Pharmacotherapy of unlicensed medicines prepared and distributed by Dutch pharmacies.

INTRODUCTION AND OBJECTIVE: In the Netherlands, preparing and distributing pharmacies (PDPs) are taking over a large proportion of pharmacy preparations. PDPs prepare and distribute medicinal products to dispensing pharmacies. Many pharmacies have stopped pharmacy preparation. However, this contravenes the Dutch Medicines Act and the European Union (EU) Directive 2001/83/EC on which Dutch law is based. This is because the medicinal products of PDPs are unlicensed and PDPs do not have a manufacturing licence. METHODS: To solve the conflict with the Dutch Medicines Act, PDPs have since 2007 been authorised by the Dutch Health Care Inspectorate by means of a circular letter. This circular letter describes the qualitative conditions that must be fulfilled by PDPs. The circular letter's conditions state that PDPs must perform verifiable investigations to assess the availability, or not, of licensed pharmacotherapeutic alternatives (PA investigations) and to assess the pharmacotherapeutic rationale and the needs of the patient (PT investigations). RESULTS: Regular visits were performed by the Dutch Health Care Inspectorate to check the compliance of PDPs with the circular letter. This article describes the results of these inspections for PA and PT investigations. CONCLUSIONS: The results of the inspections show that so far almost all PDPs inspected have complied with the PA and PT conditions of the circular level at system level. However, in a substantial proportion of cases, the rationale of the pharmacy-made products is insufficient or insufficiently documented.

The association between insulin use and volumetric bone mineral density, bone micro-architecture and bone strength of the distal radius in patients with type 2 diabetes - The Maastricht study.

Type 2 diabetes mellitus (T2DM) has been associated with an increased risk of fractures, despite normal to increased bone mineral density (BMD). Insulin use is one of the factors linked to this increased fracture risk. However, direct negative effects of insulin on bone quality are not expected since insulin is thought to be anabolic to bone. In this cross-sectional study the association between insulin use and volumetric BMD (vBMD), bone micro-architecture and bone strength of the distal radius, as measured with HR-pQCT, was examined. Data from 50 participants with T2DM of The Maastricht Study (mean age 62±7.5years, 44% women) was used. Participants were classified as insulin user (n=13) or non-insulin user (n=37) based on prescription data. Linear regression analysis was used to estimate the association between current insulin use and HR-pQCT derived parameters. After adjustment for age, sex, body mass index, glycated hemoglobin A1c and T2DM duration, insulin use was associated with lower total vBMD (standardized beta (ß):-0.56 (95% CI:-0.89 to -0.24)), trabecular vBMD (ß:-0.58 (95% CI:-0.87 to -0.30)), trabecular thickness (ß:-0.55 (95% CI:-0.87 to -0.23)), cortical thickness (ß:-0.41 (95% CI:-0.74 to -0.08)), log cortical pore volume (ß:-0.43 (95% CI:-0.73 to -0.13)), bone stiffness (ß:-0.39 (95% CI:-0.62 to -0.17)) and failure load (ß:-0.39 (95% CI:-0.60 to -0.17)) when compared to the non-insulin users. Insulin use was not associated with cortical vBMD, trabecular number, trabecular separation, cortical porosity and cortical pore diameter. This study indicates that insulin use is negatively associated with bone density, bone micro-architectural and bone strength parameters. These findings may partly explain the previously observed increased fracture risk in insulin users, although there may be residual confounding by other factors related to disease severity in insulin users.

Treatment of cefuroxime-induced neurotoxicity with continuous venovenous haemofiltration.

A 61-year-old woman with decreased consciousness, myoclonus, tremors, nystagmus and bradypnoea, due to cefuroxime-induced neurotoxicity, was admitted to the intensive care unit. Continuous venovenous haemofiltration (CVVH) rapidly reduced plasma cefuroxime concentrations and improved neurological manifestations within the next few hours. Retrospective pharmacokinetic assessment showed a total cefuroxime clearance of 166 ml/min during the CVVH.

