An Observational Study to Identify Drug-related Problems (DRP) in Routine Care and An Expert Panel Assessment to Rate Clinical Risk and Preventability by Unit-dose Dispensing Systems (UDDS) with Computerized Physician Order Entry (CPOE) and Clinical Decision-Support Systems (CDSS).

Background and aim: Drug-related problems (DRP) jeopardize patient safety. Unit-dose dispensing systems (UDDS) with computerized-physician-order-entry (CPOE) and clinical-decision-support-systems (CDSS) were reported as a promising concept for preventing DRP. We aimed at identifying and categorizing DRP in peroral drug administration considering their clinical risk and preventability by UDSS/CPOE/CDSS. Investigations: In surgical and internal-medicine departments, we observed routine procedures in peroral drug administration for DRP. An expert panel including pharmaceutical and nursing expertise categorized the identified 18 DRP categories into three levels: DRP that have not yet resulted in medication errors (ME) (Level-I), DRP where ME have occurred but have not yet reached the patient (Level-II), and DRP where ME have occurred and have reached the patient (Level-III). Additionally, the panel categorized DRP according to their clinical risk and whether the implementation of UDSS/CPOE/CDSS can prevent them. Results: In 77 surgical patients, 1,849 peroral drug administration procedures, and in 149 internal-medicine patients, 1,405 procedures were observed. The 18 DRP categories were identified with a frequency of 0.6%-26.7% (Level-I), 0.1%-21.5% (Level-II), and 0.0%-1.0% (Level-III). Of those, four categories were considered of high clinical risk: "Name of the medication is not readable", "Prescribed medication is not prepared for administration", "An incorrect or non-prescribed medication is prepared", and "A medication is prepared for the wrong patient (mix-up)". Twelve DRP categories were categorized as highly preventable by UDSS/CPOE/CDSS. Conclusions:Under routine conditions, we identified a substantial number of DRPs. An expert panel categorized many of those DRPs as clinically highly relevant and highly preventable by UDSS/CPOE/CDSS.

[Diagnosis and treatment of interstitial cystitis (IC/PBS) : S2k guideline of the German Society of Urology]. / Diagnostik und Therapie der interstitiellen Zystitis (IC/BPS) : S2k-Leitlinie der Deutschen Gesellschaft für Urologie.

In this review article, the authors describe all relevant aspects of the new S2k guideline from the German Society of Urology (Deutschen Gesellschaft für Urologie, DGU) for the diagnosis and treatment of IC/PBS (interstitial cystitis/painful bladder syndrome). A list of necessary and optional examinations and the necessity of diagnosis of exclusion are summarized and evaluated. The treatment options listed (ranging from conservative, oral drug, and complementary medicine to interventional surgical procedures) also give the reader a good overview of the contents of the guideline and possible therapeutic approaches. Finally, the recommendations including consensus of the guideline group are also summarized in various information boxes.

[Hyponatremia and tolvaptan : what is the situation 5 years after approval?]. / Hyponatriämie und Tolvaptan : Wo stehen wir 5 Jahre nach der Zulassung?

The diuretic tolvaptan has been approved for more than 5 years for the indications of euvolemic hyponatremia due to syndrome of inappropriate antidiuretic hormone (SIADH) secretion. In recent years many patients have been treated with tolvaptan and many physicians could gather practical experience. Other countries, such as the USA had already gained greater experience, also in the indications for hypervolemic hyponatremia. After approval was granted more than 5000 patients worldwide were included in the so-called hyponatremia register and 22 active centers in Germany with 317 patients participated. Although some details from this now concluded register have been published, the final publication of the multinational post-authorization safety study on tolvaptan in the treatment of SIADH has not yet been published. In the years 2012 and 2013 two warning letters were issued on tolvaptan. The first letter warned of the risk of a faster increase in serum sodium using tolvaptan and provided detailed information on how the risk of osmotic demeyelination can be minimized. So far only one proven case of osmotic demelination syndrome (ODS) is known; however, this occurred following incorrect use of tolvaptan in a monotherapy. The second warning letter provided information on the potential risk (reversible) of liver damage by tolvaptan, which resulted from the TEMPO 3:4 study. In this study tolvaptan was used in a higher dosage for therapy of autosomal dominant polycystic kidney disease. Although the European renal best practice (ERBP) guidelines from 2014 did not recommend tolvaptan for the indications of SIADH, other guidelines came to different conclusions. In summary, 5 years after the approval of tolvaptan there is still no consensus. At the current time many questions still remain unanswered. Initiation of therapy with tolvaptan remains reserved for experienced physicians in hospitals. Treatment must be adapted on the basis of a clinical estimation of the individual situation of each patient.

