ABSTRACT
Integrating CYP2D6 genotyping and therapeutic drug monitoring (TDM) is crucial for guiding individualized atomoxetine therapy in children with attention-deficit/hyperactivity disorder (ADHD). The aim of this retrospective study was (1) to investigate the link between the efficacy and tolerability of atomoxetine in children with ADHD and plasma atomoxetine concentrations based on their CYP2D6 genotypes; (2) to offer TDM reference range recommendations for atomoxetine based on the CYP2D6 genotypes of children receiving different dosage regimens. This retrospective study covered children and adolescents with ADHD between the ages of 6 and <18, who visited the psychological and behavioral clinic of Children's Hospital of Nanjing Medical University from June 1, 2021, to January 31, 2023. The demographic information and laboratory examination data, including CYP2D6 genotype tests and routine TDM of atomoxetine were obtained from the hospital information system. We used univariate analysis, Mann-Whitney U nonparametric test, Kruskal-Wallis test, and the receiver operating characteristic (ROC) curve to investigate outcomes of interest. 515 plasma atomoxetine concentrations of 385 children (325 boys and 60 girls) with ADHD between 6 and 16 years of age were included for statistical analysis in this study. Based on genotyping results, >60% of enrolled children belonged to the CYP2D6 extensive metabolizer (EM), while <40% fell into the intermediate metabolizer (IM). CYP2D6 IMs exhibited higher dose-corrected plasma atomoxetine concentrations by 1.4-2.2 folds than those CYP2D6 EMs. Moreover, CYP2D6 IMs exhibited a higher response rate compare to EMs (93.55% vs 85.71%, P = 0.0132), with higher peak plasma atomoxetine concentrations by 1.67 times than those of EMs. Further ROC analysis revealed that individuals under once daily in the morning (q.m.) dosing regimen exhibited a more effective response to atomoxetine when their levels were ≥ 268 ng/mL (AUC = 0.710, P < 0.001). In addition, CYP2D6 IMs receiving q.m. dosing of atomoxetine were more likely to experience adverse reactions in the central nervous system and gastrointestinal system when plasma atomoxetine concentrations reach 465 and 509 ng/mL, respectively. The findings in this study provided promising treatment strategy for Chinese children with ADHD based on their CYP2D6 genotypes and plasma atomoxetine concentration monitoring. A peak plasma atomoxetine concentration higher than 268 ng/mL might be requisite for q.m. dosing. Assuredly, to validate and reinforce these initial findings, it is necessary to collect further data in controlled studies with a larger sample size.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Adolescent , Child , Female , Humans , Male , Adrenergic Uptake Inhibitors/adverse effects , Atomoxetine Hydrochloride/adverse effects , Attention Deficit Disorder with Hyperactivity/drug therapy , Attention Deficit Disorder with Hyperactivity/genetics , Cytochrome P-450 CYP2D6/genetics , Drug Monitoring , Genotype , Propylamines/adverse effects , Retrospective Studies , Infant , Child, PreschoolABSTRACT
INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder with symptoms that may persist in up to 90% of adults diagnosed during childhood and continue to cause significant impairment throughout the lifespan. In the United States (US), amphetamine and methylphenidate formulations have been available to treat ADHD for several decades. Only one nonstimulant, atomoxetine, was available for the treatment of ADHD in adults until recently. In April 2022, a second nonstimulant, viloxazine extended-release (VLX-ER), became available in the US for the treatment of adult ADHD. Efficacy was previously established in placebo-controlled trials in children and adolescents. AREAS COVERED: VLX-ER is a norepinephrine reuptake inhibitor with serotonin activity. The efficacy in adults, adverse event profile, pharmacokinetics, drug-drug interactions, and metabolism of VLX-ER are reviewed. EXPERT OPINION: Despite the availability of effective pharmacological treatments for ADHD, many patients discontinue treatment in less than 1 year. Stimulants are effective in more than 80% of patients; however, some may have difficulty tolerating them. Although there were no head-to-head studies, the effect size of VLX-ER in an adult efficacy trial was lower than has been shown for stimulants. Nevertheless, the approval of VLX-ER adds another effective ADHD treatment option for adults.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Central Nervous System Stimulants , Methylphenidate , Viloxazine , Adolescent , Child , Humans , Adult , United States , Attention Deficit Disorder with Hyperactivity/drug therapy , Viloxazine/therapeutic use , Delayed-Action Preparations/therapeutic use , Propylamines/adverse effects , Atomoxetine Hydrochloride/therapeutic use , Methylphenidate/therapeutic use , Central Nervous System Stimulants/adverse effects , Amphetamine/therapeutic use , AttentionABSTRACT
