Model-Based Approach for Establishing the Predicted Clinical Response of a Delayed-Release and Extended-Release Methylphenidate for the Treatment of Attention-Deficit/Hyperactivity Disorder.

PURPOSE/BACKGROUND: HLD200 is an evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH) that provides a consistent delay in initial drug release to target onset of therapeutic effect from awakening and maintain it into the evening. Building on a modeling framework established with other extended-release methylphenidate formulations, pharmacokinetic (PK) and PK/pharmacodynamic (PD) models for DR/ER-MPH were developed to describe the time course of effect in response to a range of doses and administration times. METHODS/PROCEDURES: Using available PK data from healthy adults, a population PK model was developed using a 1-compartment model with a time-varying absorption rate described by a single Weibull function. A PK/PD model was then developed using Swanson, Kotkin, Agler, M-Flynn, and Pelham combined scores from a phase 3 trial of children with attention-deficit/hyperactivity disorder and simulated plasma concentration-time data. Simulations using the PK/PD model were performed for doses of 60, 80, and 100 mg of DR/ER-MPH, administered 4 to 14 hours before the classroom day. FINDINGS/RESULTS: The PK/PD model predicts that DR/ER-MPH produces a clinical response from early morning into the late afternoon or evening, with increased duration of response occurring with increasing doses. Furthermore, the PK/PD model predicts that maximal clinical effect is achieved with DR/ER-MPH administered 12 hours before the start of the classroom day. IMPLICATIONS/CONCLUSIONS: Model-predicted duration of benefit with DR/ER-MPH is consistent with trial data documenting improvements in functional impairment during the early morning and evening. This model may facilitate dosage optimization by predicting changes in clinical benefit with dose and administration time adjustment.

Functional Impairment in Youth With ADHD: Normative Data and Norm-Referenced Cutoff Points for the Before School Functioning Questionnaire and the Parent Rating of Evening and Morning Behavior Scale, Revised.

OBJECTIVE: Children with attention-deficit/hyperactivity disorder (ADHD) frequently manifest behavioral difficulties in the morning prior to school and in the afternoons and evenings. We sought to establish norms for 2 time-specific measures of functioning: the Before School Functioning Questionnaire (BSFQ) and the Parent Rating of Evening and Morning Behavior Scale, Revised (PREMB-R), which includes Morning (AM) and Evening (PM) subscales. METHODS: The normative online survey of a representative US sample of 1,200 primary caregivers of children and adolescents aged between 6 and 17 years was conducted in June 2016. A quota system was used whereby caregivers of 50 male and 50 female children or adolescents were recruited in each age group, ie, 100 parents for each of the 12 age groups. Diagnosis of ADHD relied on a caregiver's report that his or her child was so diagnosed by a health professional. RESULTS: Across all items of the BSFQ, youth with current untreated ADHD or a history of ADHD were rated as more severely ill than those without ADHD (all unadjusted P values < .001), even after adjustment for psychiatric comorbidity (all adjusted P values < .001). A similar pattern was observed for the PREMB-R AM (all unadjusted P values < .001; all adjusted P values < .001, except for item 1 [P = .01]) and PREMB-R PM (all unadjusted P values < .001; all adjusted P values < .001). The use of a large population sample allowed for computation of age-stratified norms for 4 thresholds of risk: screening risk (80th percentile), mild functional impairment (90th percentile), moderate functional impairment (93rd percentile), and severe functional impairment (98th percentile). CONCLUSIONS: The norms generated by this study can guide clinicians in the use of the BSFQ and PREMB-R for identifying those ADHD youth who may be experiencing difficulties in the early morning and late afternoon/evening. Such tools are needed given the availability of treatments that can target ADHD symptoms and impairments at these extremes of the daily routine.

An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations.