Impact of interleukin-1ß antibody (canakinumab) on glycaemic indicators in patients with type 2 diabetes mellitus: results of secondary endpoints from a randomized, placebo-controlled trial.

AIMS/HYPOTHESIS: This study was conducted to determine the optimal monthly subcutaneous dose of canakinumab (a human monoclonal anti-human IL-1ß antibody) needed to improve glucose control in metformin-treated patients with type 2 diabetes mellitus (T2DM). METHODS: This was a parallel-group, randomized, double-blind, multicentre, placebo-controlled study designed to assess the effect on HbA(1c) and the safety/tolerability of four monthly doses of canakinumab (5, 15, 50, or 150 mg) as an add-on to metformin over 4 months. RESULTS: Patients (n=551; mean age 54.1 years; mean baseline HbA(1c) 7.4%) were randomized and treated in a double-blind fashion to canakinumab 5 mg (n=93), 15 mg (n=95), 50 mg (n=92), 150 mg (n=92) or placebo (n=179) monthly. There was no dose response detected between active canakinumab doses, but all doses numerically lowered HbA(1c) (primary endpoint) from baseline between 0.19% and 0.31% (placebo-unadjusted), with maximal effect noted in the 50mg dose of canakinumab (-0.18% difference vs placebo; multiplicity-adjusted, P=0.13902) as reported earlier (Ridker et al., 2012). No other glycaemic control parameters (FPG, fasting insulin, plasma glucose AUC(0-4h), 2-h PPG, peak glucose, C-peptide AUC(0-4h), peak C-peptide, insulin AUC(0-4h), peak insulin, ISR(0-2h), HOMA-ß and HOMA-IR) showed any meaningful changes by canakinumab therapy. Canakinumab treatment was safe and well tolerated. There were no relevant differences in adverse events between the canakinumab and placebo groups. CONCLUSIONS/INTERPRETATION: A 4-month course of monthly canakinumab (50 mg) produced a numerical reduction of HbA(1c) in T2DM patients on metformin, potentially by improving beta-cell function. The safety and tolerability profile of canakinumab was consistent with prior trials. TRIAL REGISTRATION: Registry: http://www.ClinicalTrials.gov, Registration No.: NCT00900146.

[Hyponatremia : The water-intolerant patient]. / Hyponatriämie : Der "wasserintolerante" Patient.

Hyponatremia due to intolerance to water is a frequent clinical condition and associated with increased mortality. Besides the well known neurological symptoms, gait disturbances, falls, fractures and osteoporosis have also been described recently in patients with chronic hyponatremia. Acute hyponatremia is a more dramatic situation and needs rapid action when severe neurological symptoms are present. Hypertonic saline is recommended to treat this condition until relief of severe symptoms. The causes of hyponatremia have to be carefully examined. Especially diuretics, antidepressants and endocrine causes, e.g. hypothyroidism, hypocortisolism and hypoaldosteronism should be excluded by examination of the patient history, clinical examination and by laboratory tests. Patients should be classified as being euvolemic, hypovolemic or hypervolemic. Whereas acute hyponatremia with severe symptom should be treated with hypertonic saline, euvolemic hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) with mild and moderate symptoms can now be treated with tolvaptan, a selective V(2)-vasopressin antagonist. Oral tolvaptan has been shown to be an effective and potent aquaretic to treat hyponatremia caused by SIADH as evidenced by a simultaneous increase in serum sodium and a decrease in urine osmolality. The condition of patients with mild or moderate hyponatremia is also improved. Side effects associated with tolvaptan include increased thirst, dry mouth, polyuria and hypernatremia. Rapid increases in serum sodium should be avoided by close monitoring in a hospital setting.

