Off-label prescribing of psychotropic drugs in a Danish child and adolescent psychiatric outpatient clinic.

This study aimed to describe the level of off-label treatment with psychotropic drugs at a child and adolescent psychiatric outpatient clinic in Denmark. We performed a cross-sectional study assessing records on patients treated with medicine at two outpatient clinics at the child and adolescent psychiatric ward, on 1 day in 2014. Prescriptions of drugs from ATC group N05-N06 were classified according to label status. Six hundred and fifteen drug prescriptions distributed on nine different drugs were prescribed to 503 children eligible for this study. Overall results showed that 170 of the 615 prescriptions were off-label, which corresponds to 27.6 %. Attention deficit hyperkinetic disorder (ADHD) drugs were prescribed 450 times (73.2 %) of which 11 prescriptions were off-label (2.4 %). Other psychotropic drugs comprised 165 (26.8 %) prescriptions and of these 159 (96.4 %) were off-label. With 106 prescriptions, melatonin was the most prescribed of these drugs; all prescriptions were off-label. The main reasons for classifying prescriptions as off-label were age and indication of treatment. This cross-sectional study reveals that medical treatment of children with other psychotropic drugs than ADHD drugs is usually off-label. ADHD drugs were, as the only drug group, primarily prescribed on-label. Although off-label prescription may be rational and even evidence based, the responsibility in case of, e.g. adverse drug reactions is a challenge, and clinical trials in children should be incited.

Effects of human insulin and insulin aspart preparations on levels of IGF-I, IGFBPs and IGF bioactivity in patients with type 1 diabetes.

BACKGROUND: Insulin aspart (IAsp) and its biphasic preparations BIAsp50 and BIAsp70 (containing 50% and 70% IAsp, respectively) have distinct glucose-lowering properties as compared to human insulin (HI). We investigated whether this affected the circulating IGF-system which depends on the hepatic insulin exposure. METHODS: In a randomized, four-period crossover study, 19 patients with type 1 diabetes received identical doses (0.2 U/kg sc) of IAsp, BIAsp70, BIAsp50 and HI together with a standardized meal. Serum total IGF-I and IGFBP-1 to -3 were measured by immunoassays for nine hours post-prandially. Bioactive IGF was determined by an in-house, cell-based IGF-I receptor kinase activation (KIRA) assay. RESULTS: Despite marked differences in peripheral insulin concentrations and plasma glucose, the four insulin preparations resulted in parallel decreases in IGFBP-1 levels during the first 3 hours, and parallel increases during the last part of the study (3-9 hours). Thus, only minor significances were seen. Insulin aspart and human insulin resulted in a lower area under the curve (AUC) during the first 3 hours as compared to BIAsp70 (p = 0.009), and overall, human insulin resulted in a lower IGFBP-1 AUC than BIAsp70 (p = 0.025). Nevertheless, responses and AUCs of bioactive IGF were similar for all four insulin preparations. Changes in levels of bioactive IGF were inversely correlated to those of IGFBP-1, increasing during the first 3 hours, whereafter levels declined (-0.83 ≤ r ≤ -0.30; all p-values <0.05).Total IGF-I and IGFBP-3 remained stable during the 9 hours, whereas IGFBP-2 changed opposite of IGFBP-1, increasing after 3-4 hours whereafter levels gradually declined. The four insulin preparations resulted in similar profiles and AUCs of total IGF-I, IGFBP-2 and IGFBP-3. CONCLUSIONS: Despite distinct glucose-lowering properties, the tested insulin preparations had similar effects on IGF-I concentration and IGF bioactivity, IGFBP-2 and IGFBP-3 as compared to HI; only small differences in IGFBP-1 were seen and they did not affect bioactive IGF. Thus, insulin aspart containing preparation behaves as HI in regards to the circulating IGF-system. However, bioactive IGF appeared to be more sensitive to insulin exposure than total IGF-I. The physiological significance of this finding remains to be determined. TRIAL REGISTRATION: NCT00888732.

The short-term and long-term adverse effects of melatonin treatment in children and adolescents: a systematic review and GRADE assessment.

