Dasotraline in adults with attention deficit hyperactivity disorder: a placebo-controlled, fixed-dose trial.

In a previous study, dasotraline demonstrated efficacy at a dose of 8 mg/day in adults with attention deficit hyperactivity disorder (ADHD). The aim of the current study was to evaluate the efficacy and safety of dasotraline in doses of 4 and 6 mg/day. Adults meeting Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria for ADHD were randomized to 8 weeks of double-blind, once-daily, fixed-dose treatment with dasotraline 4 mg/day, 6 mg/day, or placebo. The primary efficacy endpoint was changed in the ADHD Rating Scale, Version IV (ADHD RS-IV) total score. Secondary efficacy endpoints included the Clinical Global Impression, Severity (CGI-S) Scale. Least squares mean reduction at week 8 in the ADHD RS-IV HV total score was not significantly greater (vs. placebo) in the dasotraline 4 mg/day group (-15.0 vs. -13.9; n.s.; or in the dasotraline 6 mg/day group (-16.5 vs. -13.9; P = 0.074; Hochberg correction). Treatment with dasotraline 6 mg/day was significant at week 8 (uncorrected) on the ADHD RS-IV total score (P = 0.037) and the CGI-S score (P = 0.011). Treatment with the 4 mg/day dose of dasotraline was NS. Treatment with dasotraline was generally well tolerated. The results provide additional evidence that supports the potential efficacy of dasotraline, in doses of 6 mg/day, in adults with ADHD.

Efficacy and safety of dasotraline in adults with binge-eating disorder: a randomized, placebo-controlled, fixed-dose clinical trial.

OBJECTIVE: The aim of this fixed-dose study was to evaluate the efficacy and safety of dasotraline in the treatment of patients with binge-eating disorder (BED). METHODS: Patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for BED were randomized to 12 weeks of double-blind treatment with fixed doses of dasotraline (4 and 6 mg/d), or placebo. The primary efficacy endpoint was change in number of binge-eating (BE) days per week at week 12. Secondary efficacy endpoints included week 12 change on the BE CGI-Severity Scale (BE-CGI-S) and the Yale-Brown Obsessive-Compulsive Scale Modified for BE (YBOCS-BE). RESULTS: At week 12, treatment with dasotraline was associated with significant improvement in number of BE days per week on the dose of 6 mg/d (N = 162) vs placebo (N = 162; -3.47 vs -2.92; P = .0045), but not 4 mg/d (N = 161; -3.21). Improvement vs placebo was observed for dasotraline 6 and 4 mg/d, respectively, on the BE-CGI-S (effect size [ES]: 0.37 and 0.27) and on the YBOCS-BE total score (ES: 0.43 and 0.29). The most common adverse events on dasotraline were insomnia, dry mouth, headache, decreased appetite, nausea, and anxiety. Changes in blood pressure and pulse were minimal. CONCLUSION: Treatment with dasotraline 6 mg/d (but not 4 mg/d) was associated with significantly greater reduction in BE days per week. Both doses of dasotraline were generally safe and well-tolerated and resulted in global improvement on the BE-CGI-S, as well as improvement in BE related obsessional thoughts and compulsive behaviors on the YBOCS-BE. These results confirm the findings of a previous flexible dose study.

Efficacy and Safety of Dasotraline in Adults With Binge-Eating Disorder: A Randomized, Placebo-Controlled, Flexible-Dose Clinical Trial.

