Ingeborg M. van Geijlswijk

Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia

Abstract:  We conducted this study to assess long‐term melatonin treatment course, effectiveness and safety in children with attention‐deficit/hyperactivity disorder (ADHD) and chronic sleep onset insomnia (CSOI). This was conducted by means of a structured questionnaire for the parents. The subjects of this study consisted of participants who previously participated in a randomised clinical trial on melatonin efficacy. The response rate was 93% (94/101). The mean time to follow up was 3.7 yr. No serious adverse events or treatment related co‐morbidities were reported. Sixty‐five percent of the children still used melatonin daily and 12% occasionally. Temporal discontinuation of treatment resulted in a delay of sleep onset in 92% of the children. Nine percent of the children could discontinue melatonin completely because of improvement of sleep onset insomnia. Long‐term melatonin treatment was judged to be effective against sleep onset problems in 88% of the cases. Improvement of behaviour and mood was reported in 71% and 61% respectively. We conclude that melatonin remains an effective therapy on the long term for the treatment of CSOI in children with ADHD and has no safety concerns regarding serious adverse events or treatment related co‐morbidity. Discontinuation of melatonin treatment usually leads to a relapse of sleep onset insomnia and in resuming melatonin treatment, even after several years of treatment.

Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysis.

Recent meta‐analyses on melatonin has raised doubts as to whether melatonin is effective in treating sleep problems in people without intellectual disabilities. This is in contrast to results of several trials on melatonin in treating sleep problems in individuals with intellectual disabilities. To investigate the efficacy of melatonin in treating sleep problems in individuals with intellectual disabilities, we performed a meta‐analysis of placebo‐controlled randomized trials of melatonin in individuals with intellectual disabilities and sleep problems. Data were selected from articles published on PubMed, Medline, and Embase between January 1990 and July 2008. We examined the influence of melatonin on sleep latency, total sleep time, and number of wakes per night. Quality of trials was assessed using the Downs and Black checklist. Nine studies (including a total of 183 individuals with intellectual disabilities) showed that melatonin treatment decreased sleep latency by a mean of 34 minutes (p<0.001), increased total sleep time by a mean of 50 minutes (p<0.001), and significantly decreased the number of wakes per night (p<0.05). Melatonin decreases sleep latency and number of wakes per night, and increases total sleep time in individuals with intellectual disabilities.

Site-Specific Intracoronary Heparin Delivery in Humans After Balloon Angioplasty A Radioisotopic Assessment of Regional Pharmacokinetics

BACKGROUND Demonstration and quantification of site-specific intracoronary administration of compounds has been confined thus far to the experimental animal laboratory. The aim of this study was to describe a scintigraphic method to demonstrate site-specific intracoronary drug delivery in humans. The methods allow on-line visualization and off-line quantification of site-specifically infused gamma-emitting compounds. METHODS AND RESULTS In 12 patients after balloon angioplasty, 99mTc-labeled heparin was administered at the site of dilatation by use of a coil balloon. Both the infusion period and the washout period after the end of infusion were monitored with a gamma-camera. A curve of counts per pixel as a function of time was derived that showed an accumulation phase during infusion followed by washout phase after the end of infusion. Both phases were fitted by regression analysis and showed a linear accumulation pattern and a biexponential washout pattern. After correction for background counts, 99mTc decay, and body attenuation, peak heparin amount and regional bioavailability were calculated. Peak amount was defined as the initial point of the slow washout component of the biexponential curve (elimination component), and regional bioavailability was defined as the area under the curve of accumulation and washout phase. Half-life and retention time, define as seven half-lives, were obtained by use of the elimination component after correction for 99mTc decay. Mean peak delivered amount was 45 +/- 44 IU (236 +/- 228 micrograms), corresponding to an efficiency of delivery ranging from 1% to 8% of the totally infused dose. Total regionally bioavailable heparin reached 244 +/- 194 IU.h (1.28 +/- 1.01 mg.h). Retention time varied from 12 to 90 hours (mean, 50:33 +/- 22:50 hours:minutes). CONCLUSIONS Site-specific intracoronary heparin delivery after angioplasty by means of the coil balloon was demonstrated in humans, and regional pharmacokinetics was quantified by use of a radioisotopic technique.

Ciprofloxacin pharmacokinetics in critically ill patients: a prospective cohort study.