Background: Currently, melatonin is used to treat children and adolescents with insomnia without knowing the full extent of the short-term and long-term consequences. Our aim was to provide clinicians and guideline panels with a systematic assessment of serious-and non-serious adverse events seen in continuation of melatonin treatment and the impact on pubertal development and bone health following long-term administration in children and adolescents with chronic insomnia. Methods: We searched PubMed, Embase, Cinahl and PsycINFO via Ovid, up to March 17, 2023, for studies on melatonin treatment among children and adolescents (aged 5-20 years) with chronic insomnia. The language was restricted to English, Danish, Norwegian, and Swedish. Outcomes were non-serious adverse events and serious adverse events assessed 2-4 weeks after initiating treatment and pubertal development and bone health, with no restriction on definition or time of measurement. Observational studies were included for the assessment of long-term outcomes, and serious and non-serious adverse events were assessed via randomised studies. The certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The protocol is registered with the Danish Health Authority. Findings: We identified 22 randomised studies with 1350 patients reporting on serious-and non-serious adverse events and four observational studies with a total of 105 patients reporting on pubertal development. Melatonin was not associated with serious adverse events, yet the number of patients experiencing non-serious adverse events was increased (Relative risk 1.56, 95% CI 1.01-2.43, 17 studies, I2 = 47%). Three studies reported little or no influence on pubertal development following 2-4 years of treatment, whereas one study registered a potential delay following longer treatment durations (>7 years). These findings need further evaluation due to several methodological limitations. Interpretation: Children who use melatonin are likely to experience non-serious adverse events, yet the actual extent to which melatonin leads to non-serious adverse events and the long-term consequences remain uncertain. This major gap of knowledge on safety calls for caution against complacent use of melatonin in children and adolescents with chronic insomnia and for more research to inform clinicians and guideline panels on this key issue. Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation.

Use of melatonin for children and adolescents with chronic insomnia attributable to disorders beyond indication: a systematic review, meta-analysis and clinical recommendation.

Background: Melatonin has become a widely used sleeping aid for young individuals currently not included in existing guidelines. The aim was to develop a recommendation on the use of melatonin in children and adolescents aged 2-20 years, with chronic insomnia due to disorders beyond indication. Methods: We performed a systematic search for guidelines, systematic reviews, and randomised trials (RCTs) in Medline, Embase, Cochrane Library, PsycInfo, Cinahl, Guidelines International Network, Trip Database, Canadian Agency for Drugs and Technologies in Health, American Academy of Sleep Medicine, European Sleep Research Society and Scandinavian Health Authorities databases. A separate search for adverse events was also performed. The latest search for guidelines, systematic reviews, and adverse events was performed on March 17, 2023. The latest search for RCTs was performed on to February 6, 2023. The language was restricted to English, Danish, Norwegian, and Swedish. Eligible participants were children and adolescents (2-20 years of age) with chronic insomnia due to underlying disorders, in whom sleep hygiene practices have been inadequate and melatonin was tested. Studies exclusively on autism spectrum disorders or attention deficit hyperactive disorder were excluded. There were no restrictions on dosage, duration of treatment, time of consumption or release formula. Primary outcomes were quality of sleep, daytime functioning and serious adverse events, assessed at 2-4 weeks post-treatment. Secondary outcomes included total sleep time, sleep latency, awakenings, drowsiness, quality of life, non-serious adverse events, and all-cause dropouts (assessed at 2-4 weeks post-treatment), plus quality of sleep and daytime functioning (assessed at 3-6 months post-treatment). Pooled estimates were calculated using inverse variance random effects model. Statistical heterogeneity was calculated using I2 statistics. Risk of bias was assessed using Cochrane risk of bias tool. Publication bias was assessed using funnel plots. A multidisciplinary guideline panel constructed the recommendation using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The certainty of evidence was considered either high, moderate, low or very low depending on the extent of risk of bias, inconsistency, imprecision, indirectness, or publication bias. The evidence-to-decision framework was used to discuss the feasibility and acceptance of the constructed recommendation and its impact on resources and equity. The protocol is registered with the Danish Health Authority. Findings: We identified 13 RCTs, including 403 patients with a wide range of conditions. Melatonin reduced sleep latency by 14.88 min (95% CI 23.42-6.34, 9 studies, I2 = 60%) and increased total sleep time by 18.97 min (95% CI 0.37-37.57, 10 studies, I2 = 57%). The funnel plot for total sleep time showed no apparent indication of publication bias. No other clinical benefits were found. The number of patients experiencing adverse events was not statistically increased however, safety data was scarce. Certainty of evidence was low. Interpretation: Low certainty evidence supports a moderate effect of melatonin in treating sleep continuity parameters in children and adolescents with chronic insomnia due to primarily medical disorders beyond indication. The off-label use of melatonin for these patients should never be the first choice of treatment, but may be considered by medical specialists with knowledge of the underlying disorder and if non-pharmacological interventions are inadequate. If treatment with melatonin is initiated, adequate follow-up to evaluate treatment effect and adverse events is essential. Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation.

