Use of thyroid hormones in hypothyroid and euthyroid patients: A 2020 THESIS questionnaire survey of members of the Danish Endocrine Society.

PURPOSE: The standard treatment of hypothyroidism is levothyroxine (LT4), which is available as tablets or soft-gel capsules in Denmark. This study aimed to investigate Danish endocrinologists' use of thyroid hormones in hypothyroid and euthyroid patients. METHODS: An e-mail with an invitation to participate in an online survey investigating practices about substitution with thyroid hormones was sent to all members of the Danish Endocrine Society (DES). RESULTS: Out of 488 eligible DES members, a total of 152 (31.2%) respondents were included in the analysis. The majority (94.1%) of responding DES members use LT4 as the treatment of choice. Other treatment options for hypothyroidism are also used, as 58.6% prescribe combination therapy with liothyronine (LT3) + LT4 in their clinical practice. LT4 + LT3 combination is preferred in patients with persistent symptoms of hypothyroidism despite biochemical euthyroidism on LT4 treatment. Over half of the respondents answered that thyroid hormone therapy is never indicated for euthyroid patients, but 42.1% will consider it for euthyroid infertile women with high antibody levels. In various conditions that could interfere with the absorption of LT4, most responding Danish endocrinologists prefer tablets and do not expect a significant difference when switching from one type of tablet formulation to another. CONCLUSION: The treatment of choice for hypothyroidism is LT4. Combination therapy with LT4 + LT3 is considered for patients with persistent symptoms. Even in the presence of conditions affecting bioavailability, responding Danish endocrinologists prefer LT4 tablets rather than newer LT4 formulations, such as soft-gel capsules.

[Is there an improvement of drug safety in Germany in recent years?]. / Hat sich die Arzneitherapiesicherheit in den letzten Jahren in Deutschland verbessert?

The goal of drug therapy to prolong life or to improve the quality of life can be accomplished by modern drug therapy to a respectable degree. However, the risks of drug therapy have increased through more specific drugs and lead to often surprisingly multi-faceted side effects as in the case of biologicals. We have performed a systematic review of meta analyses, clinical studies, and reviews of the last five years concerned with adverse drug reactions (ADR) and adverse drug events (ADE). From these data emerges a distinct lack of reliable studies for Germany on incidence, severity and preventability of ADR and ADE; however, there are indications of their increase as is also evident from other countries. There are indications also for a better incidence management culture and better documentation. The step to utilize computerized physician order entry and decision support systems is a proven method to reduce medication related problems, leading also to reduction of in-hospital time and reduced drug expenses. Taking this decisive step to improve drug safety requires an appreciation of the magnitude of the problem and the determination to change an established but inferior system of drug administration in a fundamental way.

Effects of normalization of plasma testosterone levels in hypogonadal men on plasma levels and urinary excretion of asymmetric dimethylarginine (ADMA).

Elevated plasma levels of asymmetric dimethylarginine (ADMA) inhibit nitric oxide formation and exert a proatherogenic action. Low testosterone (T) levels are associated with increased cardiovascular risks. This study analyzed the effects of normalization of plasma T levels on plasma levels and urinary excretion of ADMA in hypgonadal men (n=10) receiving transdermal T administration. Plasma T levels, starting from clearly hypogonadal T plasma concentrations with a mean level of 4.0+/-2.72 nmol/l at baseline, rose to >10 nmol/l after 2 weeks, with plasma T levels within the normal range of men (mean level of 22.5+/-11.3 nmol/l) over the last 16 weeks of the 24 weeks of T administration. Normalization of plasma T led to a small but significant fall of plasma ADMA (519+/-55 vs. 472+/-59 nmol/l, p=0.031). The outcome of this study may be viewed as a favorable effect of normalization of plasma testosterone on plasma ADMA since even small elevations of plasma ADMA significantly increase cardiovascular risk. While this effect of normalization of plasma T may impress as favorable, most available studies on effects of T administration to hypogonadal men have not shown beneficial effects on functions of the vascular wall.

Safety and efficacy of rosuvastatin therapy for the prevention of hyperlipidemia in adult cardiac transplant recipients.