Introduction: Long-acting stimulant formulations are recommended as first-line pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD). Over the past 20 years, extended-release (ER) methylphenidate (MPH) and amphetamine (AMP) formulations have evolved to include varying drug delivery technologies, enantiomers/salts, and dosage forms. All formulations are characterized by a unique pharmacokinetic profile that is closely mirrored by pharmacodynamic response allowing clinicians to individualize therapy based on their patient's clinical needs and dosing preferences.Areas covered: This review provides an update on the pharmacokinetic properties of approved and investigational ER MPH and AMP formulations and highlights pharmacokinetic features that clinicians should consider when selecting a long-acting stimulant.Expert opinion: Since there are no reliable biomarkers that can predict individualized response to long-acting stimulants, clinicians need to consider their distinctive pharmacokinetic properties, including the pharmacokinetic profile, rate and extent of absorption, variability, dose proportionality, bioequivalence, and potential for accumulation. Clinicians also need to understand that certain factors can contribute to increased variability in pharmacokinetics and potentially affect outcomes. Less invasive, high-throughput techniques and novel time-based scales are being developed to advance research on the pharmacokinetic-pharmacodynamic relationships of stimulants. Model-based pharmacokinetic-pharmacodynamic approaches can be applied to aid the development of novel formulations and individualize therapy with existing drugs.

Sleep-Associated Adverse Events During Methylphenidate Treatment of Attention-Deficit/Hyperactivity Disorder: A Meta-Analysis.

OBJECTIVE: Sleep disturbances are a feature of attention-deficit/hyperactivity disorder (ADHD) and an adverse event (AE) of methylphenidate treatment. The authors sought to clarify methylphenidate-associated sleep problems and how studies are affected by confounding factors. DATA SOURCES: Published studies in English collected via online databases and unpublished data from www.clinicaltrials.gov and US Food and Drug Administration websites. Sources were searched from inception to August 2017. STUDY SELECTION: Included were blinded placebo-controlled studies of youth with ADHD conducted in naturalistic settings, leading to 35 studies yielding 75 observations of sleep-related AEs. These studies comprised 3,079 drug-exposed and 2,606 placebo-treated patients. DATA EXTRACTION: Two PhD-level reviewers reviewed each study for inclusion. Four PhD/PharmD-level reviewers extracted data in duplicate. Discrepancies were resolved by discussion or, if needed, by the senior author. RESULTS: Increased pooled relative risks (RRs) were found for methylphenidate-associated sleep-related AEs for insomnia (general), initial insomnia, middle insomnia, combined insomnia, and sleep disorder. Several sample or study design features were significantly associated with the RR for sleep-related AEs and the methylphenidate formulation studied (P < .05). After correction for confounding variables, significant differences among drugs were found for initial insomnia, insomnia (general), and sleep disorder (P < .0001) as the other categories could not be tested due to insufficient studies. The findings also show that the RR and its interpretation are constrained by the placebo AE rate. CONCLUSIONS: Several types of insomnia and sleep problems are associated with methylphenidate treatment. Study design and sample features influence the RR statistic. By showing that the rate of placebo AEs impacts the RR, this study provides the field with a useful covariate for adjusting RR statistics.

A Canadian evidence-based guideline for the first-line treatment of follicular lymphoma: joint consensus of the Lymphoma Canada Scientific Advisory Board.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (NHL) in North America. Because of the heterogeneity of the disease, treatment options vary from observation to aggressive therapies or stem cell transplantation, or both. Although advances in treatment have improved outcomes, the disease remains largely incurable. In Canada, no unified national guideline exists for the front-line treatment of FL; provincial guidelines vary and are largely based on funding. There is therefore a need for evidence-based national treatment guidelines that are supported by Canadian hematologists to ensure that patients with FL have equitable access to the best available care. A group of experts from across Canada developed a national evidence-based treatment guideline to provide health care professionals with clear guidance on the first-line management of FL. Results of a systematic review of the literature are presented with consensus recommendations based on available evidence.

Altered vascular resistance properties and acute pressure-natriuresis mechanism in neonatal and weaning spontaneously hypertensive rats.