BACKGROUND AND OBJECTIVE: In our outpatient pediatric and adult psychiatry centers, we reserve psychostimulants for predominantly inattentive attention deficit hyperactivity disorder (ADHD) due to the potential for appetite and growth suppression, insomnia, wear off, exacerbation of mood, anxiety, and tics, or misuse. We utilize extended-release (ER) alpha-2 agonists primarily for hyperactivity/impulsivity but find them less effective for inattention, and they can cause sedation and hypotension. Oftentimes, we need to combine an alpha-2 agonist for behavior with psychostimulants for inattention. We employ atomoxetine or viloxazine ER (VER) for combined ADHD. However, our patients' insurers mandate a trial of generic atomoxetine prior to covering branded VER. The objective of this study was to determine whether pediatric and adult patients taking atomoxetine for DSM-5-TR ADHD combined type would experience improvement in ADHD symptoms following voluntary, open-label switch to VER. METHODS: 50 patients (35 children) received mean doses of atomoxetine 60 mg (25-100 mg once daily) followed by VER 300 mg (100-600 mg once daily) after a 5-day atomoxetine washout. Both atomoxetine and VER were flexibly titrated according to US Food and Drug Administration (FDA) guidelines. The pediatric ADHD-Rating Scale-5 (ADHD-RS-5) and the Adult Investigator Symptom Rating Scale (AISRS) were completed prior to starting atomoxetine, and 4 weeks after treatment with atomoxetine or upon earlier response or discontinuation due to side effects, whichever occurred first; the same protocol was used after treatment with VER. We conducted a blinded, de-identified, retrospective review of charts from these 50 patients in the regular course of outpatient practice. Statistical analysis was performed using a within-subject, 2-tailed t-test with significance level of p < 0.05. RESULTS: From the baseline total ADHD-RS-5 mean score (40.3 ± 10.3), improvements were greater on VER (13.9 ± 10.2) than atomoxetine (33.1 ± 12.1; t = - 10.12, p < 0.00001) in inattention (t = - 8.57, p < 0.00001) and in hyperactivity/impulsivity (t = - 9.87, p < 0.00001). From the baseline total AISRS mean score (37.3 ± 11.8), improvements were greater on VER (11.9 ± 9.4) than atomoxetine (28.8 ± 14.9; t = - 4.18, p = 0.0009) in inattention (t = - 3.50, p < 0.004) and in hyperactivity/impulsivity (t = - 3.90, p < 0.002). Of patients on VER, 86% reported positive response by 2 weeks versus 14% on atomoxetine. A total of 36% discontinued atomoxetine for side effects, including gastrointestinal (GI) upset (6 patients), irritability (6), fatigue (5), and insomnia (1), versus 4% who discontinued VER due to fatigue. A total of 96% preferred VER over atomoxetine, with 85% (22 out of 26) choosing to taper psychostimulants following stabilization on VER. CONCLUSIONS: Pediatric and adult ADHD patients who have experienced less than optimal response to atomoxetine demonstrate rapid improvement in inattention and in hyperactivity/impulsivity with greater tolerability on extended-release viloxazine.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Central Nervous System Stimulants , Sleep Initiation and Maintenance Disorders , Viloxazine , Adult , Humans , Child , Atomoxetine Hydrochloride/therapeutic use , Attention Deficit Disorder with Hyperactivity/drug therapy , Sleep Initiation and Maintenance Disorders/chemically induced , Retrospective Studies , Propylamines/therapeutic use , Propylamines/adverse effects , Treatment Outcome , Central Nervous System Stimulants/therapeutic use , Adrenergic alpha-2 Receptor Agonists/therapeutic use , Adrenergic Uptake Inhibitors , Double-Blind MethodABSTRACT