OBJECTIVE: Binge-eating disorder (BED) is the most prevalent eating disorder; however, few evidence-based treatments are available. The aim of this study was to evaluate the efficacy and safety of dasotraline, a novel dopamine and norepinephrine reuptake inhibitor, in adults with BED. METHODS: Patients with a DSM-5 diagnosis of BED (intent-to-treat sample, N = 315) were randomized to 12 weeks of double-blind treatment with once-daily, flexible doses (4, 6, or 8 mg/d) of dasotraline or placebo. Primary endpoint was change in diary-based assessment of number of binge-eating days per week at week 12. Key secondary endpoints included changes from baseline in Clinical Global Impressions-Severity of Illness scale (CGI-S) and Yale-Brown Obsessive Compulsive Scale Modified for Binge-Eating (YBOCS-BE) and percentage of subjects with cessation of binge eating in the final 4 weeks. RESULTS: Treatment with dasotraline was associated with a significantly greater reduction in binge-eating days per week at study endpoint (vs placebo; least squares mean [SE] difference score, -0.99 [0.17]; P < .0001; effect size [ES], 0.74). Significant endpoint improvement was observed for the 3 key secondary measures, CGI-S (P < .0001; ES, 0.95), YBOCS-BE (P < .0001; ES, 0.96), and 4-week cessation of binge eating (46.5% vs 20.6%; P < .0001). The most common adverse events in the dasotraline vs placebo groups were insomnia (44.6% vs 8.1%), dry mouth (27.4% vs 5.0%), decreased appetite (19.7% vs 6.9%), and anxiety (17.8% vs 2.5%). Discontinuation due to adverse events occurred in 11.3% of patients on dasotraline vs 2.5% on placebo. CONCLUSIONS: The results of this placebo-controlled, double-blind study found dasotraline to be an efficacious, safe, and generally well-tolerated treatment for BED. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02564588.

Dasotraline in Children with Attention-Deficit/Hyperactivity Disorder: A Six-Week, Placebo-Controlled, Fixed-Dose Trial.

OBJECTIVE: Dasotraline is a potent inhibitor of presynaptic dopamine and norepinephrine reuptake with a pharmacokinetic profile characterized by slow absorption and a long elimination half-life. The aim of this study was to evaluate the efficacy and safety of dasotraline in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Children aged 6-12 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of ADHD were randomized to 6 weeks of double-blind once-daily treatment with dasotraline (2 or 4 mg) or placebo. The primary efficacy endpoint was change from baseline in the ADHD Rating Scale Version IV-Home Version (ADHD RS-IV HV) total score at week 6. RESULTS: A total of 342 patients were randomized to dasotraline or placebo (mean age 9.1 years, 66.7% male). Treatment with dasotraline was associated with significant improvement at study endpoint in the ADHD RS-IV HV total score for the 4 mg/day dose versus placebo (-17.5 vs. -11.4; p < 0.001; effect size [ES], 0.48), but not for the 2 mg/day dose (-11.8 vs. -11.4; ns; ES, 0.03). A regression analysis confirmed a significant linear dose-response relationship for dasotraline. Significant improvement for dasotraline 4 mg/day dose versus placebo was also observed across the majority of secondary efficacy endpoints, including the Clinical Global Impression (CGI)-Severity score, the Conners Parent Rating Scale-Revised scale (CPRS-R) ADHD index score, and subscale measures of hyperactivity and inattentiveness. Discontinuation rates due to adverse events (AEs) were higher in the dasotraline 4 mg/day group (12.2%) compared with the 2 mg/day group (6.3%) and placebo (1.7%). The most frequent AEs associated with dasotraline were insomnia, decreased appetite, decreased weight, and irritability. Psychosis-related symptoms were reported as AEs by 7/219 patients treated with dasotraline in this study. There were no serious AEs or clinically meaningful changes in blood pressure or heart rate on dasotraline. CONCLUSION: In this placebo-controlled study, treatment with dasotraline 4 mg/day significantly improved ADHD symptoms and behaviors, including attention and hyperactivity, in children aged 6-12 years. The most frequently reported AEs observed on dasotraline included insomnia, decreased appetite, decreased weight, and irritability.

The compound 2-(naphthalene-2-thio)-5,8-dimethoxy-1,4-naphthoquinone induces apoptosis via reactive oxygen species-regulated mitogen-activated protein kinase, protein kinase B, and signal transducer and activator of transcription 3 signaling in human gastric cancer cells.