[Treatment of hyponatremia: new developments and controversies]. / Therapie der Hyponatriämie: neue Erkenntnisse und Kontroversen.

This article summarizes improvements in diagnosis and therapy in patients with symptomatic hyponatremia. The available treatment options for hyponatremia have been limited, and consisted mainly of isotonic or hypertonic saline, urea, and fluid restriction. Vasopressin receptor antagonists, also known as vaptans or aquaretics are a new class of drugs that now offer an additional treatment option for hyponatremic patients with euvolemic hyponatremia due to SIADH in Europe. In short and long term studies, tolvaptane has been shown to be effective in raising serum sodium levels in a predictable fashion in patients with SIADH with only few side effects, when serum sodium was frequently monitored and dosage of tolvaptans was properly adjusted. Further studies are needed to find out which patients benefit from treatment with respect to morbidity and mortality. Until now, therapy is limited to the treatment of moderate symptomatic hyponatremia in SIADH due to the high cost of therapy.

[Treatment of hyponatremia: role of vaptans]. / Behandlung der Hyponatriämie: Die Rolle der Vaptane.

Hyponatremia is encountered quite frequently in everyday clinical practice. The symptomatology mainly includes neurological manifestations. In addition, it has been noted in recent years that uncertain gait, falls, fractures, and osteoporosis are also associated with hyponatremia. Based on clinical and laboratory analyses, hyponatremia can be classified into three categories: hypovolemic (decreased volume), hypervolemic (with venous edema), and euvolemic. The severity of the neurological symptoms related to hyponatremia should serve to guide the therapeutic approach. Severe cerebral symptoms due to acute cerebral edema require a prompt and closely monitored course of action with administration of hypertonic saline solution. Milder and moderate symptoms as well as the syndrome of inappropriate ADH secretion (SIADH) can now also be managed with controlled use of the ADH antagonist tolvaptan, one of a new class of vaptans. Tolvaptan is a selective antagonist of the antidiuretic effect of vasopressin without primarily affecting blood pressure and depending on the dose leads to increased excretion of free water (aquaresis). Side effects predominantly concern thirst, polyuria, and hypernatremia. Under these conditions, vaptans represent a valuable asset to the therapeutic spectrum in SIADH. Further studies are needed to determine whether falls and fractures can also be beneficially influenced.

[Thyroid disorders and pregnancy]. / Schilddrüsenerkrankungen und Schwangerschaft.

Disorders of the thyroid in women are common during the reproductive years. Incorrect or delayed treatment during pregnancy can adversely affect the health of mother and child. Knowledge of the physiological changes during this time is essential. Thyroid disorders, in particular hypothyroidism, may compromise fertility. Autoimmune thyroiditis is associated with a higher risk of fetal loss. In women on thyroid hormone replacement therapy, the thyroxine dose has to be adjusted to meet the enhanced requirement during pregnancy. Thyroid hormone is vital to fetal brain development. During pregnancy and lactation, iodine supplementation is also recommended due to alterations in iodine metabolism. Hyperthyroidism during pregnancy can adversely affect pregnancy outcome and has to be treated accordingly. Propylthiouracil should be given using the least effective dose to keep free thyroxine levels at the upper limit of normal or slightly above. Hyperthyroidism in the fetus and the neonate can be induced by thyroid stimulating antibodies capable of passing the placenta.

Effects of tibolone and raloxifene on bone mineral density in osteopenic postmenopausal women.

UNLABELLED: A randomized trial was conducted in osteopenic postmenopausal women to compare the efficacy of tibolone versus raloxifene on BMD of the lumbar spine and hip. Tibolone increased lumbar spine and total hip BMD to a statistically significantly greater extent than raloxifene after two years of treatment. INTRODUCTION: Both tibolone, a selective tissue estrogenic activity regulator (STEAR), and raloxifene, a selective estrogen receptor modulator (SERM), are known to prevent postmenopausal bone loss. However, no head-to-head studies to compare the efficacy on bone have been performed. METHODS: A double-blind, randomized trial was conducted in osteopenic postmenopausal women aged 60-79 years to compare the effects of tibolone 1.25 mg/day to raloxifene 60 mg/day on bone mineral density (BMD). Serum osteocalcin and serum type I collagen C-telopeptides were measured as biochemical markers of bone metabolism. RESULTS: Three hundred and eight subjects were allocated to treatment. Both treatments significantly increased lumbar spine BMD, however the increase was significantly larger after tibolone treatment than after raloxifene treatment (at year 1: 2.2% versus 1.2%, p<0.01 and at year 2: 3.8% versus 2.1%, p<0.001). After 2 years of treatment, the increase in total hip BMD in the tibolone group was significantly larger than in the raloxifene group (p<0.05). Both treatments significantly reduced type I collagen C-telopeptides and osteocalcin levels when compared to baseline. CONCLUSIONS: Tibolone 1.25 mg/day for 2 years prevents postmenopausal bone loss in older women and results in a larger increase of BMD both at the lumbar spine and hip than raloxifene.