BACKGROUND: PTSD and ADHD often occur comorbidly. Research indicates that the cognitive deficits in PTSD may be related to the same disturbance of fronto-temporal systems as observed in ADHD, and ADHD has been shown to impact PTSD treatment outcomes. The presented study evaluated the safety and efficacy of atomoxetine in Veterans with comorbid ADHD/PTSD. METHODS: A double blind, randomized, placebo controlled, cross-over pilot and feasibility study was conducted. Atomoxetine was examined as an adjunctive treatment over this 10 weeks, two phase, crossover study which compared treatment with atomoxetine 80 mg daily to placebo daily. The primary outcome was improvement in ADHD symptoms as measured by the Conners' Adult ADHD Rating Scales-Self-Report: Short Version (CAARS-S:S), the Barkley Adult ADHD Rating Scale-IV (BAARS-IV), and the Adult ADHD Quality of Life-29 (AAQoL-29). Secondary outcomes included the Clinician Administered PTSD Scale (CAPS), Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and the response inhibition task Go/NoGo (GNG). RESULTS: Atomoxetine treated patients had greater reductions in ADHD symptoms as defined by total scores on the CAARS-S:S (F(1, 29) = 6.37, p = .017); both the BAARS-IV (F(1, 26) = 3.16, p = .087); and GNG overall errors test (F(1, 29) = 3.88, p = .06), reached a trend level of significance. No significant differences were noted in quality of life assessments, GNG latency periods, or CAPS scores. Atomoxetine was well-tolerated with no serious adverse events observed. CONCLUSIONS: In Veterans with ADHD comorbid with PTSD, atomoxetine demonstrated modest efficacy for ADHD symptoms; quality of life measures and PTSD symptoms were not affected.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Stress Disorders, Post-Traumatic , Adrenergic Uptake Inhibitors/adverse effects , Adult , Atomoxetine Hydrochloride/therapeutic use , Attention Deficit Disorder with Hyperactivity/drug therapy , Attention Deficit Disorder with Hyperactivity/epidemiology , Cross-Over Studies , Double-Blind Method , Feasibility Studies , Humans , Propylamines/adverse effects , Quality of Life , Stress Disorders, Post-Traumatic/drug therapy , Stress Disorders, Post-Traumatic/epidemiology , Treatment OutcomeABSTRACT
BACKGROUND: Attention Deficit Hyperactivity Disorder is a common child neurobehavioral disorder whose pathogenesis is not completely understood. However, some evidence indicates a crucial link between this disorder and the degree of oxidative stress. Coenzyme Q10 (ubiquinol) is an antioxidant that may play a significant role in the treatment of Attention Deficit Hyperactivity Disorder. OBJECTIVE: To assess the safety and efficacy of coenzyme Q10 as an add-on drug treatment for attention deficit hyperactivity disorder. METHODS: Sixty children, aged 6-16 years, with attention deficit hyperactivity disorder, non-responders to atomoxetine treatment for 6 months, were included in this double-blind, randomized, and controlled study. Group 1 received atomoxetine plus coenzyme Q10, and group 2 received atomoxetine plus placebo for 6 months. Follow-up by CONNERS parent rating scale questionnaire (CPRS-48) was performed before and after 1, 3, and 6 months of treatment, and any drug-related side effects were reported. RESULTS: The addition of coenzyme Q10 to atomoxetine in group 1 improved symptoms in a shorter time with minimal adverse effects. Group 1 showed improvement of about 33.87% in CPRS-48 total score versus 18.24% in group 2. There was a statistically significant decrease in CPRS-48 total score and its three subscales (learning problems, impulsive hyperactive subscale, and 10-items hyperactivity index) in group 1 versus group 2 after six months of treatment (p-value <0.001). CONCLUSION: Coenzyme Q10 has an important role as an add-on drug treatment for attention deficit hyperactivity disorder by improving symptoms, particularly hyperactivity, and in minimizing atomoxetine adverse effects.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Atomoxetine Hydrochloride/therapeutic use , Attention Deficit Disorder with Hyperactivity/drug therapy , Child , Double-Blind Method , Humans , Propylamines/adverse effects , Propylamines/therapeutic use , Treatment Outcome , Ubiquinone/analogs & derivativesABSTRACT
A rising number of cases of misuse and abuse of propylhexedrine (Benzedrex), an over-the-counter nasal decongestant, have been documented. Misuse of this drug can lead to serious and potentially fatal cardiac and psychiatric adverse effects.
