaluable patients, one had a partial response, 6 had stable disease and 7 progressive disease. Twenty % of patients had stable disease for ≥ 6 months. Common toxicities included nausea (73.3%), anorexia (60%), hyperglycemia (53.3%), hypophosphatemia (46.7%), fatigue (66.7%) and cough (33.0%). Grade 3 toxicities were uncommon, and included hypophosphatemia (13%) and rash (6.3%). Rash was the only DLT observed at 140 mg/d. Results suggest a possible recommended phase 2 dose of 90 mg/d. Ten patients with evaluable archival tissue showed expression of PKCα, which correlated with expression of Notch4. Mammospheres from a PKCα-expressing, endocrine-resistant T47D cell line were inhibited by a GSI-fulvestrant combination CONCLUSIONS: Our data indicate that combinations including endocrine therapy and Notch inhibitors deserve further investigation in endocrine-resistant ERα-positive breast cancer.