Inspectorate surveillance of preparing and distributing pharmacies in The Netherlands.

INTRODUCTION AND OBJECTIVE: The preparation of medicines in pharmacies is essential for accommodating the individual needs and medical conditions of patients in Europe and beyond. This article describes the state of pharmacy preparation in preparing and distributing pharmacies (PDPs) in the Netherlands. The Medicines Act in the Netherlands is based on the European Union Directive 2001/83/EC, which forbids a PDP from preparing and distributing unlicensed medicinal products to dispensing pharmacies. In order not to obstruct patient care, the Dutch Inspectorate has sent a Circular Letter on large-scale preparation to all Dutch pharmacists. This Circular describes the qualitative conditions that must be fulfilled by the PDPs. The aim of this study was to assess the overall compliance of Dutch PDPs with the conditions of the Circular. These conditions are: an absence of licensed pharmacotherapeutic alternatives, rational pharmacotherapy, a product dossier for all products and compliance with Good Manufacturing Practice (GMP). METHODS: PDPs are obliged to fulfil the conditions of the Circular. If PDPs do not fulfil these conditions, then they have to stop preparing and distributing medicinal products. A questionnaire was sent to all Dutch pharmacies to get information about the number of PDPs and the number of pharmacies served by each PDP. The instrument that was used in this observational study to assess the compliance of the PDPs with all conditions of the Circular is described. RESULTS: The results of the inspections until now show that on 1 November 2014, 18 out of 21 PDPs fulfilled the four conditions of the Circular. Only minor deficiencies were found with 3 out of 21 PDPs. Twenty out of the 21 PDPs visited fulfilled the condition concerning the absence of pharmacotherapeutic alternatives and 19 out of 21 PDPs visited complied with the condition of rational pharmacotherapy. Nineteen out of the 21 PDPs visited fulfilled the Circular condition that a product dossier was available for all products. All of the 21 PDPs visited complied with GMP. Regular visits, at least every 3 years, were performed by the Inspectorate to check the compliance of the PDPs with the Circular. The publication of the inspection reports on the website of the Inspectorate allowed, probably, many PDPs to be better prepared. The inspection visits showed that the PDPs have invested in compliance with the conditions of the Circular. CONCLUSIONS: Most of the PDPs fulfilled the requirements of the Circular. The Inspectorate is in consultation with the Ministry of Health, Welfare and Sport about how to proceed with the question of PDPs and the conditions they have to fulfil. Recent European case law will have to be taken into account.

Impact of the Council of Europe Resolution on quality and safety assurance requirements for medicinal products prepared in pharmacies for the special needs of patients.

INTRODUCTION AND OBJECTIVE: The regulation of pharmacy preparations, especially for standards for quality assurance and safety, is not harmonised across Europe and falls under the national competencies of individual states. There are concerns about quality control and safety for the medicinal products made in pharmacies, which is widespread in European countries. There are, however, good reasons to continue this practice, which is able to tailor preparations to the specific needs of a particular patient or patient group and to provide a supplementary source of supply when an industrially manufactured product, which is authorised for marketing is not available or when there are temporary shortages of licensed medicines. In seeking to provide guidelines for legislation and acting on the advice of an expert group dealing in pharmaceutical practices, the Committee of Ministers of the Council of Europe passed a resolution in 2011. The Council of Europe Resolution provides authorities and pharmacists with the means to reinforce safety measures for medicinal products prepared in pharmacies and to harmonise quality assurance and safety standards. It dealt with aspects of pharmacy preparation such as quality standards for preparation and distribution, marketing authorisation, product dossiers, labelling, reporting, and safety. In 2013 and 2014 the Committee of Experts carried out a survey to evaluate the impact of the resolution within a cross section of member states. The objectives of this study were both to monitor the extent to which the recommendations had been enshrined in national legislation and also to understand current differences in legislation and practice between the member states. METHODS: In the resolution of 2011 the member states were recommended to adapt their legislation in line with its provisions. The survey that was carried out in 2013 and 2014 followed the recommendations in the resolution. A questionnaire was made and sent to a cross section of member states. RESULTS: Among the member states involved, the results of this survey show a clear commitment to implement the recommendations of the resolution. CONCLUSIONS: This report presents the results of the survey with a discussion of outstanding issues.

