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Background: Exposure to isotretinoin during pregnancy must be avoided due to its teratogenicity, but real-world data on its use are scarce. We aimed to describe (i) isotretinoin use in women of childbearing age in Germany; (ii) the occurrence of isotretinoin-exposed pregnancies; and (iii) malformations among children exposed in utero. Methods and findings: Using observational data from the German Pharmacoepidemiological Research Database (GePaRD, claims data from approximately 20% of the German population), we conducted annual cross-sectional analyses to determine age-standardized prevalence of isotretinoin use between 2004 and 2019 among girls and women aged 13 to 49 years. In cohort analyses, we estimated the number of exposed pregnancies by assessing whether there was prescription supply overlapping the beginning of pregnancy (estimated supply was varied in sensitivity analyses) or a dispensation within the first 8 weeks of pregnancy. Data of live-born children classified as exposed in a critical period according to these criteria were reviewed to assess the presence of congenital malformations. The age-standardized prevalence of isotretinoin use per 1,000 girls and women increased from 1.20 (95% confidence interval [CI]: 1.16, 1.24) in 2004 to 1.96 (95% CI: 1.92, 2.01) in 2019. In the base case analysis, we identified 178 pregnancies exposed to isotretinoin, with the number per year doubling during the study period, and at least 45% of exposed pregnancies ended in an induced abortion. In sensitivity analyses, the number of exposed pregnancies ranged between 172 and 375. Among live-born children, 6 had major congenital malformations. The main limitation of this study was the lack of information on the prescribed dose, i.e., the supply had to be estimated based on the dispensed amount of isotretinoin. Conclusions: Isotretinoin use among girls and women of childbearing age increased in Germany between 2004 and 2019, and there was a considerable number of pregnancies likely exposed to isotretinoin in a critical period. This highlights the importance of monitoring compliance with the existing risk minimization measures for isotretinoin in Germany. Jonas Reinold and colleagues investigate how isotretinoin use has changed over a 15 year period in Germany and the potential for in-utero exposure. Author summary: Why was this study done?: Systemic (oral) isotretinoin is used in the treatment of moderate to severe acne. Given that isotretinoin is one of the strongest human teratogens known today, it is important to monitor the use of isotretinoin in girls and women of childbearing age as well as the occurrence of pregnancies exposed to this drug. There is a lack of population-based studies addressing these research questions. What did the researchers do and find?: Using a database covering 20% of the German population, we conducted cross-sectional analyses to assess the prevalence of isotretinoin use between 2004 and 2019 in girls and women of childbearing age. We found that the age-standardized prevalence of isotretinoin use increased from 1.20 to 1.96 per 1,000 girls/women during this period. In cohort analyses, we estimated the number of pregnancies likely exposed to isotretinoin in a critical period. In the base case analysis, we identified 178 of such pregnancies. Sensitivity analyses considering the recommended one-month washout period suggested that there could have been additional pregnancies exposed to isotretinoin because they started before the end of the washout period. What do these findings mean?: Isotretinoin use among girls and women of childbearing age increased in Germany between 2004 and 2019, and there were a considerable number of pregnancies likely exposed to isotretinoin in a critical period. This highlights the importance of monitoring compliance with the existing risk minimization measures for isotretinoin in Germany. It also seems important to increase awareness regarding the component of the pregnancy prevention program that recommends contraception also in the month after treatment cessation. The main limitation of this study was the lack of information on the prescribed dose of isotretinoin. We therefore estimated the dose based on the dispensed amount of isotretinoin and varied the underlying assumptions. [ABSTRACT FROM AUTHOR]

Aim: Sclerotherapy is the targeted chemical ablation of varicose veins by intravenous injection of a liquid or foamed sclerosing drug. The treated veins may be intradermal, subcutaneous, and/or transfascial as well as superficial and deep in venous malformations. The aim of this guideline is to give evidence-based recommendations for liquid and foam sclerotherapy. Methods: This guideline was drafted on behalf of 23 European Phlebological Societies during a Guideline Conference on 7th–10th May 2012 in Mainz. The conference was organized by the German Society of Phlebology. Results: This guideline focuses on the two sclerosing drugs which are licensed in the majority of the European countries, Polidocanol (POL) and Sodium tetradecyl sulphate (STS). Other sclerosants are not discussed in detail. In this paper the recommendations concerning indications, contraindications, concentrations, volumes and technique of liquid and foam sclerotherapy of varicose veins and venous malformations are reviewed. [ABSTRACT FROM AUTHOR]