Subject(s)
Nasal Decongestants/adverse effects , Propylamines/adverse effects , Humans , Nasal Decongestants/administration & dosage , Nonprescription Drugs/adverse effects , Propylamines/administration & dosage , Propylamines/pharmacologyABSTRACT
The management of Parkinson's disease (PD) is frequently compromised by complications induced by dopaminergic treatment such as involuntary movements (dyskinesias) and psychosis. Mesdopetam (IRL790) is a novel dopamine D3 receptor antagonist developed for the management of complications of therapy in PD. This study evaluated the safety, tolerability, and pharmacokinetics of escalating single and multiple doses of mesdopetam. We conducted a prospective, single-center, randomized, double-blind, placebo-controlled phase I, and first-in-human (FIH) study with mesdopetam administered to healthy male subjects. Overall, mesdopetam was well-tolerated up to a 120 mg single dose and up to 80 mg upon multiple dosing. Adverse events (AEs) were mainly related to the nervous system and were dose-dependent. No serious adverse events occurred and no AEs led to withdrawal. The results of the single-ascending-dose and multiple-ascending-dose parts indicated dose- and time-independent pharmacokinetics with rapid absorption and maximum plasma levels that were generally reached within 2 h after dosing. No accumulation was observed upon multiple dosing. It is concluded that mesdopetam was safe and well-tolerated in healthy male volunteers. Pharmacokinetic analysis indicated rapid absorption and dose-linear pharmacokinetics of mesdopetam, with a plasma half-life of around 7 h, upon single and repeated dosing. The pharmacokinetics of mesdopetam supports twice-daily use in patients.
Subject(s)
Dopamine Antagonists/administration & dosage , Phenyl Ethers/administration & dosage , Propylamines/administration & dosage , Receptors, Dopamine D3/antagonists & inhibitors , Administration, Oral , Adolescent , Adult , Biological Availability , Dopamine Antagonists/adverse effects , Dopamine Antagonists/pharmacokinetics , Dose-Response Relationship, Drug , Double-Blind Method , Fasting/metabolism , Food-Drug Interactions , Half-Life , Healthy Volunteers , Humans , Male , Middle Aged , Phenyl Ethers/adverse effects , Phenyl Ethers/pharmacokinetics , Propylamines/adverse effects , Propylamines/pharmacokinetics , Young AdultABSTRACT
Cardiotoxicity has been one of the most common causes of withdrawal of drugs from the market, and prolongation of the QT interval is one of the manifestations of drug cardiotoxicity. Iptakalim hydrochloride (ITKL) is a selective ATP-sensitive potassium channel opener used to treat hypertension. It is crucial to assess the risk of cardiac repolarization of ITKL in clinical trials. This study was conducted to determine the effect of ITKL on corrected QT (QTc) interval. A randomized, double-blind, placebo-controlled single- and multidose regimen was carried out to investigate the QTc and ITKL concentration correlation. ITKL was administered at doses of 5, 10, 15, and 20 mg with single oral administration and 10 and 20 mg with multiple oral administration, along with placebo, in 83 healthy subjects. Electrocardiograms (ECGs) and blood samples were collected on a preset time schedule. A ΔΔQTcF effect above 10 milliseconds was excluded at all observed plasma levels. Among them, the highest dose was 20 mg, which is twice the therapeutic dose. We concluded that ITKL did not prolong the QT interval in healthy subjects within the therapeutic dose. Retrospectively registered: The study was registered at Chinese Clinical Trial Registry with registration number ChiCTR1800014466.