Although it has been extensively scrutinized, the factor(s) involved in the initiation and development of hypertension in spontaneously hypertensive rats (SHRs) remains unresolved. The objective of the present study was to determine whether, early in development, the causal mechanism(s) for the development of hypertension in young SHRs involves an integration of 2 processes, specifically an upregulation of structurally based vascular resistance properties and a rightward shift in the hemodynamic component of pressure-natriuresis. Mean arterial pressure was determined in conscious 4-week-old SHRs and Wistar-Kyoto rats via previously implanted aortic catheters. Structurally based hindlimb vascular resistance properties were assessed in 2- and 4-week-old SHRs and Wistar-Kyoto rats. Renal interstitial hydrostatic pressure was measured after short-term manipulations of renal arterial pressure (RAP) in 4-week-old, anesthetized rats. Although mean arterial pressure in conscious SHRs (113±5 mm Hg) and Wistar-Kyoto rats (110±6 mm Hg) was not significantly different at 4 weeks of age, SHRs at 2 and 4 weeks of age already had increases in structurally based vascular resistance properties of ≈30% above age- and weight-matched Wistar-Kyoto rats. Furthermore, the acute RAP-renal interstitial hydrostatic pressure relationship was found to be linear in both strains, and the temporal coupling of the stimulus to response was rapid; that is, renal interstitial hydrostatic pressure responses to changes in RAP were <2 s. Although the slope of the RAP-renal interstitial hydrostatic pressure relationship was not significantly different between strains, the relationship was significantly shifted (18%) to higher RAPs in SHRs. These results suggest that alterations in both vascular structure and renal function in young SHRs occur before elevations in mean arterial pressure.

Caloric restriction prevents visceral adipose tissue accumulation and maintains erectile function in aging rats.

INTRODUCTION: Increased adiposity is an important risk factor for erectile dysfunction (ED) and cardiovascular disease (CVD). Although accumulation of visceral adipose tissue (VAT) is recognized as a key mediator in the pathogenesis of CVD, its role in ED has not been elucidated. AIM: To determine whether caloric restriction (CR) could prevent VAT accumulation and thereby prevent the onset of ED in normotensive rats. METHODS: Male Sprague Dawley rats (10 weeks) were randomized into three dietary groups: ad libitum control (CON), mild CR (CR(MI)), and moderate CR (CR(MOD)). Body weight (BW), body length abdominal girth (AG), and VAT (g-magnetic resonance imaging based) were assessed longitudinally. Erections were assessed using the apomorphine bioassay (80 µg/kg, SQ) after 20 weeks of CR. Excised VAT (mesenteric, epididymal, omental, and retroperitoneal), the internal pudendal artery (IPA) and serum were collected postmortem. Structure and function of the IPA was assessed at study end. MAIN OUTCOME MEASURES: Erectile responses, adiposity (VAT), abdominal girth, serum analysis. RESULTS: BW (CON = 653 ± 58.6 g; CR(MI) = 535 ± 47.4 g; CR(MOD) = 409 ± 17.4 g) and VAT (CON = 39 ± 9.0 g; CR(MI) = 30 ± 9.9 g; CR(MOD) = 14 ± 3.5 g) were markedly different between the three groups. AG significantly correlated with longitudinal changes in VAT (R(2) = 0.61) and excised VAT (R(2) = 0.87). CR preserved erectile responses (CON = 0.6 ± 0.45, CR(MI) = 1.2 ± 0.77 g, CR(MOD) = 2.5 ± 0.43 g). A strong inverse correlation between VAT (%) and erectile function was found (R(2) = 0.74) whereas BW was less predictive of ED (R(2) = 0.48). There were no changes in traditional biomarkers (glucose, lipids) which could account for the ED. IPA structure was not different between groups, while CR(MOD) preserved endothelial function. CONCLUSIONS: CR effectively prevented VAT accumulation in normotensive rats. Independently of changes in other metabolic markers, this intervention ameliorated the negative impact on erectile responses that occurs with age. Functional changes of the IPA may be a key mechanism by which erections are preserved with CR. AG was shown to be a strong index of VAT in rats.

Perinatal iron deficiency combined with a high-fat diet causes obesity and cardiovascular dysregulation.