Copyright of Zeitschrift für Medizinische Physik is the property of Elsevier GmbH, Urban & Fischer Verlag and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: This online survey looked at the experiences and general perceptions of midwives concerning induction of labour and the specific use of misoprostol. Methods: We published an online questionnaire with 24 questions in German on midwives' experiences and perceptions of different methods of induction of labour. Results: The online survey was answered by 412 midwives between February 2016 and February 2017. At least 20% of the 24 questions were answered in 333 questionnaires, which were included in this analysis. Oral misoprostol was the most common induction method for primipara and for women with a previous vaginal birth and an unfavourable cervix. Apart from alternative methods for induction of labour like castor oil and complementary/alternative methods, oral misoprostol was the preferred method of induction of labour by midwives. Midwives described a wide range of dosage schedules concerning application intervals, starting doses, and the maximum daily dose of misoprostol. Approximately 50% of the participants of this study described prescriptions of more than 200 µg misoprostol daily for induction of labour. Conclusion: Misoprostol is widely used in Germany and was one of the three preferred methods of induction of labour among midwives in our study next to castor oil and complementary/alternative methods. The preparation and dosage of misoprostol vary significantly among hospitals and do not adhere to international guidelines. Midwives voiced their concerns about inconsistent indications and heterogenous use of different methods and dosages of induction. They wished for more patience with late-term pregnancies and individualized shared decision-making between pregnant women and obstetricians. [ABSTRACT FROM AUTHOR]

Background: Drug-related problems (DRP) are common in the elderly population, especially in people living with dementia (PwD). DRP are associated with adverse outcomes that could result in increased costs.Objective: The objective of the study was to analyze the association between DRP and healthcare costs in PwD.Methods: The analysis was based on the cross-sectional data of 424 PwD. Compliance, adverse effects, and drug administration of prescribed and over-the-counter drugs taken were assessed. DRP were identified and classified by pharmacists using an adapted German version of "PIE-Doc®". Healthcare utilization was assessed retrospectively used to calculated costs from a public payer perspective using standardized unit costs. The associations between DRP and healthcare costs were analyzed using multiple linear regression models.Results: 394 PwD (93%) had at least one DRP. An inappropriate drug choice was significantly associated with increased total costs (b = 2,718€; CI95% 1,448-3,988) due to significantly higher costs for hospitalization (b = 1,936€; 670-3,202) and for medications (b = 417€; 68-765). Problems with medication dosage and drug interactions were significantly associated with higher medication costs (b = 679€; 31-1,328; and b = 630€; 259-1,001, respectively).Conclusions: DRP could significantly lead to adverse outcomes for PwD and healthcare payers, reflected by a higher hospitalization and costs, respectively. Further research is needed to clarify on interventions and approaches efficiently avoiding DRP and on the effect on patient-reported and economic outcomes. [ABSTRACT FROM AUTHOR]

Background: Monitoring the reasons why a considerable number of people do not receive recommended vaccinations allows identification of important trends over time, and designing and evaluating strategies to address vaccine hesitancy and increase vaccine uptake. Existing validated measures assessing vaccine hesitancy focus primarily on confidence in vaccines and the system that delivers them. However, empirical and theoretical work has stated that complacency (not perceiving diseases as high risk), constraints (structural and psychological barriers), calculation (engagement in extensive information searching), and aspects pertaining to collective responsibility (willingness to protect others) also play a role in explaining vaccination behavior. The objective was therefore to develop a validated measure of these 5C psychological antecedents of vaccination. Methods and findings: Three cross-sectional studies were conducted. Study 1 uses factor analysis to develop an initial scale and assesses the sub-scales’ convergent, discriminant, and concurrent validity (N = 1,445, two German convenience-samples). In Study 2, a sample representative regarding age and gender for the German population (N = 1,003) completed the measure for vaccination in general and for specific vaccinations to assess the potential need for a vaccine-specific wording of items. Study 3 compared the novel scale’s performance with six existing measures of vaccine hesitancy (N = 350, US convenience-sample). As an outcome, a long (15-item) and short (5-item) 5C scale were developed as reliable and valid indicators of confidence, complacency, constraints, calculation, and collective responsibility. The 5C sub-scales correlated with relevant psychological concepts, such as attitude (confidence), perceived personal health status and invulnerability (complacency), self-control (constraints), preference for deliberation (calculation), and communal orientation (collective responsibility), among others. The new scale provided similar results when formulated in a general vs. vaccine-specific way (). In a comparison of seven measures the 5C scale was constantly among the scales that explained the highest amounts of variance in analyses predicting single vaccinations (between 20% and 40%; ). The present studies are limited to the concurrent validity of the scales. Conclusions: The 5C scale provides a novel tool to monitor psychological antecedents of vaccination and facilitates diagnosis, intervention design and evaluation. Its short version is suitable for field settings and regular global monitoring of relevant antecedents of vaccination. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to assess the quality of the information sources on the modification of solid medication dosage forms (crushing, suspending) used on the wards of a large university hospital in Germany. Methods: We performed on-site visits of all 79 wards of the hospital and collected available sources of information on the modification of solid medication dosage forms. To evaluate the quality of such information, we gathered reference information for each listed brand from the respective pharmaceutical company, transferred this information to a knowledge base, and classified it into three categories, i.e., modification not allowed, modification allowed, and modification allowed under certain circumstances. Results: Twenty-two lists of information on drug modification were identified in the 79 wards. Each list contained errors, and on average 17.0 % (range 8.0-32.3 %) of the brands listed had been withdrawn from the market or the information on crushing and/or suspending was inappropriate. Most of the incorrect information either concerned brands containing ingredients that were potentially hazardous to the staff members who prepared the drugs or referred to special dosage forms such as capsules and modified release formulations (e.g., cytotoxic drugs). Conclusion: We found that the lists posted on the wards were often outdated and did not take into account the limitations/problems of preparing drugs on the ward. Our results emphasize that lists posted in wards need to be checked regularly and that 'ready-to-use' lists from third parties might require adaptation to site-specific conditions in order to protect healthcare staff from exposure to potentially hazardous drugs during drug preparation and ensure safe drug application to the patient. [ABSTRACT FROM AUTHOR]