Hit, Lead & Candidate Discovery It is reported that 1,4-naphthoquinones and their derivatives have potent antitumor activity in various cancers, although their clinical application is limited by observed side effects. To improve the therapeutic efficacy of naphthoquinones in the treatment of cancer and to reduce side effects, we synthesized a novel naphthoquinone derivative, 2-(naphthalene-2-thio)-5,8-dimethoxy-1,4-naphthoquinone (NTDMNQ). In this study, we explored the effects of NTDMNQ on apoptosis in gastric cancer cells with a focus on reactive oxygen species (ROS) production. Our results demonstrated that NTDMNQ exhibited the cytotoxic effects on gastric cancer cells in a dose-dependent manner. NTDMNQ significantly induced mitochondrial-related apoptosis in AGS cells and increased the accumulation of ROS. However, pre-treatment with N-acetyl-L-cysteine (NAC), an ROS scavenger, inhibited the NTDMNQ-induced apoptosis. In addition, NTDMNQ increased the phosphorylation of p38 kinase and c-Jun N-terminal kinase (JNK) and decreased the phosphorylation of extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and Signal Transducer and Activator of Transcription 3 (STAT3); these effects were blocked by mitogen-activated protein kinase (MAPK) inhibitor and NAC. Taken together, the present findings indicate that NTDMNQ-induced gastric cancer cell apoptosis via ROS-mediated regulation of the MAPK, Akt, and STAT3 signaling pathways. Therefore, NTDMNQ may be a potential treatment for gastric cancer as well as other tumor types.

Randomized, Double-Blind, Placebo-Controlled Studies to Assess Safety and Prophylactic Efficacy of Naphthoquine-Azithromycin Combination for Malaria Prophylaxis in Southeast Asia.

New prophylactic drugs against malaria infections are urgently needed. We conducted randomized, double-blind, placebo-controlled, phase 2 trials of a new antimalarial drug combination, naphthoquine-azithromycin (NQAZ), to determine its safety and protective efficacy in a low-endemicity area of Southeast Asia. In the first trial, 127 healthy volunteers were randomized to receive two single doses of either 400 mg of NQAZ (200 mg of each drug), 800 mg of NQAZ (400 mg of each drug), or placebo on day 0 and day 30. Weekly follow-ups were performed for 2 months, and physical and clinical laboratory exams were done during the second and eighth week. Both drug regimens were well tolerated, without any serious adverse events. Four adverse events (transient and slight elevations of serum transaminase concentrations) were found only in the two drug-treated groups and thus might be drug-related. In the second trial, 353 volunteer villagers were randomized into the same three groups as in the first trial, and malaria infections were followed for a month. For the intention-to-treat analysis, both regimens offered greater than 90% prophylactic efficacies against all malaria infections. When the analysis was done according to parasite species, 400 mg and 800 mg NQAZ provided 81.63 and 90.59% prophylactic efficacies, respectively, against Plasmodium falciparum infections, whereas both offered 100% prophylactic efficacy against Plasmodium vivax and Plasmodium ovale These trials showed that NQAZ had a good safety profile, and monthly single doses of 400 mg or 800 mg for adults offered excellent prophylaxis against malaria infections, especially the two relapsing species.

Assessment of human abuse potential of dasotraline compared to methylphenidate and placebo in recreational stimulant users.

AIMS: The aim of this study was to evaluate the abuse potential of dasotraline, a novel dopamine and norepinephrine reuptake inhibitor with slow absorption (tmax, 10-12h) and elimination (t1/2=47-77 h) that is in development for the treatment of attention deficit hyperactivity disorder (ADHD). METHODS: Recreational stimulant users (N=48) who had specific experience with cocaine, and who were able to distinguish methylphenidate (60 mg) versus placebo in a qualification session, were randomized, in a 6-period, double-blind, crossover design, to receive single doses of dasotraline 8 mg, 16 mg, and 36 mg, methylphenidate (MPH) 40 mg and 80 mg, and placebo. The primary endpoint was the Drug Liking Visual Analog Scale (VAS) score at the time of peak effect (Emax). RESULTS: There were no significant differences between the 3 doses of dasotraline and placebo on the drug liking VAS at Emax, and on most secondary endpoints. Both doses of MPH had significantly higher VAS-drug liking scores at Emax relative to both placebo (P<0.001 for all comparisons) and dasotraline 8 mg (P<0.001), 16 mg (P<0.001) and 36 mg (P<0.01). The increase in heart rate for MPH and dasotraline 36 mg showed a time-course that closely matched subject-rated measures such as Any Effects VAS. CONCLUSIONS: In this study, dasotraline was found to have low potential for abuse, which may be, in part, related to its established pharmacokinetics (PK) profile, which is characterized by slow absorption and gradual elimination.