Consumption of a high-fat Western diet (WD) and the resultant obesity is linked to a number of chronic pathologies, including cardiovascular dysregulation. The purpose of the present study was to determine whether perinatal iron deficiency (PID) added to the consumption of a WD would precipitate an obese phenotype with exacerbated metabolic and cardiovascular outcomes in adult offspring. Female Sprague Dawley rats were fed either a control (225 mg/kg Fe) or an iron-restricted diet (3-10 mg/kg Fe) prior to and throughout gestation. At birth, all dams were fed an iron-replete diet. At weaning, offspring were fed a normal diet or WD for up to 21 wk. Hemodynamics and locomotor activity were assessed by radiotelemetry starting at 15 wk of age. Iron restriction during pregnancy caused severe anemia in dams and offspring, resulting in 15% lower birth weights in the offspring. PID offspring fed the WD had greater caloric intake and exhibited reduced locomotor activity compared with their normal diet-fed littermates; no such effects were observed in normal iron control offspring. Despite having a similar effect on serum lipid profiles, consumption of the WD had a greater impact on body weight in the PID group, and this weight gain was due largely to visceral adipose tissue accumulation. A significant correlation between visceral adipose tissue weight and mean arterial pressure was observed in the PID offspring but not in controls. These observations demonstrate that PID predisposes offspring to an enhanced response to WD characterized by increased fat accumulation and cardiovascular dysregulation.

Moment-to-moment characteristics of the relationship between arterial pressure and renal interstitial hydrostatic pressure.

The kidney is a key controller of the long-term level of arterial pressure, in part through pressure-natriuresis. Although direct coupling of changes in renal arterial pressure to renal interstitial hydrostatic pressure (RIHP) and consequent sodium excretion is well established, few studies have characterized the moment-to-moment aspects of this process. These studies characterized the short-term hemodynamic component of pressure-natriuresis in vivo before and after autonomic nervous system and renin-angiotensin system inhibition. Changes in RIHP were determined over a range of renal arterial pressures in Wistar rats receiving no treatment, a ganglionic blocker (hexamethonium; 20 mg/kg per hour IV), or an angiotensin II type 1 receptor blocker (losartan; 10 mg/kg per hour IV). After a series of changes in renal arterial pressure, a delay of only ≈1 second was found for the onset of RIHP responses that was independent of the stimulus magnitude and neurohumoral manipulation; however, completion of the full RIHP response was within ≈15 seconds for renal arterial pressure changes of ≤30 mm Hg. The overall slope of the renal arterial pressure- RIHP relationship (0.09±0.01) was also not affected by autonomic nervous system and renin-angiotensin system inhibition despite decreasing renal arterial pressure (↓40% and ↓28%, respectively). Separate assessment of this relationship above and below the prevailing arterial pressure revealed that the pressor versus the depressor portion was blunted (P<0.001), a difference that was abolished after autonomic nervous system and renin-angiotensin system inhibition. The results suggest that spontaneous changes in arterial pressure are coupled to moment-to-moment changes in RIHP over a wide range of pressures, emphasizing a likely role for the dynamic component of the renal arterial pressure-RIHP relationship in the modulation of sodium excretion and, hence, arterial pressure.

Beneficial impact of exercise and obesity interventions on erectile function and its risk factors.

