Avasopasem manganese (GC4419) protects against cisplatin-induced chronic kidney disease: An exploratory analysis of renal metrics from a randomized phase 2b clinical trial in head and neck cancer patients.

Head and neck squamous cell carcinoma (HNSCC) patients treated with high-dose cisplatin concurrently with radiotherapy (hdCis-RT) commonly suffer kidney injury leading to acute and chronic kidney disease (AKD and CKD, respectively). We conducted a retrospective analysis of renal function and kidney injury-related plasma biomarkers in a subset of HNSCC subjects receiving hdCis-RT in a double-blinded, placebo-controlled clinical trial (NCT02508389) evaluating the superoxide dismutase mimetic, avasopasem manganese (AVA), an investigational new drug. We found that 90 mg AVA treatment prevented a significant reduction in estimated glomerular filtration rate (eGFR) three months as well as six and twelve months after treatment compared to 30 mg AVA and placebo. Moreover, AVA treatment may have allowed renal repair in the first 22 days following cisplatin treatment as evidenced by an increase in epithelial growth factor (EGF), known to aid in renal recovery. An upward trend was also observed in plasma iron homeostasis proteins including total iron (Fe-blood) and iron saturation (Fe-saturation) in the 90 mg AVA group versus placebo. These data support the hypothesis that treatment with 90 mg AVA mitigates cisplatin-induced CKD by inhibiting hdCis-induced renal changes and promoting renal recovery.

Attention deficit disorder and conduct disorder: longitudinal evidence for a familial subtype.

BACKGROUND: An obstacle to the successful classification of attention deficit hyperactivity disorder (ADHD) is the frequently reported co-morbidity between ADHD and conduct disorder (CD). Prior work suggested that from a familial perspective, ADHD children with CD may be aetiologically distinct from those without CD. METHODS: Using family study methodology and three longitudinal assessments over 4 years, we tested hypotheses about patterns of familial association between ADHD, CD, oppositional defiant disorder (ODD) and adult antisocial personality disorder (ASPD). RESULTS: At the 4-year follow-up, there were 34 children with lifetime diagnoses of ADHD + CD, 59 with ADHD + ODD and 33 with ADHD only. These were compared with 92 non-ADHD, non-CD, non-ODD control probands. Familial risk analysis revealed the following: (1) relatives of each ADHD proband subgroup were at significantly greater risk for ADHD and ODD than relatives of normal controls; (2) rates of CD and ASPD were elevated among relatives of ADHD + CD probands only; (3) the co-aggregation of ADHD and the antisocial disorders could not be accounted for by marriages between ADHD and antisocial spouses; and (4) both ADHD and antisocial disorders occurred in the same relatives more often than expected by chance alone. CONCLUSIONS: These findings suggest that ADHD with and without antisocial disorders may be aetiologically distinct disorders and provide evidence for the nosologic validity of ICD-10 hyperkinetic conduct disorder.

Is ADHD a risk factor for psychoactive substance use disorders? Findings from a four-year prospective follow-up study.

OBJECTIVE: To evaluate whether attention-deficit hyperactivity disorder (ADHD) is a risk factor for psychoactive substance use disorders (PSUD), attending to issues of psychiatric comorbidity, family history, and adversity. METHOD: Using assessments from multiple domains, the authors examined 140 ADHD and 120 normal control subjects at baseline and 4 years later. Drug and alcohol abuse and dependence were operationally defined. RESULTS: No differences were detected in the rates of alcohol or drug abuse or dependence or in the rates of abuse of individual substances between the groups; both ADHD and control probands had a 15% rate of PSUD. Conduct and bipolar disorders predicted PSUD, independently of ADHD status. Family history of substance dependence and antisocial disorders was associated with PSUD in controls but less clearly so in ADHD probands. Family history of ADHD was not associated with risk for PSUD. ADHD probands had a significantly shorter time period between the onsets of abuse and dependence compared with controls (1.2 years versus 3 years, p < .01). CONCLUSIONS: Adolescents with and without ADHD had a similar risk for PSUD that was mediated by conduct and bipolar disorder. Since the risk for PSUD has been shown to be elevated in adults with ADHD when compared with controls, a sharp increase in PSUD is to be expected in grown-up ADHD children during the transition from adolescence to adulthood.

Is childhood oppositional defiant disorder a precursor to adolescent conduct disorder? Findings from a four-year follow-up study of children with ADHD.

OBJECTIVE: To evaluate the overlap between attention-deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD), addressing whether ODD is subsyndromal form of conduct disorder (CD) and, if so, whether it is a precursor or prodrome syndrome of CD. METHOD: Assessments from multiple domains were used to examine 140 children with ADHD and 120 normal controls at baseline and 4 years later. RESULTS: Of children who had ADHD at baseline, 65% had comorbid ODD and 22% had CD. Among those with ODD, 32% had comorbid CD. All but one child with CD also had ODD that preceded the onset of CD by several years. ODD+CD children had more severe symptoms of ODD, more comorbid psychiatric disorders, lower Global Assessment of Functioning Scale scores, more bipolar disorder, and more abnormal Child Behavior Checklist clinical scale scores compared with ADHD children with non-CD ODD and those without ODD or CD. In addition, ODD without CD at baseline assessment in childhood did not increase the risk for CD at the 4-year follow-up, by midadolescence. CONCLUSIONS: Two subtypes of ODD associated with ADHD were identified: one that is prodromal to CD and another that is subsyndromal to CD but not likely to progress into CD in later years. These ODD subtypes have different correlates, course, and outcome.