Management of diabetes mellitus and hospital-related hyperglycemia in patients of a medical ICU, with the use of two "down-to-earth" protocols: a feasibility study.

OBJECTIVE: Optimal control of blood glucose in the ICU has been shown to significantly decrease mortality and morbidity of severely ill patients. The purpose of the present project was to develop and implement undemanding, "down-to-earth" protocols, enabling tight glucose control in critically ill patients, in the setting of a city hospital ICU with limited personnel and facilities. RESEARCH DESIGN AND METHODS: From January 2003 to January 2006, a total of 745 patients (3197 patient-days) were treated for hyperglycemia in our medical ICU. On July 2003 two different intensive insulin therapy protocols were implemented: A protocol of continuous intravenous insulin, including specific algorithms for calculation of initial insulin bolus, initial infusion rate and further adjustment plan, was used for patients with compromised peripheral tissue perfusion. For patients with stable circulation, a protocol of subcutaneous intensive insulin therapy, including a formula for calculation of daily insulin dosage in previously non-insulin-treated diabetics, was adopted. 134 patients were treated during the run-in phase of the project and 539 patients were treated during the main treatment phase. 72 patients treated for hyperglycemia in our ICU prior to the implementation of the two protocols (from January 2003 to July 2003) served as controls. RESULTS: After the implementation of the two protocols, a marked overall increase of normoglycemic blood glucose values (64.7% vs. 48.5%, P<0.001), a decrease of manifest hyperglycemias (6.4% vs. 17.4%, P<0.001) and an increase in hypoglycemic events (1.8% vs. 0.7%, P<0.001) was observed. Seven cases of severe hypoglycemia requiring glucose infusion were observed during the main treatment phase (0.3%). No hypoglycemia-associated deaths occurred. CONCLUSIONS: The combined implementation of the two protocols presents a simple, safe and effective way of pursuing normoglycemia in critically ill patients.

Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1.

BACKGROUND: Multiple-endocrine-neoplasia-type-1 (MEN1) is an autosomal-dominant inherited disorder characterized by the combined occurrence of primary hyperparathyroidism (pHPT), gastroenteropancreatic neuroendocrine tumors (GEP), adenomas of the pituitary gland (APA), adrenal cortical tumors (ADR) and other tumors. As the tumors appear in an unpredictable schedule, uncertainty about screening programs is persisting. OBJECTIVE: To optimize screening and to analyze possible differences in sporadic versus familial cases. METHODS: We analyzed data of 419 individuals including 306 MEN-1 patients (138 isolated and168 familial cases out of 102 unrelated families). RESULTS: A total of 683 tumors occurred consisting of 273 pHPT, 138 APA, 166 GEP, 57 ADR, 24 thymic- and bronchial-carcinoids as well as 25 neoplasms of other tissues. The age-related penetrance was determined as 10%, 35%, 67%, 81% and 100% at 20, 30, 40, 50 and 65 years respectively. Although pHPT being the most frequent first manifestation (41%), also GEP (22%) or APA (21%) were found to be the first presentation. APA occurred significantly more frequent (p<0,05) in isolated (n=138) than in familial (n=168) cases, whereas GEP showed a tendency to occur more often in familial cases. Genotype/phenotype correlation in 140 clinically affected MEN-1 cases showed a tendency for truncating mutations, especially nonsense mutations to be associated to GEP and carcinoids of the lungs and thymus. CONCLUSION: In view of the morbidity and frequency in familial cases an effective screening programme should aim at an early diagnosis of GEP particularly when truncating, especially nonsense mutations are found.