We created the final bill of 'Intravenous cyclophosphamide (IVCY) for the treatment of rheumatic disease of children in general' in order to get approval for the off-label use of IVCY from the Study Group on Pediatric Drug Therapy. As a result, this study group approved IVCY's off-label use in children via public applications. We could create IVCY regimen specific for Japanese children independently of the efficacy, dosage, and administration applied in Germany, which at the time of application was the only country in Europe and the USA where IVCY was approved. Later, its use in adults was given approval through public applications after being fully reviewed by the Study Group on Unapproved and Off-label Drugs of High Medical Need. Consequently, IVCY is now available for the treatment of both childhood and adult rheumatic diseases in general. [ABSTRACT FROM AUTHOR]

Purpose: The anticoagulation response to vitamin K antagonists is characterised by high inter-individual variability. The impact of single nucleotide polymorphisms (SNPs) in several genes of enzymes involved in the vitamin K cycle on phenprocoumon dose variability and phenprocoumon plasma concentrations is still under investigation. Methods: We assessed the influence of VKORC1 c.-1639G>A, CYP2C9*2, CYP2C9*3, CYP4F2 c.1297G>A, CALU c.*4A>G, EPHX1 c.337T>C, GGCX c.214+597G>A, F7 c.-402G>A, F7 c.-401G>T, PROC c.-228C>T and PROC c.-215G>A along with clinical and demographic parameters on steady-state phenprocoumon therapy in 75 patients. A prediction model was developed for total phenprocoumon plasma concentrations and daily phenprocoumon doses required for therapeutic anticoagulation. Results: The VKORC1 c.-1639 genotype was the main predictor of the phenprocoumon daily dose (adjusted R = 37.6%) and the total phenprocoumon concentration (adjusted R = 38.3%). CYP2C9 affected the phenprocoumon concentration, but not the dose requirements. SNPs in the other genes of the vitamin K cycle, concomitant medication, nicotine use and alcohol consumption did not predict phenprocoumon concentrations and phenprocoumon dose requirements in a multiple linear regression model. Phenprocoumon concentrations were predicted by VKORC1 c.-1639, CYP2C9 genotype, age and BMI. The final prediction model for the daily phenprocoumon dose requirements comprised VKORC1 c.-1639 genotype, age and height accounting for 48.6% of the inter-individual variability. Conclusions: A rough prediction of phenprocoumon maintenance doses can be achieved by a limited set of parameters ( VKORC1, age, height). The investigated SNPs in CYP4F2, CALU, EPHX1, GGCX, F7, and PROC did not improve the predictive value of a pharmacogenetic-based dosing equation for phenprocoumon. [ABSTRACT FROM AUTHOR]