Use of melatonin in children and adolescents with idiopathic chronic insomnia: a systematic review, meta-analysis, and clinical recommendation.

Background: Melatonin prescriptions for children and adolescents have increased substantially during the last decade. Existing clinical recommendations focus on melatonin as a treatment for insomnia related to neurodevelopmental disorders. To help guide clinical decision-making, we aimed to construct a recommendation on the use of melatonin in children and adolescents aged 5-20 years with idiopathic chronic insomnia. Methods: A systematic search for guidelines, systematic reviews and randomised controlled trials (RCT) were performed in Medline, Embase, Cochrane Library, PsycInfo, Cinahl, Guidelines International Network, Trip Database, Canadian Agency for Drugs and Technologies in Health, American Academy of Sleep Medicine, European Sleep Research Society and Scandinavian Health Authorities databases. A search for adverse events in otherwise healthy children and adolescents was also performed. The latest search for guidelines, systematic reviews, and adverse events was performed on March 18, 2023. The latest search for RCTs was performed on to February 6, 2023. The language was restricted to English, Danish, Norwegian, and Swedish. Eligible participants were children and adolescents (5-20 years of age) with idiopathic chronic insomnia, in whom sleep hygiene practices have been inadequate and melatonin was tested. There were no restrictions on dosage, duration of treatment, time of consumption, or release formula. Primary outcomes were quality of sleep, daytime functioning and serious adverse events. Secondary outcomes included total sleep time, sleep latency, awakenings, drowsiness, quality of life, all-cause dropouts, and non-serious adverse events. Outcomes were assessed at different time points to assess short-term and long-term effects. Meta-analysis was performed using inverse variance random-effects model and risk of bias was assessed using Cochrane risk of bias tool. If possible, funnel plots would be constructed to investigate publication bias. Heterogeneity was calculated via I2 statistics. A multidisciplinary guideline panel formulated the recommendation according to Grading of Recommendations Assessment, Development and Evaluation (GRADE). The certainty of evidence was considered either high, moderate, low or very low depending on the extent of risk of bias, inconsistency, imprecision, indirectness, or publication bias. The evidence-to-decision framework was subsequently used to discuss the feasibility and acceptance of the constructed recommendation alongside the impact on resources and equity. The protocol is registered with the Danish Health Authority. Findings: We included eight RCTs with 419 children and adolescents with idiopathic chronic insomnia. Melatonin led to a moderate increase in total sleep time by 30.33 min (95% confidence interval (CI) 18.96-41.70, 4 studies, I2 = 0%) and a moderate reduction in sleep latency by 18.03 min (95% CI -26.61 to -9.44, 3 studies, I2 = 0%), both as assessed by sleep diary. No other beneficial effects were found. None of the studies provided information on serious adverse events, yet the number of participants experiencing non-serious adverse events was increased (Relative risk 3.44, 95% CI 1.25-9.42, 4 studies, I2 = 0%). Funnel plots were not constructed due to the low number of studies. The certainty of evidence was very low on the quality of sleep and low for daytime functioning. Interpretation: Evidence of very low certainty shows that benefits are limited and unwanted events are likely when melatonin is used to treat otherwise healthy children and adolescents with chronic insomnia. Melatonin should never be the first choice of treatment for this particular population, yet carefully monitored short-term use may be considered if sleep hygiene practices and non-pharmacological interventions have proven inadequate, and only if daytime function is compromised. Funding: The Danish Health Authority and the Parker Institute, Bispebjerg and Frederiksberg Hospital supported by the Oak Foundation.