[Diabetic coma. Management of diabetic ketoacidosis and nonketotic hyperosmolar coma]. / Coma diabeticum. Management der diabetischen Ketoazidose und des nicht ketoazidotischen hyperosmolaren Komas.

This review describes the current guidelines of German diabetes association for the management of diabetic coma, both of diabetic ketoacidosis and hyperosmolal coma. The outline focuses on emergency treatment and the management on the intensive care unit, in particular, volume and insulin therapy, and potassium replacement. The delineation of the concept of low insulin therapy is emphasized to avoid the incidence of disequilibrium syndrome. Also, the indications for bicarbonate therapy in diabetic ketoacidosis are critically discussed, as well as phosphate and magnesium replacement. With today's therapeutic possibilities the therapeutic goal, i.e. a low mortality, may be achieved, dependent on the underlying illness.

Influence of antihypertensive medication on aldosterone and renin concentration in the differential diagnosis of essential hypertension and primary aldosteronism.

OBJECTIVE: Antihypertensive drugs influence the neurohumoral cardiovascular system and the concentration of hormones involved in blood pressure regulation. Little is known, however, about the extent to which various antihypertensive drugs influence cardiovascular hormone concentrations and thus disturb the differential diagnosis of hypertension in clinical practice. In this study we compare the impact of different antihypertensive medicaments on the renin-angiotensin-aldosterone system in patients with essential hypertension who are screened for primary aldosteronism. DESIGN AND SUBJECTS: We analysed serum aldosterone (SAC) and plasma renin concentration (PRC) in 37 normotensive controls, 144 hypertensive patients with essential hypertension, and 19 patients with primary aldosteronism. Patients were on different treatment regimens such as single drug or combination therapy with beta-blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II subtype 1 (AT1) receptor antagonists, calcium channel blockers, spironolactone and no treatment. RESULTS: In patients with essential hypertension, beta-blocker therapy (n = 47) led to a highly significant suppression of renin, whereas serum levels of aldosterone were not significantly altered. ACE inhibitors and AT1 receptor antagonists (n = 55) decreased aldosterone levels only to a minor extent. Calcium channel blockers (n = 23) had no significant influence on SAC or PRC. In patients with primary aldosteronism treated with spironolactone (n = 8), renin escaped suppression and reached very high levels. CONCLUSION: Beta-blockers and aldosterone antagonists have the strongest impact on the renin-angiotensin system. The decrease in renin concentration by beta-blockers leads to an increase in the ratio of aldosterone to renin, and thus to false-positive results in patients with essential hypertension. Calcium channel blockers, and probably also ACE inhibitors and AT1 receptor antagonists alone or in combination, may be continued during screening for primary aldosteronism by determination of renin and aldosterone concentration.

Multiple endocrine neoplasia 2A syndrome: Surgical management.

BACKGROUND/PURPOSE: Currently, molecular genetic diagnostics allow familial types of medullary thyroid carcinoma to be detected at an asymptomatic stage and surgery thus to be performed at a time when prognosis is good. The current report aims to determine the appropriate age for safe prophylactic thyroidectomy in children with multiple endocrine neoplasia (MEN) 2A and mutations at codon 609 according to genotype-phenotype correlations and will discuss surgical procedures. METHODS: The authors describe the case of a family with hereditary MEN 2A syndrome. A DNA analysis of 7 family members confirmed the diagnosis by a mutation at codon 609 of the RET proto-oncogene. RESULTS: A phaeochromocytoma developed in 2 family members. Four had medullary thyroid carcinoma. A grandson underwent a prophylactic thyroidectomy at the age of 5 on account of genetic evidence. Despite the negative preoperative and intraoperative findings he already had an invasive medullary thyroid carcinoma. CONCLUSIONS: Few genotype-phenotype correlations have been established for MEN 2A disease. According to the natural history of the disease, families with the genotype RET cys609gly should have a more benign disease than high-risk families (mutations at codon 634, 618). From this report the authors conclude that prophylactic thyroidectomy in "609" families should be performed earlier than actually recommended, favorably at the age of 2 to 4 years. Further multicenter studies are needed to provide more clinical and prognostic data for less frequent (codon 609, 630, 791, and 891) RET genotypes.