Natural and synthetic modulators of SK (K(ca)2) potassium channels inhibit magnesium-dependent activity of the kinase-coupled cation channel TRPM7.

BACKGROUND AND PURPOSE: Transient receptor potential cation channel subfamily M member 7 (TRPM7) is a bifunctional protein comprising a TRP ion channel segment linked to an α-type protein kinase domain. TRPM7 is essential for proliferation and cell growth. Up-regulation of TRPM7 function is involved in anoxic neuronal death, cardiac fibrosis and tumour cell proliferation. The goal of this work was to identify non-toxic inhibitors of the TRPM7 channel and to assess the effect of blocking endogenous TRPM7 currents on the phenotype of living cells. EXPERIMENTAL APPROACH: We developed an aequorin bioluminescence-based assay of TRPM7 channel activity and performed a hypothesis-driven screen for inhibitors of the channel. The candidates identified were further assessed electrophysiologically and in cell biological experiments. KEY RESULTS: TRPM7 currents were inhibited by modulators of small conductance Ca²âº -activated K⁺ channels (K(Ca)2.1-2.3; SK) channels, including the antimalarial plant alkaloid quinine, CyPPA, dequalinium, NS8593, SKA31 and UCL 1684. The most potent compound NS8593 (IC50 1.6 µM) specifically targeted TRPM7 as compared with other TRP channels, interfered with Mg²âº -dependent regulation of TRPM7 channel and inhibited the motility of cultured cells. NS8593 exhibited full and reversible block of native TRPM7-like currents in HEK 293 cells, freshly isolated smooth muscle cells, primary podocytes and ventricular myocytes. CONCLUSIONS AND IMPLICATIONS: This study reveals a tight overlap in the pharmacological profiles of TRPM7 and K(Ca)2.1-2.3 channels. NS8593 acts as a negative gating modulator of TRPM7 and is well-suited to study functional features and cellular roles of endogenous TRPM7.

Biological activity resulting from exposure to aquatic environmental genotoxic pollutants in northern Egypt.

We estimated pollution in Lake Edku and the Mediterranean Sea, El-Maadiya Region, with 3 aromatic amines (1-naphthylamine, 2-naphthylamine and benzidine) in the muscle tissue of fish. There were marked seasonal variations in the aromatic amine levels. We also determined oxidative stress (blood glutathione, and catalase activity) and genotoxic effects (chromosomal aberrations and urinary metabolites) in fishermen from each area. The fishermen suffered from oxidative stress and had high levels of the urinary metabolite sulfanilamide [mean (microg/mg creatinine): Lake Edku 20.7, Mediterranean 14.5, controls 5.3]. Frequencies for total chromosomal aberrations were significantly raised in the peripheral blood lymphocytes of fishermen in both areas [frequency (per 100 metaphases): Mediterranean 67, Lake Edku 45, controls 14].

Contact allergy to 2,5-dimercapto-1,3,4-thiadiazole and phenyl-alpha-naphtylamine, allergens in industrial greases and lubricant oils--contact allergy to water-insoluble greases is uncommon but needs to be considered in some workers.