BACKGROUND: Hyperlipidemia after orthotopic heart transplantation (OHT) is associated with immunosuppression. Many OHT patients have increased lipid levels above published guidelines despite treatment with high doses of statins. Treatment with rosuvastatin (ROS) in OHT patients has not yet been evaluated. Therefore, we assessed its efficacy and safety in an OHT population. METHODS: Twenty-one OHT recipients, median age 66 years, whose lipid levels were sub-optimal on the highest tolerated doses of statins, received ROS in addition to standard immunosuppression. Total cholesterol (TC), low-density lipoprotein (LDL-C) and high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), liver transaminases (AST) and creatinine kinase (CK) were measured before and during treatment with ROS. RESULTS: After 6 weeks on an average ROS dose of 10 mg/day, a TC:HDL-C ratio of <4 was reached in 76% of patients, and 70% of patients reached an LDL-C level of <2.5 mmol/liter (100 mg/dl). TC decreased to <5.2 mmol/liter (200 mg/dl) in 80% of patients and TG decreased to <2 mmol/liter (175 mg/dl) in 61% of patients. Except for the HDL-C increase, all changes were statistically significant. The decrease in the median TC:HDL-C ratio between baseline and 6 weeks was also statistically significant (p = 0.001). There were no significant changes in CK or AST levels, and no clinical evidence of myositis. One patient developed myalgia and 2 were withdrawn from the study because of mild elevation of CK (<3-fold upper limit of normal [ULN]). CONCLUSIONS: In the setting of tertiary referral centers, ROS appears to be safe and effective in lowering LDL-C in OHT recipients in whom treatment with other statins failed to achieve target LDL-C. No evidence of liver or muscle dysfunction was noted. Long-term studies are needed to ascertain the effect of ROS therapy on incidence of coronary artery disease (CAD) in this population.

Low dialysance of asymmetric dimethylarginine (ADMA)--in vivo and in vitro evidence of significant protein binding.

BACKGROUND: Increased blood levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) predict cardiovascular mortality in patients with end-stage renal disease. Despite its low molecular weight, available information on the impact of hemodialysis (HD) on ADMA plasma levels is controversial. METHODS: We assessed plasma concentrations, dialyzer clearance and total amount of ADMA removed in 30 patients with end-stage renal disease during regular HD. In addition, plasma ADMA levels were assessed in 10 patients with acute renal failure treated with extended HD. RESULTS: Regular HD decreased plasma creatinine (from 774 +/- 42 to 312 +/- 17 micromol/l) and urea (from 24.5 +/- 1.5 to 8.4 +/- 0.5 mmol/l) concentrations significantly (both p < 0.001), whereas plasma ADMA remained unchanged (4.35 +/- 0.19 vs. 4.76 +/- 0.24 micromol/l). ADMA clearance was 92 +/- 6 ml/min, and the total amount removed in the spent dialysate was 37 +/- 4 micromol. The clearances of creatinine (161 +/- 3 ml/min) and of urea (173 +/- 3 ml/min) were significantly higher. Furthermore, even during extended HD, plasma ADMA concentrations did not decrease significantly (1.73 +/- 0.22 vs. 1.63 +/- 0.18 micromol/l). CONCLUSION: In conclusion, dialysance of ADMA is markedly lower than expected from its molecular weight because of significant protein binding of the substance. Since markedly increased ADMA blood concentrations have been linked to cardiovascular complications due to atherosclerosis in patients with ESRD, new strategies should be evaluated to remove this putative uremic toxin.

[Pharmacological treatment in adults with attention deficit hyperactivity disorder]. / Die medikamentöse Behandlung der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung im Erwachsenenalter.

Treatment in adults with attention deficit hyperactivity disorder predominantly relies on pharmacotherapeutic approaches especially with psychostimulants. Empirical studies indicate that their clinical effectiveness may be as high as in children and adolescents, especially in higher dosages. However, due to the high prevalence of comorbidities, e.g. depression, psychopharmacological treatment requires an extended use of other substance groups, especially antidepressants. An optimal treatment response necessitates the choice of an adequate substance depending on the leading clinical symptoms and a procedure of an individual titration of different dosages. This article reviews the current empirical results in the pharmacological treatment of ADHD in adults and provides possible treatment strategies for clinical practice.

[Incidence and prevention of lethal undesirable drug effects]. / Zur Häufigkeit und Vermeidbarkeit von tödlichen unerwünschten Arzneimittelwirkungen.