Subject(s)
Electrocardiography/drug effects , Heart Rate/drug effects , Propylamines/administration & dosage , Propylamines/blood , Adult , China/epidemiology , Dose-Response Relationship, Drug , Double-Blind Method , Electrocardiography/methods , Female , Heart Rate/physiology , Humans , KATP Channels/metabolism , Long QT Syndrome/blood , Long QT Syndrome/chemically induced , Long QT Syndrome/epidemiology , Male , Propylamines/adverse effectsABSTRACT
ABSTRACT: "Activation syndrome" represents a cluster of symptoms of excessive emotional arousal or behavioral activation, which emerges after the first few weeks of antidepressant treatment or a dose increase and resolves with dose reduction or cessation of treatment. It was reported after treatment with selective serotonin reuptake inhibitor and serotonin-norepinephrine reuptake inhibitor group of agents, but no case of activation syndrome has been reported with the norepinephrine reuptake inhibitor group. Atomoxetine is a norepinephrine reuptake inhibitor and nonstimulant and is used to manage symptoms of attention-deficit/hyperactivity disorder (ADHD). Atomoxetine-related symptoms of mania and hypomania were reported in literature previously. Here, we report a case of activation syndrome arising after atomoxetine (ATX) dose titration in a prepubertal male child with ADHD. Differentiation of activation symptoms from mania/hypomania symptoms after treatment with ATX may be important for the clinicians to manage the adverse effects and understand the risk factors behind activation syndrome with use of ATX in children and adolescents diagnosed with ADHD.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Adolescent , Adrenergic Uptake Inhibitors/adverse effects , Atomoxetine Hydrochloride/adverse effects , Attention Deficit Disorder with Hyperactivity/drug therapy , Child , Humans , Male , Propylamines/adverse effects , Treatment OutcomeABSTRACT
Attention Deficit-Hyperactivity Disorder is one of the most common psychiatric disorders of childhood, characterized by attention deficit, hyperactivity and impulsivity. The most effective treatment in ADHD is drug treatment. Stimulant and nonstimulant drug treatments are preferentially used. Atomoxetine is one of the nonstimulant treatments. Although sexual side effects of atomoxetine in adults are reported, there is limited knowledge about sexual side effects in children and adolescents. In this case report, we aimed to describe an adolescent 16-year old with spontaneous ejaculation, a rare sexual side effect, that started at the third day of the treatment and ended by discontinuing atomoxetine.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Central Nervous System Stimulants , Adolescent , Adult , Atomoxetine Hydrochloride/adverse effects , Attention Deficit Disorder with Hyperactivity/drug therapy , Child , Ejaculation , Humans , Male , Propylamines/adverse effects , Treatment OutcomeABSTRACT
BACKGROUND: Surfactants are common ingredients in topical products, which can cause both irritant and allergic contact dermatitis. OBJECTIVE: The aim of this study was to determine the prevalence of 12 common groups of surfactants and 12 common individual surfactants among products in each category in the American Contact Dermatitis Society Contact Allergen Management Program (CAMP). METHODS: The American Contact Dermatitis Society CAMP was queried for the 12 surfactant groups and the 12 individual surfactants. RESULTS: The laureth/pareth sulfate group was the most prevalent surfactant group in CAMP products (17.9%). Laureth/pareth sulfates were the most common surfactant group in all product categories, except household and eye care products. The betaine/sultaine group (13.5%) and glucosides (10.0%) were also found in a significant proportion of CAMP products. Oleamidopropyl dimethylamine has the highest positive reaction rate (3.5%) but was tied for the lowest prevalence (0.20%) of the 12 individual surfactants studied. In contrast, cocamidopropyl betaine has a lower positive reaction rate (1.6%) with a higher prevalence (10.4%). CONCLUSIONS: Surfactants were commonly found across all product types in CAMP. This study provides important information on allergen and irritant exposures in care products.