Towards a Göttingen minipig model of adult onset growth hormone deficiency: evaluation of stereotactic electrocoagulation method.

BACKGROUND: Adult onset growth hormone (GH) deficiency (AGDH) is a potentially underdiagnosed condition, caused by damage to the pituitary gland. AGHD is treated with growth hormone replacement therapy. A large variety of clinical symptoms and changes in the metabolic homeostasis can be observed and quantified. New large animal models are needed for future drug development. NEW METHOD: In this study, we evaluate methods for a new large non-primate animal model of GH deficiency in post pubertal Göttingen Minipigs (minipig). Lesions in the pituitary gland were made by stereotaxic monopolar thermo-coagulation guided by magnetic resonance imaging (MRI), and pituitary function was evaluated using insulin tolerance test (ITT) with measurements of growth hormone secretion induced by hypoglycemia. RESULTS: Lesions were successfully applied to the pituitary gland without any damage to surrounding tissue including the hypothalamus, which was confirmed by post-operative MRI and post mortem histology. Plasma levels of GH during ITT showed no decrease in secreted levels one week after surgery compared to levels obtained before surgery. COMPARISON WITH EXISTING METHODS: Compared to other GH insufficiency models, eloquent brain tissue is spared. Furthermore, alternatively to rodent models, a large animal model would allow the use of human intended equipment to evaluate disease. Using the minipig avoids social, economical and ethical issues, compared with primates. CONCLUSION: The lesions did not remove all GH production, but proof of concept is demonstrated. In addition, the ITT is presented as a safe and efficient method to diagnose GH deficiency in minipigs.

The effect of exercise on the absorption of inhaled human insulin in healthy volunteers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Exercise is known to affect absorption of other inhaled substances, but so far there are no reports on the effect of exercise on the absorption of inhaled insulin in humans. WHAT THIS PAPER ADDS: This report is the first to investigate the effect of exercise on the absorption of inhaled insulin. In this study in healthy volunteers we found that exercise early after dosing increased absorption (15-20%) of inhaled insulin over the first 2 h after start of exercise, with an approximately 30% increase in maximal insulin concentration, and unchanged overall absorption. AIMS: To investigate the effect of moderate exercise on the absorption of inhaled insulin. METHODS: A single-centre, randomized, open-label, three-period cross-over trial was carried out in 12 nonsmoking healthy subjects. A dose of 3.5 mg inhaled human insulin was administered via a nebulizer and followed in random order by either 1) no exercise (NOEX), 2) 30 min exercise starting immediately after dosing (EX0), or 3) 30 min exercise starting 30 min after dosing (EX30). The study was carried out as a 10 h euglycaemic glucose clamp (90 mg dl(-1) (5.0 mmol l(-1))). RESULTS: The absorption of insulin over the first 2 h after start of exercise was 16% increased for EX0 (ratio (95%CI) 1.16 (1.04, 1.30), P = 0.01) and 20% increased for EX30 (1.20 (1.05, 1.36), P < 0.01), both compared with NOEX; the overall insulin absorption during 6 h and 10 h after dosing was not influenced by exercise. The maximum insulin concentration (C(max)) increased by 32% for EX0 and 35% for EX30 (both P < 0.01) compared with NOEX, while the time to C(max) was 31 min faster for EX0 (P < 0.01), but not significantly different after EX30, compared with NOEX. CONCLUSIONS: A significant and clinically relevant increase of insulin absorption over the first 2 h after the beginning of exercise was observed. Until data from studies using the specific insulin inhalers exists, patients using inhaled insulin should be made aware of a potential increased absorption and higher concentration of insulin in connection with exercise.

