Efficacy of theophylline compared to methylphenidate for the treatment of attention-deficit hyperactivity disorder in children and adolescents: a pilot double-blind randomized trial

Attention-deficit hyperactivity disorder (ADHD) is a common disorder of childhood that affects 3-6% of school children. Conventional stimulant medications are recognized as useful symptomatic treatments by both specialists and parents. Nevertheless, approximately 30% of ADHD children treated with them do not respond adequately or cannot tolerate the associated adverse effects. Such difficulties highlight the need for alternative, safe and effective medications in the treatment of this disorder. Theophylline is a psychomotor stimulant most widely used as a broncodilator. Purinergic modulation may be therapeutically beneficial in the treatment of psychiatric disorders. We hypothesized that theophylline would be beneficial for the treatment of ADHD and report results of a trial of theophylline compared with methylphenidate for the treatment of ADHD. A total of 32 children with ADHD as defined by DSM IV were randomized to theophylline and methylphenidate dosed on an age and weight-adjusted basis at 4 mg/kg/day (under 12 years) and 3 mg/kg/day theophylline (over 12 years) (group 1) and 1 mg/kg/day methylphenidate (group 2) for a 6-week double-blind and randomized clinical trial. The principal measure of the outcome was the Teacher and Parent ADHD Rating Scale. Patients were assessed by a child psychiatrist, at baseline and at 14, 28 and 42 days after start of the medication. No significant differences were observed between theophylline and methylphenidate on the Parent and Teacher Rating Scale scores over the trial (t = 0.49, d.f. = 24 P = 0.62 and t = 0.19, d.f. = 24 P = 0.54 respectively). Although the number of dropouts in the methylphenidate group was higher than the theophylline group, there was no significant difference between the two protocols in terms of the dropouts. In addition, headaches were observed more often in the methylphenidate group. The results suggest that theophylline may be a useful for the treatment of ADHD. In addition, a tolerable side-effect profile is one of the advantages of theophylline in the treatment of ADHD. Nevertheless, our study is small and our results would need to be confirmed in a larger study.     

Sensory Processing Disorder: Implications for Primary Care Nurse Practitioners

Children are being seen more readily by nurse practitioners when behavioral concerns arise. Attention-deficit/hyperactivity disorder (ADHD) is a common and costly behavioral condition seen by nurse practitioners. ADHD may also affect children’s sensory processing. Symptoms of ADHD often include those of sensory processing dysfunction. Sensory processing disorder, a condition in which sensory processing dysfunction impacts everyday functioning, is a condition commonly seen with ADHD. For children with ADHD and associated conditions, it is important for nurse practitioners to be versed in conservative management of these conditions, including occupational therapy.     

Evaluation of the effect of methylphenidate by computed tomography, electroencephalography, neuropsychological tests, and clinical symptoms in children with attention-deficit/hyperactivity disorder: A prospective cohort study