BACKGROUND: Industrial lubricants are usually made of petroleum and contain no water. Industrial greases and neat oils (insoluble metalworking oils) cause contact allergy relatively seldom, and reported allergies to the components of engine oils, such as hydraulic oils, are extremely scarce. OBJECTIVE: The aim was to describe patients with contact allergy to the components of industrial lubricants. RESULTS: We describe 2 patients with allergic reactions to 2,5-dimercapto-1,3,4-thiadiazole. Their allergies derived from guide-way oil and grease. Guide-way oils are lubricants for metalworking machines. Machinists may have continuous skin contact to these oils, as the oils are leaked to the circulating metalworking fluid system and form the so-called 'tramp oil'. We also report a new case with allergy to phenyl-alpha-naphtylamine in grease. CONCLUSION: 2,5-Dimercapto-1,3,4-thiadiazole is an aromatic compound used in oils and greases. It has previously caused contact allergy to workers who have handled the pure chemical, but to our knowledge, there are no previous reports of contact allergy from products containing the chemical in a relatively low concentration. 1 of our 2 cases had been sensitized from grease and the other from a guide-way oil. The latter case shows that machinists may become sensitized to lubricants that leak to the metalworking fluid system.

Occupational contact dermatitis from a grease.

BACKGROUND: Contact allergy to grease is rare and often not even suspected. We investigated such a case in which the detected allergen was the stabilizer in the grease, which is rarely found as an allergen. OBJECTIVE: Thin-layer chromatography (TLC) was used in a novel way and helped detect the allergen. METHODS: Patch testing with our standard series, a metal-working series, the different substances individually, the grease in serial dilution and extracts of personal objects, the TLC plate. Gas chromatography-mass spectrometry was also used. RESULTS: Test results indicated contact allergy to grease containing N-phenyl-1-naphthylamine and contact allergy to Disperse Orange 1, N-cyclohexyl-N'-phenyl-4-phenylenediamine, N-isopropyl-N'-phenyl-4-phenylenediamine, and N,N'-diphenyl-4-phenylenediamine. CONCLUSION: N-phenyl-1-naphthylamine was the main cause of the patient's dermatitis. This case report underlines the importance of testing the patient's own products and also underlines the benefit of using TLC strips for patch testing and of visiting the workplace to get correct information about exposure conditions.

The micronucleus assay in human exfoliated urothelial cells: application in a genotoxicity study of workers exposed to a mineral jelly containing sodium nitrite and N-phenyl-1-naphthylamine.

Exposure to certain chemical agents in occupational settings has been identified as carcinogenic to the human bladder. Micronucleus (MN) analysis in exfoliated urothelial cells is an interesting method for biomonitoring genetic damage in human populations. However, few studies have been performed in an occupational context. The aim of this study was to examine whether the occupational use of a mineral jelly induced a genotoxic risk for workers employed at a single factory producing bearings using the MN test on exfoliated urothelial cells. The prevalence of micronucleated exfoliated urothelial cells (MNC) was determined in 35 female workers with dermal exposure to the jelly and 41 female controls. The mean percentage of MNC (expressed as percent cells with MN per 1000 cells scored) observed in the exposed worker group was 0.46 +/- 0.11% (range 0-2.8) and in the control group 0.14 +/- 0.03% (range 0-0.8). There is a significant job effect (P = 0.0018, MANCOVA) on the prevalence of MNC, whereas age and smoking habit had no significant effect (P = 0.90 and 0.91, respectively). There is no interaction between job and smoking habit (P = 0.4421). Exposure to the mineral jelly appeared to be the main factor inducing the increased prevalence of MNC. This may be due to the presence of mutagens/carcinogens in the jelly: an aromatic amine, N-phenyl-1-naphthylamine (CAS no. 90-30-2), which is carcinogenic in mice, or sodium nitrite (CAS no. 7632-00-0), which is genotoxic in human cell systems. In conclusion, these results suggest that use of the mineral jelly could present a genotoxic risk for workers. We think that the MN assay on exfoliated cells could be valuable for biological monitoring purposes in occupational contexts as a marker of significant exposure to bladder mutagenic/carcinogenic agents.

Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial.