Mortality and GH deficiency: a nationwide study.

OBJECTIVE: To estimate the mortality in Denmark in patients suffering from GH deficiency (GHD). DESIGN: Mortality was analyzed in 1794 GHD patients and 8014 controls matched on age and gender. All records in GHD patients were studied and additional morbidity noted. Patients were divided into childhood onset (CO) and adult onset (AO), discriminated by an age cutoff below or above 18 years at onset of GHD. METHOD: Data on death were identified in national registries. Sex- and cause-specific mortalities were identified in CO and AO GHD when compared with controls. RESULTS: Mortality was increased in CO and AO GHD in both genders, when compared with controls. The hazard ratio (HR) for CO males was 8.3 (95% confidence interval (CI) 4.5-15.1) and for females 9.4 (CI 4.6-19.4). For AO males, HR was 1.9 (CI 1.7-2.2) and for females 3.4 (CI 2.9-4.0). We found a significantly higher HR in AO females versus AO males, both compared with controls (P < 0.001). In AO, mortality was increased due to cancer in all subgroups, due to circulatory diseases in all age groups for females and for males in the oldest age group. For CO, the increased mortality was due to cancer. CONCLUSIONS: We found a significantly increased mortality in GHD patients when compared with controls, possibly due to their hypopituitary status. Mortality was increased in AO female patients when compared with males. For CO and AO GHD, different causes of significantly increased mortality were identified.

Mortality and reduced growth hormone secretion.

BACKGROUND: Data regarding the mortality rates of patients with growth hormone deficiency (GHD), whether or not treated with growth hormone (GH), are limited, but an increased mortality rate among hypopituitary patients compared with the general population has been documented. Cardiovascular disease has been suggested as a primary cause of death, whereas cancer statistics might be influenced by the number of malignancies causing the pituitary disease. Furthermore, differences in mortality rates in females and males have been reported. METHODS: Epidemiological studies of mortality in hypopituitary and GHD patients were identified and reviewed. RESULTS: Most studies showed an increased mortality rate in hypopituitary and GHD patients and an increased mortality among female compared with male patients. There is a possibility that differences between patients with adult-onset and childhood-onset GHD might also exist. Two studies showed a normal mortality rate in GHD patients treated with GH compared with the general population. CONCLUSIONS: Although an increased mortality rate in hypopituitary patients is well documented, further research is needed to provide more reliable estimates of the actual causes. Caution should be taken in the interpretation of results regarding mortality and GH treatment due to the limited amount of data and the limitations of the study designs.

The impact of large tidal volume ventilation on the absorption of inhaled insulin in rabbits.

Previous studies have shown that ventilation patterns affect absorption of inhaled compounds. Thus, the aim of this study was to investigate the effect of large tidal volume ventilation (LTVV) on the absorption of inhaled insulin in rabbits. Mechanically ventilated rabbits were given human insulin via a nebuliser system, and plasma insulin was measured for the following 120min. Ventilation was adjusted to (1) normal tidal volume ventilation (NTVV) for the entire period after dosing (NTVV group), to (2) LTVV for the entire period after dosing (LTVV group), to (3) NTVV except for 15min LTVV immediately after dosing (Early LTVV group), or to (4) NTVV except for 15min LTVV starting at 60min after dosing (late LTVV group). Insulin absorption (AUC(ins(0-120min))) was increased by 149% for the LTVV group compared to NTVV group (p<0.01) with increased maximal insulin concentration (106%, p=0.03). The Early LTVV group showed a changed absorption profile. For the late LTVV group an increase in insulin levels was observed after the LTVV period (not significant compared to the NTVV group). These data could potentially have implications for patients using inhaled insulin in situations where a change in breathing pattern is seen, such as exercise.

Trends in Off-Label Prescribing of Sedatives, Hypnotics and Antidepressants among Children and Adolescents - A Danish, Nationwide Register-Based Study.