PURPOSE Optimal dosing of antibiotics is important for efficacy and avoidance of resistance. Fluoroquinolones are frequently used to treat severe infections in critically ill patients. We studied ciprofloxacin pharmacokinetics after administration of 400 mg twice a day (bid) intravenously (IV). MATERIAL AND METHODS Serum concentrations were measured in 32 intensive care unit patients (age, 68.7 +/- 17.4 years; Sepsis-related Organ Failure Assessment (SOFA) scores, 7.3 +/- 3.4). Blood samples were drawn at 7 time points after ciprofloxacin infusion. We evaluated whether areas under the curve (AUCs) exceeded minimal inhibitory concentration (MIC) values of 0.125, 0.25, 0.5, 1.0, and 2.0 mg/L by 125 times and peak concentrations (C(max)) 10 x MIC (C(max)/MIC >10). RESULTS The AUC/MIC more than 125 was achieved in 100% for MIC 0.125. For MIC values 0.25, 0.5, 1.0, and 2.0, results were 84%, 31%, 3%, and 0%, respectively (P < .01). The C(max)/MIC more than 10 for MIC values of 0.125, 0.25, 0.5, 1.0, and 2.0 was realized in 100%, 97%, 69%, 25%, and 0%, respectively (P < .01). Female sex, SOFA(pulmonary) points, and SOFA(renal) points predicted higher AUC. Cumulative SOFA scores were most predictive of high AUCs. CONCLUSIONS Ciprofloxacin 400 mg bid IV leads to inadequate AUC/MIC and C(max)/MIC ratios in many cases. Effective killing concentrations were only achieved in pathogens with MIC less than 0.25. As bacteria in intensive care unit patients often exceed this threshold, we recommend to use higher doses of ciprofloxacin (1200 mg daily) to ensure optimal bacterial killing and avoid antibiotic resistance.

Consumption of antimicrobials in pigs, veal calves, and broilers in the Netherlands: quantitative results of nationwide collection of data in 2011.

In 2011, Dutch animal production sectors started recording veterinary antimicrobial consumption. These data are used by the Netherlands Veterinary Medicines Authority to create transparency in and define benchmark indicators for veterinary consumption of antimicrobials. This paper presents the results of sector wide consumption of antimicrobials, in the form of prescriptions or deliveries, for all pig, veal calf, and broiler farms. Data were used to calculate animal defined daily dosages per year (ADDD/Y) per pig or veal calf farm. For broiler farms, number of animal treatment days per year was calculated. Furthermore, data were used to calculate the consumption of specific antimicrobial classes per administration route per pig or veal calf farm. The distribution of antimicrobial consumption per farm varied greatly within and between farm categories. All categories, except for rosé starter farms, showed a highly right skewed distribution with a long tail. Median ADDD/Y values varied from 1.2 ADDD/Y for rosé finisher farms to 83.2 ADDD/Y for rosé starter farms, with 28.6 ADDD/Y for white veal calf farms. Median consumption in pig farms was 9.3 ADDD/Y for production pig farms and 3.0 ADDD/Y for slaughter pig farms. Median consumption in broiler farms was 20.9 ATD/Y. Regarding specific antimicrobial classes, fluoroquinolones were mainly used on veal calf farms, but in low quantities: P75 range was 0 – 0.99 ADDD/Y, and 0 – 0.04 ADDD/Y in pig farms. The P75 range for 3rd/4th-generation cephalosporins was 0 – 0.07 ADDD/Y for veal calf farms, and 0 – 0.1 ADDD/Y for pig farms. The insights obtained from these results, and the full transparency obtained by monitoring antimicrobial consumption per farm, will help reduce antimicrobial consumption and endorse antimicrobial stewardship. The wide and skewed distribution in consumption has important practical and methodological implications for benchmarking, surveillance and future analysis of trends.