Background: Stimulant drugs are the most commonly used treatments for attention-deficit/hyperactivity disorder (ADHD), although the mechanism of action of these drugs is still not entirely understood.Objective: The aim of this study was to investigate the effects of the psychostimulant drug methylphenidate (MPH) on regional cerebral blood flow (rCBF), electrical activity of the brain, and clinical symptoms in children with ADHD using single-photon emission computed tomography (SPECT), electroencephalography (EEG), and neuropsychological tests.Methods: In this prospective cohort study, pediatric outpatients received MPH for 3 months at a mean dose of 1 mg/kg · d (range, 0.5-1.5 mg/kg · d). They were then administered the Wechsler Intelligence Scale for Children-Revised, the Bender Visual-Motor Gestalt Test (BGT), EEG, and SPECT of the brain. The parents and/or teacher of each child were asked to complete the Conners' Parent Rating Scale (CPRS), the Conners' Teacher Rating Scale (CTRS), and the Turgay Diagnostic and Statistical Manual of Mental Disorders Fourth Edition-based Child and Adolescent Behavior Disorders Screening and Rating Scale (T-DSM-IV-S). All of the evaluations were performed at baseline and after 3 months of MPH treatment. Each child underwent a Stroop test as an activation method 15 minutes before the SPECT procedure.Results: Sixty patients were assessed for inclusion. Twenty-one children (18 boys [85.7%], 3 girls [14.3%]; mean [SD] age, 9.7 [1.7] years; range, 8-13 years) with a diagnosis of ADHD were included in and completed the study. Mean (SD) BGT scores before MPH treatment compared with after MPH treatment were significantly decreased (9.8 [4.2] vs 6.3 [3.4]; Z = -3.27; P = 0.001). After treatment with MPH, the visual SPECT results suggested that low rCBF was normalized in the right frontotemporal areas in 10 children with ADHD. After treatment, 12 patients (57.1%) had no change in EEG activity, 5 (23.8%) had improvement, and 4 (19.0%) had worsening activity. Patients who had improvement or no worsening on EEG after MPH treatment were associated with significant improvement after MPH treatment compared with before treatment in mean (SD) CTRS scores (25.9 [14.3] vs 35.0 [14.4]; P = 0.003), teachers' T-DSM-IV-S total score (25.1 [14.2] vs 38.4 [18.7]; P = 0.005), and CPRS scores (mothers scores: 29.7 [16.6] vs 42.6 [17.2], P = 0.002; fathers' scores: 29.4 [16.8] vs 41.9 [23.7], P = 0.004). No significant difference was found in these scores in the patients whose EEG findings showed deterioration after MPH treatment. The quantitative values for SPECT observed before treatment compared with those observed after 3 months of MPH treatment were not found to be significantly different in any areas of the brain.Conclusions: MPH use over 3 months was associated with improvement from baseline in visual-motor function and behavioral disorders in these children and adolescents with ADHD. However, no significant difference in rCBF or electrical activity in the brain was observed in this small study.     

Rheumatoid arthritis

Abstract

Objectives: To examine the clinical effects of equivalent doses of single-blind (SB; patient-blind) lisdexamfetamine (LDX) and mixed amphetamine salts-immediate release (MAS-IR) on adult attention-deficit/hyperactivity disorder (ADHD) in a placebo (PBO)-controlled, crossover design. Methods: Twenty-four subjects were treated sequentially in a fixed order with (1) SB PBO (matching LDX) for 1 week, (2) SB LDX (up to 70 mg/day) for 5 weeks, (3) SB PBO washout for 3 weeks, and (4) open-label treatment MAS-IR (tid up to 45 mg/day) for 5 weeks. Clinical effects on ADHD and executive function were assessed weekly throughout the trial with the ADHD Rating Scale with adult prompts, the Clinical Global Impression Severity Scale (CGI-S), and the Behavior Rating Inventory of Executive Function (BRIEF). Results: Lisdexamfetamine and MAS-IR were generally well tolerated. Significant and equal reductions on ADHD clinician ratings were seen. Significantly greater reductions in CGI-S and selected BRIEF subsets were observed in LDX over MAS-IR treatment. However, in general, baseline scores for MAS-IR treatment did not fully return to the LDX baseline. Adherence in this structured and monitored clinical trial was good for once daily LDX and 3 times a day MAS-IR. Conclusions: In this crossover study, both LDX and MAS-IR had significant effects on ADHD clinician ratings and measures of executive function (with response rates of about 80%); patients in this monitored clinical trial were adherent with once daily LDX and 3 times a day MAS-IR, which may not be the case in real-world clinical practice. The findings of some superiority of LDX over MAS-IR on the CGI-S and BRIEF ratings may be influenced by the variability in the baselines used, but nevertheless should be further investigated in larger scale, parallel-design clinical trials.     

Section III. Nutrients in Convalescence and Rehabilitation

Tarsal coalition is a congenital anomaly, but infection can lead to fusions that are virtually indistinguishable from the congenital lesion. The defect may be unilateral or bilateral, and symptoms increase with age. Surgical fusion of the subtalar joints will relieve the pain.     