About every second decision of a medical doctor concerns drug therapy. On the basis of a representative Norwegian study, which analyzed fatal drug reactions in stationary patients of internal medicine wards by autopsy and plasma drug concentrations, in Germany 58,000 fatalities are occurring in this patient population. The treating physicians classified only 6% of drug induced fatalities as such. Therefore, the risk of drug therapy is grossly underestimated. In half of the cases medication errors were causative and therefore these could potentially all be avoided. In addition to improved pre- and postgraduate education in clinical pharmacology the use of computer-based expert systems would be a decisive step to optimize drug therapy.

[Sleep disorders in hyperkinetic children--correlation with arousal disorders, differential diagnosis and comorbidity]. / Schlafstörungen bei hyperkinetischen Kindern--Zusammenhänge zu Arousalstörungen, differential diagnostische Abgrenzungen und Komorbiditäten.

OBJECTIVES: Sleep disorders are frequently observed in Attention Deficit-Hyperactivity Disorder (ADHD). At the same time, however, there is little evidence of their prevalence and their specific characteristics. Also unclear is a possible pathogenetic relationship between disturbed sleep and the core symptoms of ADHD. There are still very few findings on the role of comorbid internal and neurological disorders like sleep apnea and restless legs syndrome in the differential diagnosis of ADHD. METHODS: We present an overview of the current literature, describing the most important results concerning sleep disorders in ADHD. RESULTS: A principal goal of future assessments is to ascertain whether sleep problems in children with ADHD represent unspecific concurrent symptoms or whether they play a substantial role in the pathogenesis of ADHD. CONCLUSIONS: Moreover a possibly increased risk of comorbid sleep-disordered breathing disorder might be an important issue in the differential diagnostic considerations with regard to ADHD.

Comparison of different activity parameters in atopic dermatitis: correlation with clinical scores.

BACKGROUND: Several laboratory markers have been described to correlate positively with disease activity of atopic dermatitis (AD). These include soluble adhesion molecules and eosinophil granular proteins. Although the correlation of these parameters with the severity and extent of skin involvement has been repeatedly studied in the past, no systematic investigation has been performed over a lengthy period of time. In addition, no subjective disease parameters recorded by the patient have been included in studies dealing with disease activity. OBJECTIVES: To assess the validity of different objective and subjective parameters [soluble E-selectin (sE-selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1), eosinophil cationic protein (ECP), urinary nitrate excretion (reflecting endogenous nitric oxide formation) and the patients' impressions of pruritus, sleeplessness and skin status] as markers of AD disease activity. METHODS: Twenty patients were examined for 1 year and their skin status was evaluated by an established score (SCORAD). sE-selectin, sVCAM-1 and ECP were analysed by commercial test kits. Urinary nitrate concentration was measured by gas chromatography-mass spectrometry. The subjective parameters, pruritus, sleeplessness and impression of skin status, were recorded by the patients on a visual analogue scale. RESULTS: In this long-term trial, only sE-selectin and the subjective parameters showed a statistically significant correlation with the SCORAD score. CONCLUSIONS: Our data indicate that basic clinical scoring remains a most effective and relevant method of recording skin disease activity in AD.

Elevated nitric oxide levels in patients with chronic liver disease and cirrhosis correlate with disease stage and parameters of hyperdynamic circulation.

Chronic liver diseases are accompanied by changes in splanchnic and systemic circulation. These changes are characterised by a reduction in peripheral vascular resistance and an increased cardiac output at rest. An increased release of nitric oxide (NO) has been proposed to play a role in the pathogenesis of vasodilatation and vascular hypocontractility. This study was designed to determine the nitric oxide metabolism measured as circulating nitrate levels in serum/urine in patients with chronic liver disease and cirrhosis. The nitrate concentrations were significantly increased in advanced degrees in cirrhosis Child B and C, and normal or even reduced in patients with chronic active hepatitis and early cirrhosis. In our study the connections between the extent of portal hypertension and nitrate levels were evident. The presence of ascites as well as the the progression of oesophageal varices were associated with higher circulating nitrate levels. The connection between increased nitric oxide production and the haemodynamic sequelae of portal hypertension is also apparent in the significant correlation between plasma renin and serum nitrate levels. Circulating nitrate levels also correlated to the serum interleukin-6 levels. This study demonstrated that the increased nitric oxide metabolism is associated with the haemodynamic alterations induced by portal hypertension.

Knowledge on drug dosages of ward physicians.