Comparing antimicrobial exposure based on sales data

This paper explores the possibilities of making meaningful comparisons of the veterinary use of antimicrobial agents among countries, based on national total sales data. Veterinary antimicrobial sales data on country level and animal census data in both Denmark and the Netherlands were combined with information about estimated average dosages, to make model calculations of the average number of treatment days per average animal per year, at first based on the assumption that the treatment incidence is the same in all species and production types. Secondly, the exposure in respectively animals for meat production and dairy and other cattle (excluding veal and young beef) was estimated, assuming zero use in the dairy and other cattle, and thirdly by assuming respectively 100% oral and 100% parenteral administration. Subsequently, the outcomes of these model calculations were compared with treatment incidences calculated from detailed use data per animal species from the national surveillance programmes in these two countries, to assess their accuracy and relevancy. In Denmark and in the Netherlands, although the computed antimicrobial exposure would seem to be a reasonable estimation of the exposure for all animals as a whole, it differs significantly from the measured exposure for most species. The differences in exposure among animal species were much higher than the overall difference between the two countries. For example, the overall model estimate of 9 treatment days per year for Denmark is a severe overestimation of the true use in poultry (i.e. 3 days), and the overall model estimate of 13 treatment days per year for the Netherlands is a severe underestimation of the true use in veal calves (i.e. 66 days). The conclusion is that simple country comparisons, based on total sales figures, entail the risk of serious misinterpretations, especially if expressed in mg per kg. The use of more precise model calculations for making such comparisons, taking into account differences in dosages and in farm animal demographics, only slightly reduces this risk. Overall model estimates are strongly influenced by animal demographics and a very inaccurate indication of the true differences in exposure, per animal species. To get an appropriate certainty about the true differences in antimicrobial exposure between countries it is an absolute necessity to have reliable information about the use per animal species.

Antimicrobial prescription patterns of veterinarians: introduction of a benchmarking approach

Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands; Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands; Central Veterinary Institute of Wageningen UR, Lelystad, The Netherlands; Pharmacy, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands; Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, The Netherlands

Extracorporeal elimination in acute valproate intoxication

Severe poisoning with valproate may result in coma and death. The management of valproate intoxication is principally supportive. Valproate is scarcely excreted renally and is mainly protein bound and, therefore, not considered to be amenable for extracorporeal elimination. Despite these unfavourable pharmacokinetic properties, several case reports showed successful treatment of valproate intoxication with haemodialysis and/or haemoperfusion. We describe a male patient (57 years) after ingestion of 64 g of valproate. The patient was successfully treated with haemodialysis for 6 h. Haemodialysis was followed by continuous venovenous haemodiafiltration (CVVH-D) for 18 h to prevent a rebound phenomenon. This report confirms the benefit of haemodialysis in serious valproate overdose. A review of the literature shows that haemodialysis followed by CVVH-D is the treatment of choice in severe valproate intoxication.

Prudent Use of Antimicrobials in Exotic Animal Medicine

Reduction of antimicrobial use can result in reduction of resistance in commensal bacteria. In exotic animals, information on use of antimicrobials and resistance in commensals and pathogens is scarce. However, use of antimicrobials listed as critically important antimicrobials for human medicine seems high in exotic animals. Ideally, the selection of a therapy should be based on an accurate diagnosis and antimicrobial susceptibility testing. When prescribing antimicrobials based on empiricism, knowledge of the most common pathogens causing specific infections and the antimicrobial spectrum of antimicrobial agents is indispensable. Implementing antimicrobial stewardship promotes the prudent use of antimicrobials in exotic animals.

Long-Term Melatonin Therapy for Adolescents and Young Adults with Chronic Sleep Onset Insomnia and Late Melatonin Onset: Evaluation of Sleep Quality, Chronotype, and Lifestyle Factors Compared to Age-Related Randomly Selected Population Cohorts

The extent of continuance of melatonin therapy initiated in pre-pubertal children with chronic sleep onset insomnia (CSOI) was investigated in young adult life. Sleep timing, sleep quality, adverse events, reasons for cessation of therapy, and patient characteristics with regard to therapy regimen, chronotype and lifestyle factors possibly influencing sleeping behavior were assessed. With an online survey using questionnaires (Pittsburgh Sleep Quality Index, Insomnia Severity Index, Morningness-Eveningness Questionnaire, and Munich Chronotype Questionnaire), outcomes were measured and compared with age-related controls. These controls were extracted from published epidemiological research programs applying the same questionnaires. At the moment of the survey, melatonin was still continued by 27.3% of the patients, with a mean treatment duration of 10.8 years. The overall average treatment duration was 7.1 years. Sleep quality of both discontinued and persistent melatonin users did not deviate from controls. Sleep timing and chronotype scores indicated evening type preference in all responders. Adverse events were scarce but the perceived timing of pubertal development suggested a tendency towards delayed puberty in former and current users of melatonin. This study may underestimate the number of children that are able to stop using melatonin due to the response rate (47.8%) and appeal for continuing users. Sleep timing parameters were based on self-reported estimates. Control populations were predominantly students and were of varying nationalities. The statistical power of this study is low due to the limited sample size. Melatonin therapy sustained for 7.1 years does not result in substantial deviations of sleep quality as compared to controls and appears to be safe. The evening type preference suggests a causal relation with CSOI. This study shows that ten years after initiation of treatment with melatonin for CSOI, approximately 75% of the patients will have normal sleep quality without medication.