In recent years, psychotropic drug use among children and adolescents in Europe and USA has increased. However, the majority of psychotropic drugs are not formally approved for use in children and adolescents, and consequently, use is often off-label. The objectives were to describe time trends in off-label prescribing rates and the most commonly used types of psychotropic drugs by age and gender in Danish children and adolescents. Using the Register of Medicinal Product Statistics, we identified all prescriptions for sedatives, hypnotics and antidepressants filled for children and adolescents in 2006-2012. Information on diagnoses was obtained from the Danish National Registry of Patients and allowed classification of prescriptions as either on- or off-label. We identified 186,831 prescriptions filled for 29,851 children and adolescents: 88.0% of these were classified as off-label. During 2006-2012, off-label rates for sedatives and hypnotics increased significantly, except for prescriptions for girls aged 15-17 years [range 24.1-98.2% (girls), 31.9% to 99.0% (boys)]. In the same period, the number of registered melatonin prescriptions (all off-label) increased expansively. For antidepressants, we found decreasing trends in off-label rates over time [range 94.5-65.6% (girls), 93.8-71.2% (boys)]. Off-label prescribing of psychotropic drugs to Danish children and adolescents is common. Off-label rates for sedatives and hypnotics increased in the period of 2006-2012, whereas off-label rates for antidepressants declined. Off-label rates might be underestimated and should be considered a conservative estimate.

Incidence of GH deficiency - a nationwide study.

OBJECTIVE: Data on incidence rates are scarce in GH deficiency (GHD). Here, we estimate the incidence rate in childhood onset (CO) and adult onset (AO) GHD in Denmark. DESIGN: We used three national registries to identify 9131 cases with an increased risk of GHD. Date of entry was defined using the date when a registration had taken place and when a date of sufficient information could be defined from a thorough examination of a record of a GHD patient, which ever came last. We considered date of entry as the incident date. METHODS: Sex-specific incidence rates of GHD in children and adults using the background population as reference. RESULTS: During 1980-1999, 1823 patients were incident. Three-hundred and three males and 191 females had CO, 744 males and 585 females had AO GHD. The incidence rate over time was stable for females with AO GHD and increasing for the other three subgroups. Average incidence rate for CO males, 2.58 (95% confidence interval (CI), 2.30-2.88), CO females, 1.70 (95% CI, 1.48-1.96), AO males, 1.90 (95% CI, 1.77-2.04), and AO females, 1.42 (95% CI, 1.31-1.54) all per 100 000. The incidence rate was significantly higher in males compared to females in the CO GHD group (P < 0.001) and in the AO GHD group in the age ranges of 45-64 and 65+years (P < 0.001). There was no significant difference in the 18-44 years age group. CONCLUSIONS: In conclusion, we have identified the incidence rates of GHD in a nationwide study of Denmark. In this population-based study, we have identified in CO GHD and in the two oldest age groups of AO GHD, a statistically significant higher incidence rate in males when compared with females.

Pain perception after subcutaneous injections of media containing different buffers.

Several hormones are administered by daily subcutaneous injections. Pain caused by subcutaneous injection is an unpleasant condition, which can limit patient compliance. The objective of the present study was to evaluate the perception of pain by subcutaneous injection of two different and commercially available solutions for dispensing recombinant human growth hormone. The solutions are characterised by pH, conservation, and buffer. Isotonic saline was used as reference solution. Fifty-four healthy volunteers (mean age (+/-S.E.M.): 35.5+/-1.1 years) were recruited to the double-blind, randomised study. All injections were performed pairwise (right and left thigh) in one day by the same experienced nurse. Perception of pain was evaluated by the volunteers immediately after injection and 2 min. after injection into the thigh of three formulations, which differed with respect to pH and buffers (histidine, citrate and saline, respectively). Significantly more participants (38/54) found than the citrate buffer caused more pain than the histidine buffer immediately after injection (P=0.002). Histidine buffer did not cause more pain than saline (P=0.996). After 2 min., there was no difference between the histidine and the citrate buffer (P=1.00), nor between the histidine buffer and saline (P=1.00). In summary, the solution-containing citrate as buffer caused more pain after subcutaneous injection than the solution with histidine as buffer. Considering patient compliance, it seems advisable to employ histidine-buffered solution rather than citrate-buffered solution for dispensing recombinant human growth hormone by daily subcutaneous injections.