Roflumilast is an oral phosphodiesterase 4 (PDE4) inhibitor for the treatment of chronic obstructive pulmonary disease (COPD). It is metabolized by CYP1A2 and CYP3A4 to its primary metabolite, roflumilast N-oxide, through which >90% total PDE4 inhibitory activity (tPDE4i) is mediated. Fluoroquinolones, of which enoxacin is the most potent CYP1A2 inhibitor, are used to treat COPD exacerbations. This phase I, open, nonrandomized, fixed-sequence, 2-period study evaluated the effects of steady-state enoxacin on the single-dose pharmacokinetics of roflumilast and roflumilast N-oxide. Twenty healthy participants received roflumilast, 500 µg once daily, on days 1 and 12, and enoxacin, 400 mg twice daily, on days 7 to 18. Pharmacokinetic profiles were obtained for days 1 to 6 and 12 to 19. The safety and tolerability of all treatments were also assessed. In 19 evaluable participants, coadministration led to 56% higher mean systemic exposure, 20% higher mean peak concentrations, and 36% lower mean apparent oral clearance compared with roflumilast alone. For roflumilast N-oxide, 23% higher mean systemic exposure and 14% lower mean peak concentrations were seen after coadministration. Roflumilast was well tolerated both alone and in combination with enoxacin. A weak interaction was shown between roflumilast and enoxacin, as mean tPDE4i increased by 25%, but is unlikely to have clinical relevance. [ABSTRACT FROM PUBLISHER]

The objectives of the 3 phase I studies described herein were (1) to compare the pharmacokinetics of gabapentin delivered from a novel gastric-retentive dosage form vs an immediate-release formulation, (2) to assess the dose proportionality of the gastric-retentive extended-release formulation, and (3) to determine the effect of food on the pharmacokinetics of gabapentin delivered from this formulation. The time to reach maximum plasma concentration (tmax) was extended for gabapentin delivered from the gastric-retentive extended-release formulation compared with the immediate-release formulation. A dose-related increase in both the maximum plasma concentration (Cmax) and the area under the plasma concentration—time curve (AUC) was observed as the gabapentin dose increased from 600 to 2400 mg. Fed status and increased fat content delayed tmax and enhanced Cmax and AUC in proportion to the fat content. The pharmacokinetics of gabapentin delivered from this extended-release formulation allows a reduced dosing frequency while maintaining bioavailability and possibly diminishing the occurrence of adverse events attributable to a slower increase to the peak concentration compared with the immediate-release dosage form. [ABSTRACT FROM PUBLISHER]

The article offers news briefs. A U.S. national survey sponsored by the American Pain Foundation revealed physicians' misperceptions about the misuse and abuse of opioids by patients. The U.S. Food and Drug Administration's (FDA’s) Advisory Committee rejected a proposed risk mitigation and evaluation strategy (REMS) supported by the American Pain Society (APS). A study by German researchers investigating pain in hospital patients revealed poor pain control in German hospitals.

Objectives: Physiological changes occurring in patients with diabetes may affect the pharmacokinetics and penetration of antimicrobial agents into peripheral tissue. We examined the pharmacokinetics and the penetration of moxifloxacin into perinecrotic tissue of diabetic foot lesions in patients with diabetic foot infections (DFI). Patients and methods: Adult patients suffering from type 2 diabetes mellitus and hospitalized for DFI (Texas classification of at least B2) were treated with 400 mg moxifloxacin intravenously (IV) or orally (PO) once daily. The pharmacokinetics of moxifloxacin and its concentration 3 h after administration in samples of perinecrotic tissue resected from infected diabetic foot wounds were determined at steady state (days 4-8). Results: A total of 53 patients with diabetes mellitus type 2 (mean age 69.4 ± 10.8 years) were included in the study, of whom 28 received PO and 25 IV moxifloxacin therapy for a median of 8 days. In the PO and IV subgroups, the mean maximum observed plasma concentration ( C) in plasma was 2.69 and 4.77 mg/l at a median of 2 [time to reach C ( T) range 1.0-8.0 h] and 1 h after administration, respectively. A mean area under the plasma concentration-time curve from time 0 until the last quantifiable plasma concentration (AUC) of 29.36 mg h/l (PO) and 27.09 mg h/l (IV) was achieved. Mean moxifloxacin concentrations in perinecrotic tissue of infected diabetic foot wounds following PO or IV administration were 1.79 ± 0.82 and 2.20 ± 1.54 μg/g, thus exceeding the MIC (minimum inhibitory concentration required to inhibit growth of 90% of organisms) for Staphylococcus aureus (0.25 mg/l) by seven- and eightfold and the MIC for Escherichia coli (0.06 mg/l) by 29-fold and 36-fold, respectively. The mean tissue-to-plasma ratios of moxifloxacin concentration 3 h after administration were 1.01 ± 0.57 (PO) and 1.09 ± 0.69 (IV). Significant differences between the routes of administration were observed for T and C ( P < 0.01), but not for other clinically relevant parameters (AUC; moxifloxacin DFI tissue concentration). Conclusions: The plasma concentration-time curve of moxifloxacin in diabetic patients is similar to that of healthy volunteers. We also observed a good penetration of moxifloxacin into inflamed DFI tissue which taken together with the possibility of sequential IV/PO therapy suggest that moxifloxacin 400 mg once daily is a therapeutic option in the treatment of DFI caused by susceptible organisms. [ABSTRACT FROM AUTHOR]