Pain and the physician

Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section.     

Accidental hypothermia

The Editor welcomes readers' comments, and selected letters are published each month. Letters must be signed and should be sent to Editor's Mail at the address shown. The journal reserves the right to condense letters if necessary for space.     

Drug Interactions with Cimetidine

New antimicrobial pathogens resistant to vancomycin are wreaking havoc in medical centers throughout the nation. Their tendency to colonize or infect severely ill, hospitalized patients who have undergone invasive procedures and received prolonged courses of antimicrobial therapy is alarming. The most potent weapon in the physician's arsenal against these enemies is familiarity with their key features, with the guidelines for prudent use of drug therapy, and with the precautionary measures necessary to limit contact and spread.     

Treating Child and Adolescent Attention-Deficit/Hyperactivity Disorder and Behavioral Disorders in Primary Care

Attention-deficit/hyperactivity disorder (ADHD) and behavioral disorders are 2 of the most common mental health diagnoses in child and adolescent patients. Many patients seeking treatment for these disorders will initially present to a primary care provider (PCP). PCPs need to be able to identify ADHD or behavioral disorders with a thorough history, possibly aided by a screening tool. Pharmacologic interventions are considered first-line treatment for ADHD, but behavioral interventions and school modifications can enhance care. PCPs suspecting a patient of having a behavioral disorder should refer to a psychiatric specialist for treatment.     

Preventing pulmonary embolism with heparin in low doses

Wide use of heparin as prophylaxis in selected persons at high risk of thrombosis promises to reduce the incidence of pulmonary embolism dramatically. Administered in low doses, heparin prevents deep-vein thrombosis yet avoids bleeding complications and the need for laboratory monitoring.     

Hypertension

Hand injuries can often be treated in the primary care physician's office or in the emergency department, but only after careful examination has determined that referral is not necessary or can be delayed. In this article, Drs Sturm and Cicero describe the examination of the injured hand, discuss emergency treatment of minor injuries, and suggest which injuries require referral to a specialist.     

A Post Hoc Comparison of Prior ADHD Medication Dose and Optimized Delayed-release and Extended-release Methylphenidate Dose in a Pivotal Phase III Trial

PurposeHLD200 is the first evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH) designed to delay initial release of MPH and provide treatment effects throughout the day and into the evening for individuals with attention-deficit/hyperactivity disorder (ADHD). Because DR/ER-MPH is uniquely absorbed in the colon, it cannot be substituted for other ADHD medications on a milligram-per-milligram basis. To provide clinicians with a target dose range for DR/ER-MPH when transitioning patients from a prior ADHD medication, dose conversion ratios (DCRs) between prior medication doses and optimized doses of DR/ER-MPH were determined post hoc from a pivotal Phase III study of children (aged 6–12 years) with ADHD.MethodsDR/ER-MPH doses were optimized over a 6-week open-label period. DCRs were calculated between optimized doses of DR/ER-MPH at week 6 and prior stable doses of ADHD medication.FindingsMean DCRs ranged from 1.8 to 4.3 for optimized DR/ER-MPH dose versus previous stable dose for individuals taking an extended-release stimulant monotherapy. DCRs for those taking an immediate-release stimulant monotherapy ranged from 4.7 to 6.0.ImplicationsIn a Phase III trial of children with ADHD, optimized doses of DR/ER-MPH were higher than doses of prior ADHD medications, but the adverse event profile was consistent with that of other MPHs. Higher DCRs compared with those predicted by bioavailability differences are consistent with a predicted dose-dependent duration of effect for DR/ER-MPH: with increasing doses, absorption is extended but with an attenuated increase in C_max compared with MPH formulations absorbed in the upper bowel. These data may help guide clinicians to optimize DR/ER-MPH doses. ClinicalTrials.gov identifier: NCT02493777.     

The medical bookshelf

To help you save time in identifying those meetings and courses of greatest interest to you, POSTGRADUATE MEDICINE offers this objectively rated listing as a regular reader service. Each event has been rated on the factors that matter most to you: relevance of the subject to primary care, number of credit hours, cost per credit hour (registration fee only), sponsorship, and meeting site. One to four stars are awarded on the basis of the combined score for these factors.     