Clinical Pharmacology in Denmark in 2016 - 40 Years with the Danish Society of Clinical Pharmacology and 20 Years as a Medical Speciality.

The Danish Society of Clinical Pharmacology was founded in 1976, and mainly thanks to the persistent efforts of the society, clinical pharmacology became an independent medical speciality in Denmark in 1996. Since then, clinical pharmacology has gone from strength to strength. In the Danish healthcare system, clinical pharmacology has established itself as an indispensible part of the efforts to promote the rational, safe and economic use of drugs. Clinical pharmacologists are active in drug committees both in hospitals and in the primary sector. All clinical pharmacology centres offer a local medicines information service. Some centres have established an adverse drug effect manager function. Only one centre offers a therapeutic drug monitoring service. Clinical pharmacologists are responsible for the toxicological advice at the Danish Poison Information Centre at Bispebjerg University Hospital in the Capital Region. The Department of Clinical Pharmacology at Aarhus University Hospital works closely together with forensic toxicologists and pathologists, covering issues regarding illicit substances, forensic pharmacology, post-mortem toxicology, expert testimony and research. Therapeutic geriatric and psychiatric teach-inns for specialist and junior doctors are among the newest initiatives organized by clinical pharmacologists. Clinical pharmacologists work also in the Danish Medicines Agency and in the Danish pharmaceutical industry, and the latter has in particular a great growth potential for creating new jobs and career opportunities for clinical pharmacologists. As of July 2016, the Danish Society of Clinical Pharmacology has 175 members, and 70 of these are specialists in clinical pharmacology corresponding to approximately 2.5 specialists per 1000 doctors (Denmark has in total 28,000 doctors) or approximately 12 specialists per one million inhabitants.

[Polypharmacy to the elderly prevails]. / Polyfarmaci er udbredt hos ældre

The risk of chronic diseases increases with age which may result in an increased need for pharmacological treatment: polypharmacy. Polypharmacy to the elderly is particularly challenging due to altered pharmacokinetics and -dynamics, and is associated with numerous problems such as poor compliance/adherence, drug interactions, adverse drug reactions, increased mortality and hospitalization. Beers criteria and STOPP/START criteria are tools which can be used as guidance in medication of the elderly, but they cannot replace a structured medical review, which should be individualized.

Interaction between exogenous insulin, endogenous insulin, and glucose in type 2 diabetes patients.

BACKGROUND: Little is known about the influence of exogenous insulin and actual glucose levels on the release of endogenous insulin in insulin-treated type 2 diabetes mellitus (T2DM) patients. This study investigated the interaction among serum endogenous insulin (s-EI), serum exogenous insulin aspart (s-IAsp), and blood glucose levels in an experimental short-term crossover design. STUDY DESIGN AND METHODS: Eight T2DM patients (63.52 years old; range, 49-69 years; mean body mass index, 28.8±3.8 kg/m(2)) were randomized to treatment with individual fixed doses of insulin aspart (0.5-1.5 IU/h) as a continuous subcutaneous insulin infusion (CSII) during a 10-h period on two occasions with different duration of hyperglycemia: (1) transient hyperglycemia for 2 h (visit TH) and (2) continuous hyperglycemia for 12 h (visit CH). RESULTS: During steady state the variances of plasma glucose (p-glucose), s-IAsp, and s-EI were equal within visit TH and within visit CH, but variances were significantly higher during visit CH compared with visit TH. The s-IAsp reached lower levels at visit CH compared with visit TH (test for slope=1, P=0.005). The s-EI depended on p-glucose in a nonlinear fashion during the first 100 min of both visits when s-IAsp was undetectable (adjusted R(2)=0.9). A complex but statistically significant interaction among s-IAsp, s-EI, p-glucose, and patients was observed during measurable s-IAsp levels (adjusted R(2)=0.70). CONCLUSIONS: Endogenous and exogenous insulin showed higher variation during continuous hyperglycemia. Significantly lower levels of exogenous insulin were observed following CSII during continuous hyperglycemia compared with transient hyperglycemia. Endogenous insulin levels could in a complex way be explained by an individual interaction among p-glucose and serum exogenous insulin, if present.