Ratio of serum aldosterone to plasma renin concentration in essential hypertension and primary aldosteronism.

The ratio of serum aldosterone to plasma renin activity (PRA) has been proposed as sensitive screening method in the diagnosis of primary aldosteronism under random conditions. However, the method for determination of renin activity is hampered by the necessity of ice cooling during storage and transport. The present study was therefore conducted to examine the ratio of serum aldosterone to plasma renin concentration (ARR) and its usefulness in diagnosis of primary aldosteronism under ambulatory conditions and given antihypertensive medication. 146 patients with arterial hypertension who consecutively attended the outpatient clinic were studied prospectively. Patients with secondary hypertension besides primary aldosteronism were not included in the series. 37 normotensive patients served as control. Also, 17 patients with known primary aldosteronism were retrospectively examined. Among the hypertensive group 2 patients with Conn's syndrome were newly detected (1.4%). ARR was 7.92 +/- 6.04 [pg/ml]/[pg/ml] in normotensive controls (range from 2.03 to 26.98), 14.61 +/- 18.50 [pg/ml]/[pg/ml] in patients with essential hypertension (n = 144, range from 0.41 to 115.45) and 155.92 +/- 127.84 [pg/ml]/[pg/ml] in patients with primary aldosteronism (n = 19, range from 6.75 to 515). 17 of the 19 patients with Conn's syndrome had an ARR of more than 50. Under ongoing drug treatment this represents a sensitivity of 89% and a specificity of 96%. Sensitivity decreased to 84% and specificity increased to 100% when a second criteria (aldosterone > or = 200 pg/ml) was included. In summary, ARR using renin concentration is a useful screening parameter for primary aldosteronism.

A new mutation of the arginine vasopressin-neurophysin II gene in a family with autosomal dominant neurohypophyseal diabetes insipidus.

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomally dominant inherited disorder with a typical onset at one to six years of age. The genetic locus of FNDI is the arginine vasopressin-neurophysin II (AVP-NPII) gene. The gene encoding the precursor hormone (prepro-AVP-neurophysin II) is located in the chromosomal region 20p13 and contains three exons. Mutations that cause FNDI have been found to occur within the signal peptide of the prepro-AVP-neurophysin II precursor, within the coding sequence for neurophysin II and the vasopressin-coding sequence. A family (four members with FNDI, two without FNDI) in three consecutive generations was investigated. Index case was a now 22-year old man with a history of severe polyuria (18 L/day) and polydipsia first recognized at about 4-5 months of age. The arginine vasopressin-neurophysin II gene was investigated by direct sequencing of PCR products amplified from each exon. Subsequently, a restriction analysis was performed to verify the sequencing results. The affected individuals were found to have a missense mutation in exon 2 at nucleotide position 1887 (G to C) of the AVP-NPII gene. Using both restriction enzyme digestion and sequence analysis, the mutation was found in all affected family members, but not in the unaffected members studied. This mutation (1887 G to C) represents a novel mutation of the AVP-NPII gene.

[Osteoporosis and multiple pregnancy--a case report with positive outcome]. / Osteoporose und Mehrlingsgravidität--ein Erfahrungsbericht mit positivem Ausgang.

BACKGROUND: Pregnancy-associated osteoporosis is a rare condition. Due to the rareness of pregnancy-associated osteoporosis, no guidelines concerning an adequate therapy exist. However, since many antiresorptive drugs are potentially teratogenous, the therapeutic approach is limited. CASE REPORT: In a 30-year-old patient, pubic fracture occurred during her first pregnancy. Osteodensitometry revealed a distinct osteoporosis. The bone density improved under therapy with sex hormones, alendronate, 1,000 mg calcium and 1,000 IU cholecalciferol daily, but still remained osteoporotic when the patient again became pregnant 3 years later. During her triplet pregnancy the patient was treated with 3,000 mg calcium and 1,500 IU cholecalciferol daily. After delivery the bone density remained at the same level as immediately before the second pregnancy. CONCLUSION: Regarding the nonoccurrence of the expected considerable bone loss with this treatment the efficacy of this therapeutic approach during pregnancy warrants further study.