INTRODUCTION: Erectile dysfunction (ED) is a multifaceted disease involving cardiovascular, metabolic, and hormonal factors and affects over 100 million men worldwide. ED has been shown to be a harbinger of underlying cardiovascular diseases (CVD), as there are common risk factors (aging, hypertension, obesity) and mechanistic basis. AIM: To provide an update on clinical and experimental evidence regarding the impact of lifestyle modifications, such as exercise and diet, with respect to changes in erectile function. MAIN OUTCOME MEASURES: Published evidence regarding the impact of aging, hypertension, and obesity on ED and CVD, as well as new experimental data linking obesity and diminished erectile responses. METHODS: We reviewed the literature regarding common risk factors of ED and CVD, particularly involving obesity, as well as performed new analysis on the findings of other experimental studies involving diet and exercise interventions. RESULTS: Physical inactivity negatively impacts on erectile function, and experimental and clinical exercise interventions have been shown to improve sexual responses and overall cardiovascular health. Mediterranean-style diets and a reduction in caloric intake have been found to improve erectile function in men with the aspects of the metabolic syndrome. In addition, both clinical and experimental studies have confirmed that combining the two interventions provides additional benefit to erectile function, likely via reduced metabolic disturbances (e.g., inflammatory markers, insulin resistance), decreased visceral adipose tissue, and improvement in vascular function (e.g., increased endothelial function). CONCLUSIONS: Lifestyle modifications provide significant benefits to vascular health and erectile function in a population that is increasingly aged and more obese.

Altered regulation of renal interstitial hydrostatic pressure and the renal renin-angiotensin system in the absence of atrial natriuretic peptide.

BACKGROUND: Although it has been well established that atrial natriuretic peptide gene-disrupted (ANP-/-) mice are a useful model of salt-sensitive hypertension, surprisingly little is known about the control of their intrarenal renin-angiotensin system (RAS) and pressure-natriuresis mechanism, key components in blood pressure, fluid and electrolyte regulation. The aim of this study was to determine whether ANP disruption results in changes in the renal and adrenal local RAS and the acute pressure-natriuresis mechanism. METHODS: Renal and adrenal renin, angiotensin type 1 (AT1)(A and B) and angiotensin type 2 (AT2) receptor messenger RNA expression levels were determined by northern blotting or real time reverse transcriptase-polymerase chain reaction. Plasma aldosterone and renal and adrenal angiotensin II peptide levels were determined by radioimmunoassay. To examine the acute pressure-natriuresis response, changes in renal interstitial hydrostatic pressure (RIHP) were assessed after manipulations of renal arterial pressure (RAP) in anaesthetized mice. RESULTS: Renal and adrenal renin mRNA and angiotensin II levels were lower in ANP-/- and +/- mice compared with +/+mice. ANP-/- mice also had greater renal AT1A and adrenal AT2 mRNA levels compared with the other genotypes. RAP and RIHP were significantly higher in -/-mice compared with +/+mice. Furthermore, there was a blunted slope of the RAP-RIHP relationship after increases in RAP in ANP-/- mice. CONCLUSION: These data indicate that ANP disruption results in a blunting of the dynamic properties of the acute pressure-natriuresis mechanism at increased levels of RAP, as well as a reduced expression of renal and adrenal local RAS.

Long-term circulatory consequences of perinatal iron deficiency in male Wistar rats.

Perinatal iron deficiency (PID) has been reported to induce developmental abnormalities, including cardiovascular complications in rats. These complications are believed to be "programmed" by an aberrant perinatal environment because the changes persist long after the insult is corrected (ie, despite subsequent iron replenishment). Little is known about the mechanisms by which PID affects blood pressure in the offspring, although the kidney is likely to play a central role. The objective of this study was to investigate the circulatory complications of PID and the putative role of the kidney involved therein. Before and throughout gestation, female Wistar rats were fed either a low-iron diet (3 ppm/10 ppm Fe) or an iron-enriched diet (225 ppm Fe). After giving birth, all of the dams were placed on a standard grain-based diet. At 24 hours postpartum, hematocrits and hemoglobin levels from offspring of iron-deficient mothers were 60% and 59% of control values, respectively. Adult PID animals had greater mean arterial pressures (110 versus 106 mm Hg) and systolic blood pressures (129 versus124 mm Hg) than controls, as assessed by radiotelemetry. The relationship between renal arterial pressure and renal interstitial hydrostatic pressure, assessed in anesthetized rats, was blunted by 41% in the PID group compared with controls. In addition, arterial pressure changes were significantly greater in response to altered sodium in the PID animals compared with controls. These data confirm that PID adversely affects blood pressure control, which seems to be mediated, at least in part, by altered intrarenal hemodynamic properties.