Ibandronate, one of the most potent bisphosphonates, has been shown to inhibit growth of various cancer cell lines. In contrast, little is known about the effects of ibandronate on prostate cancer cells. Therefore the aim of our study was to characterize the effects of ibandronate alone and in combination with docetaxel on the growth of prostate cancer cell lines and to identify the underlying signalling pathways. Material and methods. The prostate cancer cell lines LNCaP and PC-3 were treated with increasing concentrations of ibandronate and docetaxel alone and in combination. Viable cell number was measured after five days using a hemocytometer and the MTT-method. The effects of ibandronate were tentatively antagonized by addition of farnesyl-pyrophosphate (FPP) or farnesol (FOH). Results. Ibandronate inhibits growth of both prostate cancer cell lines in a dose dependent manner. In combination with docetaxel, synergistic effects are found as evidenced by a combination index (CI) of <1. Addition of FOH and FPP completely antagonized the growth inhibitory effects of ibandronate on both cell lines. Surprisingly, in combination with ibandronate and docetaxel, FOH further increased growth inhibition instead of antagonizing the growth inhibitory effects of ibandronate. Furthermore, FOH alone appeared to be a potent inhibitor of tumor cell growth. Discussion. Ibandronate effectively inhibits growth of prostate cancer cell lines via inhibition of the farnesyl-IPP-synthase and exhibits synergistic effects with docetaxel. In addition, FOH is a potent inhibitor of prostate cancer cell lines and may display an interesting treatment option for patients with CRPC. [ABSTRACT FROM AUTHOR]

Background: A previous study from Germany showed high antibiotic use in university hospitals, particularly in intensive care units (ICU) and hematology-oncology services, but there has been no information about recent antibiotic use in non-university hospitals. In the present study, we collected data from 40 non-university regional general hospitals located in the southwestern part of the country, and analyzed use density in the medical and surgical services of these hospitals. Materials and Methods: Hospital pharmacy records for the calendar years 2001 and 2002 were evaluated. The number of defined daily doses (DDD, definition according to the WHO/ATC 2001 index) and prescribed daily doses (PDD) per 100 patient days (DDD/100 or PDD/100, respectively) were calculated to compare antibiotic use densities in medical and surgical services. Data for surgery included various subspecialties and gynecology. Results: Antibiotic use in the participating hospitals increased minimally between 2001 and 2002 both in medicine as well as in surgery. Use density in internal medicine (ICU areas excluded) in the year 2002 ranged between 13.5 and 93.7 DDD/100 with a weighted mean of 49.9 DDD/100 (corresponding to 28.6 PDD/100, respectively). Values for surgery were lower with a weighted mean of 43.4 DDD/100 (corresponding to 26.1 PDD/100, range, 10 to 65.4 DDD/100), respectively. Hospital size was not a strong predictor of use density, while large differences were observed between intensive care areas and normal wards. Mean use densities in intensive care areas in 2002 were 105.6 DDD/100 (or 49.7 PDD/100) in medical intensive care units, 116.9 DDD/100 (or 61.2 PDD/100) in surgical intensive care units, and 112.7 DDD/100 (or 66.7 PDD/100) in mixed, interdisciplinary intensive care units. Betalactams made up > 50% of all PDDs, while fluoroquinolones were the second most frequently prescribed drugs (15% of all PDDs). Fluoroquinolones were usually given orally. Overall glycopeptide and aminoglycoside use was < 1 PDD/100. Conclusion: This recent data from a large regional nonuniversity acute care hospital sample confirms that hospital antibiotic use density largely depends on patient care areas and less on hospital size. Surprisingly low use was observed for glycopeptides and aminoglycosides. The data may be useful as a benchmark for further pharmacoepidemiologic evaluation and focused drug use control interventions. [ABSTRACT FROM AUTHOR]

Copyright of GMS Hygiene & Infection Control is the property of German Medical Science Publishing House gGmbH and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)