Subject(s)
Cosmetics/chemistry , Dermatitis, Allergic Contact/etiology , Household Products , Surface-Active Agents/adverse effects , Benzalkonium Compounds/adverse effects , Betaine/adverse effects , Betaine/analogs & derivatives , Databases, Chemical , Detergents/chemistry , Ethanolamines/adverse effects , Glucosides/adverse effects , Hair Dyes/chemistry , Hair Preparations/chemistry , Humans , Propylamines/adverse effects , Soaps/chemistry , Sodium Dodecyl Sulfate/adverse effectsABSTRACT
BACKGROUND: Minimizing the risk of disease progression and exacerbations is the key goal of COPD management, as these are well-established indicators of poor COPD prognosis. We developed a novel composite end point assessing three important aspects (lung function, health status, and exacerbations) of worsening in COPD. The objective was to determine whether dual bronchodilation with umeclidinium/vilanterol (UMEC/VI) reduces clinically important deteriorations (CIDs) in COPD versus placebo or bronchodilator monotherapy. METHODS: This study is a post hoc analysis of two 24-week trials comparing UMEC/VI 62.5/25 µg with UMEC 62.5 µg, VI 25 µg, or placebo (Study A; NCT01313650), or UMEC/VI 62.5/25 µg with tiotropium (TIO) 18 µg (Study B; NCT01777334) in patients with symptomatic COPD, without a history of frequent exacerbations. Deterioration was assessed as the time to a first CID, a composite measure defined as a decrease of ≥100 mL in trough forced expiratory volume in 1 second or ≥4-unit increase in St George's Respiratory Questionnaire total score or an on-treatment moderate-to-severe COPD exacerbation. RESULTS: In Study A, fewer patients experienced a first CID with UMEC/VI (44%) versus UMEC (50%), VI (56%), and placebo (75%). The risk of a first CID was reduced with UMEC/VI (hazard ratio [HR]: 0.37 [95% confidence interval, CI: 0.30, 0.45]), UMEC (HR: 0.46 [95% CI: 0.38, 0.56]), and VI (HR: 0.55 [95% CI: 0.45, 0.66]; all P<0.001) versus placebo, and with UMEC/VI versus UMEC (HR: 0.80 [95% CI: 0.65, 0.97]; P<0.05) and versus VI (HR: 0.67 [95% CI: 0.55, 0.81]; P<0.001). In Study B, fewer patients experienced a first CID with UMEC/VI (41%) versus TIO (59%). UMEC/VI reduced the risk of a first composite CID by 43% versus TIO (HR: 0.57 [95% CI: 0.47, 0.69]; P<0.001). CONCLUSION: This exploratory analysis, using a new assessment of clinical deterioration in COPD, revealed that a majority of symptomatic patients with low exacerbation risk experienced a deterioration during the 24-week study periods. UMEC/VI reduces the risk of a first CID versus placebo or bronchodilator monotherapy.
Subject(s)
Adrenergic beta-2 Receptor Agonists/administration & dosage , Benzyl Alcohols/administration & dosage , Chlorobenzenes/administration & dosage , Lung/drug effects , Muscarinic Antagonists/administration & dosage , Phenethylamines/administration & dosage , Propylamines/administration & dosage , Pulmonary Disease, Chronic Obstructive/drug therapy , Quinuclidines/administration & dosage , Administration, Inhalation , Adrenergic beta-2 Receptor Agonists/adverse effects , Aged , Benzyl Alcohols/adverse effects , Chlorobenzenes/adverse effects , Clinical Trials, Phase III as Topic , Disease Progression , Disease-Free Survival , Drug Combinations , Female , Forced Expiratory Volume , Health Status , Humans , Lung/physiopathology , Male , Middle Aged , Multicenter Studies as Topic , Muscarinic Antagonists/adverse effects , Phenethylamines/adverse effects , Propylamines/adverse effects , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/physiopathology , Quinuclidines/adverse effects , Randomized Controlled Trials as Topic , Retrospective Studies , Spirometry , Surveys and Questionnaires , Time Factors , Treatment Outcome , Vital CapacityABSTRACT
PURPOSE: Lesogaberan, a γ-aminobutyric acid (GABA)B receptor agonist, was developed for the treatment of gastroesophageal reflux disease in patients with a partial response to proton pump inhibitor therapy. A high prevalence of paresthesia was observed in healthy individuals after dosing with lesogaberan in early-phase clinical trials. The aim of this review was to gain further insight into paresthesia caused by lesogaberan by summarizing the relevant preclinical and clinical data. METHODS: This study was a narrative review of the literature and unpublished data. FINDINGS: The occurrence of paresthesia may depend on the route or rate of drug administration; several studies were conducted to test this hypothesis, and formulations were developed to minimize the occurrence of paresthesia. Phase I clinical studies showed that, in healthy individuals, paresthesia occurred soon after administration of lesogaberan in a dose-dependent manner regardless of the route of administration. The occurrence of paresthesia could be decreased by fractionating the dose or reducing the rate of administration. These findings suggest that the initial rate of absorption plays an important part in the development of paresthesia. Modified-release formulations minimize the occurrence of paresthesia while retaining the anti-reflux activity of the drug, as measured by esophageal pH and the number of transient lower esophageal sphincter relaxations. IMPLICATIONS: The development of lesogaberan was halted because the effect on gastroesophageal reflux disease symptoms observed in Phase II studies was not considered clinically meaningful in the target patient population. Nevertheless, it is an example of successful formulation development designed to minimize the occurrence of a compound's adverse effect while retaining its pharmacodynamic action.