OBJECTIVE: Dosing errors are a common source for preventable adverse drug events. This study evaluated the knowledge of German hospital physicians with respect to the daily dosage of frequently used drugs. METHODS: A questionnaire survey was carried out among 168 ward physicians from three university and four municipal hospital departments of internal medicine asking for the daily dosage of 17 frequently used drugs. RESULTS: One hundred twenty-seven of 168 physicians returned a completed questionnaire, a response rate of 75.6%. Only 50% of the dose estimates were within the therapeutic range. Even in cases of frequent prescription 7% of the stated doses were overdosed and 15% were underdosed. CONCLUSIONS: The results of this survey suggest that adverse drug events and the lack of therapeutic effect due to dosing errors could be prevented by an improved knowledge of daily dosages.

[Multimodal therapy concept in hyperkinetic disorder. Drugs alone are not enough]. / Multimodales Therapiekonzept bei hyperkinetischer Störung. Mit Medikamenten alleine ist es nicht getan.

For the treatment of attention deficit/hyperactivity disorder, both medical and behavioral therapeutic concepts have been shown to be effective. Somewhat problematical, however, is the fact that a large percentage of these children retain residual symptoms that need treating over a longer period of time. The value of a multimodal therapeutic approach (combination of medication and behavioral treatment including counseling of parents, teachers and the patient) remains controversial. Over the long-term, and account being taken of a number of indicators extending beyond the core symptoms, however, the multimodal treatment concept would appear superior to treatment solely with psychostimulants. For effective treatment accurate titration and the recording of the changes occurring under medication are important.

Effects of intravenous oxygen on prostacyclin and thromboxane formation in patients with peripheral occlusive arterial disease.

Oxygen infusion is used in complementary medicine for treatment of peripheral occlusive arterial disease. The mechanism of action is unknown. Thus, we determined the effects of oxygen infusion on prostacyclin, thromboxane and nitric oxide synthesis. Twelve patients with peripheral occlusive arterial disease received oxygen 40 ml/d intravenously for 3 weeks. Study parameters, analyzed by gas chromatography-mass spectrometry on day 1, 3, 10, 16, 21: 2,3-dinor-6-oxo-PGF(1alpha), colour invisible 2,3-dinor-TXB2 and nitrate in one-hour-urine before and after oxygen infusion, reflecting prostacyclin, thromboxane and nitric oxide synthesis. Urinary 8-iso-PGF2alpha, indicating oxidative stress, was assessed in one patient. Urinary 2,3-dinor-6-oxo-PGF1alpha rose from baseline more than 4-fold after oxygen infusion. In contrast, urinary 2,3-dinor-TXB2 excretion remained unchanged. Oxygen infusion had no effect on urinary nitrate excretion. Urinary 8-iso-PGF(2alpha) was not influenced by oxygen infusion with and without diclofenac pretreatment. Our data demonstrate a shift of the prostacyclin/thromboxane ratio toward prostacyclin by oxygen infusion. Thus, a mechanism of action is provided and clinical trials with intravenous oxygen find a rational basis.

Blood donors on medication. Are deferral periods necessary?

OBJECTIVES: Drugs and their metabolites in transfused blood components may cause effects in the recipient. If the treated disorder is not to be regarded as an exclusion criterion from blood donation, donors on medication should be deferred for a period consistent with the drug's pharmacokinetics. GENERAL PRINCIPLES AND METHODS: Peak plasma drug concentrations of 3% or less of the therapeutic concentration were regarded to be safe for the recipient of a blood product. For teratogenic drugs a much lower safety level of less than 0.000001% has been proposed. For the calculation of deferral periods, both the type of blood component to be prepared and the drug's pharmacokinetics for a given formulation were considered. SUGGESTED WAITING PERIODS: For drugs with known teratogenic risks, we suggest a deferral period of 28 plasma-elimination half-lives. For non-teratogenic drugs, a simple, conservative approach could be based on waiting for five plasma-elimination half-lives, thus reaching the required 3% safety level already in any donor. If, however, the type of blood component to be prepared is also considered, a more differentiated approach appears to be appropriate: for blood components containing 50 ml or less plasma from a single donor, donor medication may be disregarded because of the high dilution in the recipient's plasma volume, whereas for blood components with higher plasma contents (250 ml on average) from a single donor on medication the 3% safety level will be achieved by observing the deferral period of five plasma-elimination half-lives mentioned. A guideline for 191 drugs and drug classes has been elaborated accordingly.