Physician-at-large

PREVIEW

In about 50% of patients with pulmonary embolism, the embolism is massive, that is, accompanied by at least one of several potentially compromising conditions. Unfortunately, about three fourths of patients who die of pulmonary embolism do so within 1 hour of symptom onset. Thus, expeditious assessment of patients with suspected massive pulmonary embolism is crucial. In this article, Dr Gossage discusses prompt recognition of this condition and presents several management strategies.     

The Chronic Care Model and Attention-Deficit/Hyperactivity Disorder: A Novel Approach to Improving the Transition to Postsecondary Education

The transition from high school to further education is challenging. Current studies support that young adults with attention-deficit/hyperactivity disorder (ADHD) may be at higher than average risk for academic underachievement. Currently, the management of ADHD follows a medical model emphasizing episodic care rather than a holistic, longitudinal approach befitting the chronic nature of the disorder. The symptoms and effects of ADHD are pervasive and require a concerted effort from a variety of disciplines to effectively diagnose and treat the disorder. The Chronic Care Model (CCM) offers a novel approach to the management of ADHD and through adaptation has the potential to improve treatment adherence and patient outcomes. The CCM is currently being successfully implemented in patients living with chronic illnesses such as diabetes, depression, and asthma. The CCM is a team approach deemed to be quite successful, especially for patients less likely to adhere to treatment, such as patients with ADHD. The CCM includes 6 components: health systems or organizations, delivery system, clinical information system, decision support, community resources and policy, and self-management support. The focus on patient-centered, coordinated care with an emphasis on self-management offers a novel approach to improving the outcomes for those with ADHD in their transition to college.     

The Child With Recurrent Infections

The child who has a history of recurrent infections may have any of a wide variety of diseases caused by defective functioning of the host's defenses. Clinical manifestations depend on a quantitative deficiency or a qualitative functional disturbance of an immunologically important cell or organ. These disorders are potentially disabling and often life-threatening; thus, the physician must be aware of the features of the presently known immunologic disorders.     

The Role of Alpha2-Adrenergic Agonists in Attention-Deficit/Hyperactivity Disorder

Abstract

Psychostimulants are first-line therapy for patients with attention-deficit/hyperactivity disorder (ADHD). However, some patients are not optimal responders to monotherapy or present as comorbid for a variety of other disorders that either preclude the use of stimulants or produce a symptom complex that is resistant to monotherapy. Unfortunately, there are few agents well studied in combination with psychostimulants for patients with ADHD. The combination of psychostimulants with alpha₂-adrenergic agonists may offer a complementary approach to treating such complex patients. The rationale for combination therapy is that the primary effects of stimulants and alpha₂-adrenergic agonists are mediated by different but complementary mechanisms of action, emphasizing different neurotransmitter systems, which together modulate prefrontal cortex functioning. Although immediate-release clonidine and guanfacine have long been studied in ADHD, their usage has been limited by rapid absorption and clearance, negative side effects, and reduced efficacy compared with stimulants. New controlled-release formulations of the alpha₂-adrenergic agonists have overcome some of these limitations, with recent clinical trials demonstrating their enhanced tolerability and effectiveness for treatment of ADHD in children and adolescents. Studies with each of these new formulations (ie, guanfacine extended release and clonidine hydrochloride extended-release tablets) in combination with psychostimulants have demonstrated that the addition of an alpha₂-adrenergic agonist to psychostimulant therapy significantly enhances efficacy without compromising safety. This review will encompass the clinical study database for novel formulations of alpha₂-adrenergic agonists, enabling the reader to appreciate their place in ADHD treatment as well as the potential utility of a combination approach with psychostimulants for patients with complex ADHD.     