Subject(s)
GABA-A Receptor Agonists/adverse effects , Paresthesia/chemically induced , Phosphinic Acids/adverse effects , Propylamines/adverse effects , GABA-A Receptor Agonists/therapeutic use , Gastroesophageal Reflux/drug therapy , Humans , Phosphinic Acids/therapeutic use , Propylamines/therapeutic useABSTRACT
PURPOSE: To identify the contact lens-related modifiable and nonmodifiable factors associated with corneal inflammatory events (CIEs) in a university eye care center. METHODS: Contact lens-wearing undergraduate and graduate/professional students (age range, 18 to 36 years) with CIEs and contact lens wearers without complications (non-CIEs) were surveyed about their age, education level, overnight wear, brand of lens, brand of care solution, storage case age, topping-off, and lens replacement. Logistic regression was used to assess the impact of participant characteristics (demographic and behavior) and contact lens factors on the risk of a CIE. RESULTS: There were 160 participants enrolled, with 76 presenting with a CIE. Age was significant in the multivariate model (p < 0.001) as was an interaction between disinfectant and wearing schedule (p = 0.027). When daily wear (DW) and disinfectant were compared, polyquaternium-1/myristamidopropyl dimethylamine (PQ-1/MAPD) was associated with a greater risk of CIE versus peroxide (adjusted odds ratio [aOR], 18.4; 95% confidence interval [95% CI], 1.9-173.9) and versus polyhexamethylene biguanide or polyaminopropyl biguanide (PHMB) (aOR, 15.0; 95% CI, 4.5-50.0). For PHMB users only, extended wear (EW) compared with DW increased CIE risk (aOR, 10.0; 95% CI, 2.0-51.2). There was no difference in risk between EW and DW for PQ-1/MAPD (aOR, 0.8; 95% CI, 0.2, 2.6). CONCLUSIONS: The multivariate analysis suggests that younger age and the use of PQ-1/MAPD, particularly in DW, increase the risk of acquiring a CIE with soft contact lens wear in college-aged students. For PHMB users, EW compared with DW increases the risk of a CIE; but for PQ-1/MAPD users, there is no difference between EW and DW.
Subject(s)
Contact Lenses, Hydrophilic/adverse effects , Keratitis/etiology , Adolescent , Adult , Age Factors , Biguanides/adverse effects , Cross-Sectional Studies , Disinfectants/adverse effects , Disposable Equipment , Female , Humans , Male , Odds Ratio , Polymers/adverse effects , Propylamines/adverse effects , Prospective Studies , Risk Factors , Universities , Young AdultABSTRACT
BACKGROUND: Repeated and prolonged use of surfactants can cause irritant as well as allergic contact dermatitis. OBJECTIVE: This study reports the frequency of positive patch test results to surfactants tested on the North American Contact Dermatitis Group screening series including cocamidopropyl betaine (CAPB), amidoamine (AA), dimethylaminopropylamine (DMAPA), oleamidopropyl dimethylamine (OPD), and cocamide diethanolamide (CDEA), and correlations of positive reactions between CAPB and the other surfactants. METHODS: This was a retrospective analysis of 10 877 patients patch tested between 2009 and 2014 to the surfactants CAPB, AA, DMAPA, OPD, and CDEA. Frequencies of positive reactions to these surfactants were calculated, and trends of reactivity between the surfactants analyzed. CONCLUSIONS: The OPD had the highest rate of positive patch reactions (2.3%) followed by DMAPA (1.7%), and CAPB (1.4%). The AA and CDEA had the lowest rate of positive reactions (0.8%). There was a high degree of overlap in positive patch tests between the surfactants. The CDEA was the least likely to coreact with another surfactant.