BACKGROUND: Recent reports describe discontinuation-emergent adverse events upon cessation of selective serotonin reuptake inhibitors including dizziness, insomnia, nervousness, nausea, and agitation. We hypothesized that interruption of fluoxetine treatment would be associated with fewer discontinuation-emergent adverse events than interruption of sertraline or paroxetine treatment, based on fluoxetine's longer half-life. METHODS: In this 4-week study, 242 patients with remitted depression receiving maintenance therapy with open-label fluoxetine, sertraline, or paroxetine for 4-24 months had their maintenance therapy interrupted with double-blind placebo substitution for 5-8 days. The Symptom Questionnaire (SQ), the Discontinuation-Emergent Signs and Symptoms checklist, the 28-item Hamilton Depression Rating Scale, and the Montgomery-Asberg Depression Rating Scale were used to assess somatic distress and stability of antidepressant response. RESULTS: Two hundred twenty patients (91%) completed the study. Following interruption of therapy, fluoxetine-treated patients experienced fewer discontinuation-emergent events than either sertraline-treated or paroxetine-treated patients (p < .001). The mean SQ somatic symptom scale score in fluoxetine-treated patients was significantly lower than that in sertraline-treated and paroxetine-treated patients (p < .001). Fluoxetine-treated patients also experienced less reemergence of depressive symptoms than sertraline-treated or paroxetine-treated patients (p < .001). CONCLUSIONS: Abrupt interruption of antidepressant therapy for 5-8 days was associated with the emergence of new somatic and psychological symptoms in patients treated with paroxetine and to a lesser degree sertraline, with few symptoms seen with fluoxetine.

Sertraline induced parkinsonism. A case report and an in-vivo study of the effect of sertraline on dopamine metabolism.

We report a patient with a parkinsonian syndrome induced by sertraline (Zoloft), an SSRI antidepressant, whose symptoms resolved after the drug was discontinued. This case prompted us to investigate the effect of sertraline on dopamine metabolism in animals. Sertraline (30 mg/kg, i.p.) or placebo (vehicle) was administered to two groups of six normal, anesthetized rats and using cerebral microdyalisis extracellular striatal levels of dopamine, the dopamine metabolites (HVA and DOPAC), as well as the serotonin metabolite 5-HIIA were monitored. In animals pre-treated with sertraline, DOPAC, HVA, and 5-HIAA levels were significantly decreased compared to control animals (p < 0.01). These data indicate that sertraline has an effect on dopamine metabolism, which may alter function in the striatum and induce a parkinsonian syndrome.

Methodologies and outcomes from the sertraline multicenter flexible-dose trials.

This article summarizes the results of a combined analysis from two identical multicenter clinical trials that investigated the efficacy and safety of sertraline versus placebo for treating panic disorder. Patients with panic disorder who were treated with sertraline had a statistically significant reduction in the mean number of panic attacks per week (the primary efficacy measure) as compared with placebo (4.8 vs. 2.5, p < .001). Sertraline-treated patients also showed greater improvement that was statistically significant on several ratings of panic disorder symptomatology and functioning. The design characteristics, clinical rating measures, and outcome measures in these trials included most of the features deemed essential by Shear and Maser (1994) in their summary of the NIMH Consensus Conference for the development of standardized assessments for panic disorder. This suggests that the NIMH Consensus Conference played a key role in developing successful multicenter pharmacological treatment studies, such as this one that ultimately demonstrated that sertraline was an effective treatment for panic disorder.

Lamotrigine toxicity secondary to sertraline.

Blood level monitoring helps to determine the therapeutic and toxic ranges for anticonvulsants and antidepressants. We investigated initial drug-drug interactions between lamotrigine and sertraline. We report on case histories of two epileptic patients who were initially on lamotrigine and to whom sertraline was added to control psychiatric features. In case 1, a total daily dose of 25 mg sertraline, with nondetectable sertraline and desmethylsertraline blood levels, resulted in a doubling of the lamotrigine blood level with symptoms of toxicity. In case 2, a 25 mg reduction in the total daily dose of sertraline resulted in halving of the lamotrigine blood level even though the lamotrigine dosage was increased by 33%. This shows that sertraline has potent interactions with lamotrigine metabolism. The authors hypothesize that inhibition of glucuronidation is responsible. Clinicians are advised to observe for symptoms of toxicity and to do serial blood levels to monitor this interaction.