Atomoxetine treatment in adults with attention-deficit/hyperactivity disorder

Background: Attention-deficit/hyperactivity disorder (ADHD) is a CNS disorder that has its onset in childhood, but often persists into adulthood. There is growing recognition that adult ADHD can result in multiple negative consequences for individuals. ADHD is also often associated with a number of comorbid psychiatric disorders. Atomoxetine (ATX), a nonstimulant, selective noradrenergic reuptake inhibitor, was approved in the United States in 2002 for the treatment of ADHD in children and adolescents, as well as adults. We review here the safety and efficacy of ATX in adults with ADHD, including data in special populations, functional outcomes, as well as provider and patient real-world perceptions. Methods: We searched the databases Embase, MEDLINE and PsycINFO using the terms ‘ADHD’ and ‘adult’ and ‘ATX’ capturing publications from January 1, 1998, to March 27, 2014. Only publications in English were considered. Results: ATX demonstrated significantly greater improvement than placebo (PBO) on the Conners Adult ADHD Rating Scale-Investigator rated:Screening Version (CAARS-Inv:SV) in all trials (N = 6; total score difference ranged from ?3.5 to ?5.5). For long-term trials using the CAARS-Inv:SV, ATX demonstrated significantly greater improvement than PBO in three of four trials (total score differences ranged from ?0.1 to ?6.0). In short-term studies, ATX showed significantly greater improvement than PBO on the Adult ADHD Quality-of-Life scale total score in three of three studies, but results were mixed on the Sheehan Disability Scale. Three studies of ATX have reported statistically significant improvement (compared with PBO) on the Behavior Rating Inventory of Executive Function-Adult Version Self Report scale. The most common adverse events (occurring in ≥ 10% of patients taking ATX) were nausea, dry mouth, decreased appetite, insomnia and fatigue. Conclusions: ATX is an important treatment option for the right patient. ATX can provide long-term, consistent symptom relief and functional improvement for adults with ADHD.     

Healthcare provider perspectives on diagnosing and treating adults with attention-deficit/hyperactivity disorder

Objective: This study examined adult attention-deficit/hyperactivity disorder (ADHD) screening and management patterns among healthcare provider (HCP) subgroups.

Methods: An online survey of US-based HCPs (neurologists, n = 200; nurse practitioners [NPs], n = 100; psychiatrists, n = 201; primary care physicians [PCPs], n = 201) was conducted from May to June 2017. The survey assessed issues relating to adult ADHD screening and management and HCP perceptions of factors influencing patient choice of pharmacotherapy. Participants were required to be experienced in diagnosing and/or treating ADHD in adults (≥5 patients/month for neurologists and NPs; ≥10 patients/month for psychiatrists and PCPs).

Results: Significantly greater percentages of psychiatrists than non-psychiatrists were confident in diagnosing ADHD (P < 0.001) and screened/evaluated for ADHD in patients with depression/anxiety disorders (P < 0.001). Significantly greater percentages of psychiatrists versus non-psychiatrists prescribed once-daily long-acting (LA) stimulants (71.6% vs 62.2%; P = 0.023) or short-acting (SA) stimulants more than once daily (40.3% vs 29.7%; P = 0.009) as first-line therapy. In contrast, a significantly greater percentage of non-psychiatrists than psychiatrists prescribed once-daily SA stimulants (32.9% vs 17.4%; P < 0.001). Psychiatrist and non-psychiatrist HCPs viewed insurance coverage/treatment costs (79.9%), perceived duration of effect (72.2%), and side effects (66.5%) as important factors to patients when choosing treatment. HCPs reported that the greatest mean ± SD percentages of patients changed their treatment regimen in the past 6 months because of perceptions of insufficient duration of effect (35.4% ± 22.1%) and lack of efficacy (30.3% ± 21.0%).

Conclusion: Compared with psychiatrists, non-psychiatrists exhibited less confidence in diagnosing adult ADHD and experienced greater difficulty determining optimal treatment regimens.     

Telecast of a Cholecystectomy

Three surgeons look on as a fourth removes the gallbladder of a 50 year old woman. The informal discourse between the viewers and the operating surgeon deals mainly with technic.