Subject(s)
Betaine/analogs & derivatives , Dermatitis, Allergic Contact/immunology , Surface-Active Agents/adverse effects , Betaine/adverse effects , Betaine/immunology , Diamines , Ethanolamines/adverse effects , Ethanolamines/immunology , Humans , Patch Tests , Propylamines/adverse effects , Propylamines/immunology , Retrospective StudiesABSTRACT
With the increased application of many different drug classes for the treatment of psychiatric conditions in children, the incidence of priapism has also increased. Priapism of pharmacotherapeutic etiology in the pediatric population is a complex and poorly understood entity that continues to present new management challenges for clinicians. We present 2 cases of pediatric priapism thought to be secondary to the use of pharmacotherapeutic agents. In the first case, sertraline, an antidepressant, and in the second case, atomoxetine, a nonstimulant medication, are implicated as the most likely causative agents. Both medications have a growing association with priapism in the literature.
Subject(s)
Adrenergic Uptake Inhibitors/adverse effects , Antidepressive Agents/adverse effects , Priapism/chemically induced , Propylamines/adverse effects , Sertraline/adverse effects , Atomoxetine Hydrochloride , Child , Humans , MaleABSTRACT
A series of tacrine-propargylamine derivatives were synthesised and evaluated as possible anti-Alzheimer's disease (AD) agents. Among these derivatives, compounds 3a and 3b exhibited superior activities and a favourable balance of AChE and BuChE activities (3a: IC50 values of 51.3 and 77.6 nM; 3b: IC50 values of 11.2 and 83.5 nM). Compounds 3a and 3b also exhibited increased hAChE inhibitory activity compared with tacrine by approximately 5- and 28-fold, respectively, and low neurotoxicity. Importantly, these compounds also had lower hepatotoxicity than tacrine. Based on these results, compounds 3a and 3b could be considered as potential lead compounds for the treatment of AD and other AChE related diseases, such as schizophrenia, glaucoma and myasthenia gravis.
Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/adverse effects , Cholinesterase Inhibitors/pharmacology , Hepatic Stellate Cells/drug effects , Pargyline/analogs & derivatives , Propylamines/adverse effects , Propylamines/pharmacology , Tacrine/analogs & derivatives , Tacrine/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/enzymology , Alzheimer Disease/metabolism , Cell Survival/drug effects , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Hepatic Stellate Cells/cytology , Humans , Molecular Structure , Pargyline/adverse effects , Pargyline/chemistry , Pargyline/pharmacology , Propylamines/chemistry , Structure-Activity Relationship , Tacrine/adverse effects , Tacrine/chemistryABSTRACT
The safety profile of atomoxetine in the treatment of attention deficit hyperactivity disorder has been studied in many clinical trials. We performed an integrated safety analysis of 15 clinical trials in adults with attention deficit hyperactivity disorder. The analysis pooled patient data into three groups: acute placebo-controlled trials; long-term placebo-controlled trials; all trials. In total, 4829 adults (18-77 years, median: 36 years) were exposed to atomoxetine. Statistically significantly more atomoxetine-treated than placebo-treated patients experienced treatment-emergent adverse events (81.3% vs. 68.3% acute; 90.6% vs. 76.8% long term) and discontinued due to adverse events (8.9% vs. 4.0% acute; 17.9% vs. 6.3% long term). No statistically significant differences were observed in the proportion of patients experiencing serious adverse events. No previously unknown adverse events were identified. The most common adverse events included nausea, dry mouth, decreased appetite, insomnia and erectile dysfunction. Mean increases in heart rate (+5.2 beats per min) and blood pressure (systolic +2 mmHg, diastolic +1.9 mmHg) were modest. The proportion of patients experiencing clinically significant increases in blood pressure and heart rate at any time was statistically significantly higher with atomoxetine (systolic blood pressure 13-17%, diastolic blood pressure 37-40%, heart rate 42-43%) compared to placebo (systolic blood pressure 8-13%, diastolic blood pressure 29-34%, heart rate 21-26%). There was no increased risk of suicidal ideation or behaviour. Our findings confirm atomoxetine's known safety profile. From a safety perspective, atomoxetine is a useful treatment option for adults with attention deficit hyperactivity disorder.