Short-term effects of NPH insulin, insulin detemir, and insulin glargine on the GH-IGF1-IGFBP axis in patients with type 1 diabetes.

OBJECTIVE: Insulin regulates the GH-IGF1 axis. Insulin analogs differ from human insulin in receptor affinity and possibly liver accessibility. Therefore, we compared the GH-IGF1 axis response with human NPH insulin, insulin detemir, and insulin glargine in patients with type 1 diabetes (T1D). METHODS: A total of 17 patients (seven were women) with T1D (age of 42 (24-63) years (mean and range), BMI of 24.7 (19.5-28.3) kg/m(2), HbA1c of 7.2 (6.3-8.0) % (55 (45-64) mmol/mol), T1D duration of 26 (8-45) years) were studied using a randomized, three-period crossover design. Patients received s.c. injections of equal, individual doses of NPH, detemir, and glargine at 1800 h. Plasma glucose, serum total IGF1, bioactive IGF, IGF-binding protein (IGFBPs), and GH were measured hourly for 14 h post-injection. RESULTS: When compared with the area under the curve (AUC) following NPH and glargine, detemir resulted in the lowest 6-14 h AUC (mean and range) of IGFBP1 (1518 (1280-1800)) vs 1621 (1367-1922) vs 1020 (860-1210) µg/l×h) and GH (17.1 (14.1-20.6) vs 15.4 (12.7-18.6) vs 10.2 (8.5-12.3) µg/l×h), but in the highest AUC of bioactive IGF (3.8 (3.5-4.2) vs 3.7 (3.4-4.0) vs 4.4 (4.1-4.8) µg/l×h) (all P<0.01). These differences were unrelated to plasma glucose. By contrast, profiles of total IGF1, IGFBP2, and IGFBP3 were comparable. CONCLUSIONS: Independent of plasma glucose, a single dose of detemir caused larger suppression in serum IGFBP1 than NPH and glargine, whereas bioactive IGF was higher, thereby explaining the lower GH levels. Thus, detemir appears to be more liver specific than NPH insulin and glargine.

[Prevention of skeletal related events in patients with bone metastases from solid tumours]. / Forebyggelse af skeletrelaterede hændelser hos patienter med knoglemetastaser ved solide tumorer.

This article is based on a systematic literature search and meta-analyses of clinical data regarding effects of bisphosphonates (BP) and denosumab (DS) on preventing skeletal related events (SRE) in patients with bone metastases from solid tumours. Although there are pharmacological differences between the different types of BP no major differences were observed between BP in preventing SRE or in adverse events. Treatment with DS has in three randomised trials showed a greater effect than BP in preventing SRE. The optimal choice of bone-anti-resorptive agent should depend on the patient's general condition, renal function and treatment logistics.

Potential role of linagliptin as an oral once-daily treatment for patients with type 2 diabetes.

BACKGROUND: Linagliptin is an oral antihyperglycemic agent that selectively inhibits the enzyme dipeptidyl peptidase-4 (DPP-4). Inhibition of DPP-4 increases the levels of the incretin hormones glucagon-like peptide and glucose-dependent insulinotropic polypeptide by preventing their degradation. OBJECTIVE: We reviewed the role of linagliptin as an oral once-daily treatment for patients with type 2 diabetes. METHODS: A comprehensive literature search was performed using the term "linagliptin." Original research articles and review articles were included in our examination. RESULTS: Linagliptin has a similar mode of action as other gliptins, with comparable efficacy, safety profile, and tolerability. Differences in pharmacokinetic parameters that distinguish linagliptin from other gliptins include that linagliptin is not renally excreted and does not require dose reduction with renal impairment. CONCLUSION: Linagliptin is an oral, once-daily, antihyperglycemic agent that significantly reduces glycated hemoglobin (HbA(1c)) when used alone or in combination with other antidiabetic drugs in people with type 2 diabetes. Pharmacokinetics, such as the lack of renal excretion, distinguishes linagliptin from other gliptins.