Legislation on the preparation of medicinal products in European pharmacies and the Council of Europe Resolution.

INTRODUCTION: The rights of patients should be sufficiently protected even when an appropriate authorised medicine does not exist or is unavailable on the market. The Resolution, which was adopted by the Committee of Ministers of the Council of Europe in 2011, aims at harmonising quality and safety standards for pharmacy preparation of medicinal products in Europe. TWO PILLARS OF EU REGULATION AND THE EXCEPTIONS TO THEM: The system of regulation of medicinal products is built upon two pillars: the marketing authorisation of the medicinal product and the licence for manufacturing and wholesale. This article provides insight into the recent interpretation of the European Court of Justice concerning the scope of European Union (EU) regulation of medicinal products and the circumstances in which the EU regulation does not apply: pharmacy preparations, specialties and the compassionate use of medicines, including manufacturing licence. EU REGULATION AND THE RESOLUTION CONCERNING PHARMACY PREPARATION: Pharmacy preparations are allowed under certain strict conditions according to EU regulations. However, pharmacies specialised in preparation and distributing medicinal products to local pharmacies do not fulfil these strict conditions in EU regulation. Apart from the legal context, relevant standards for safety and quality assurance are needed in Europe in order to protect patients' rights and to avoid risks from pharmacy preparations. DISCUSSION AND CONCLUSIONS: The Council of Europe Resolution provides a means of establishing standards for safety and quality assurance for pharmacy preparations through Good Manufacturing Practice Guidelines. The Resolution is available to authorities and pharmacists in order to prevent incidents with medicines prepared in pharmacies which may threaten patients' safety. The authors conclude that pharmacy practices have changed over time in Europe and this may imply a reason for a reform of EU regulation on medicinal products.

Aseptic preparation of parenteral medicinal products in healthcare establishments in Europe.

In many cases, parenteral medicines with a marketing authorisation cannot be administered directly to patients, that is, they are not presented in ready-to-administer form. Before administration to patients, these medicines have to be reconstituted. Reconstitution has a special position; it can neither be seen as industrial manufacture nor as 'regular' pharmacy preparation. There are other processes in healthcare establishments (eg, parenteral nutrition), related to the reconstitution process, where the requirements of national quality assurance standards for the safe preparation of sterile products are equally important and have to be fulfilled. In European healthcare establishments, aseptic preparation of parenteral medicinal products is considered to be a process of crucial importance for patient safety because errors in the preparation of these medicines may lead to a product that can cause immediate damage to patients. Aseptic preparation of medicinal products is carried out in hospital pharmacies as well as in clinical areas in healthcare establishments. The Committee of Experts on Quality and Safety Standards for Pharmaceutical Practices and Pharmaceutical Care (Council of Europe; hereafter: Committee of Experts), supported by the European Directorate for the Quality of Medicines & Healthcare, is undertaking work on the topic of aseptic preparation of medicines. The work is carried out in cooperation with the European Association of Hospital Pharmacists on the basis of a Resolution CM/Res AP(2011)1 on Quality and Safety Assurance requirements for Medicinal Products prepared in Pharmacies for the Special Needs of Patients, which was adopted by the Committee of Ministers on 19 January 2011. The Resolution includes some recommendations and an outlook to further work on reconstitution of parenteral medicines. A survey that was sent to the different European countries demonstrated that there is no or just limited regulation concerning reconstitution in Europe. This article describes the risks associated with poor reconstitution practices and the previous work as well as the ongoing activities concerning reconstitution at the European level. The article emphasises the need for regulation in this area, which is missing at present. It is expected that consensus can be reached on a guidance document for reconstitution at the European level.

Use of incretin agents and risk of pancreatic cancer: a population-based cohort study.

AIM: To investigate the association between the use of incretin agents and the risk of pancreatic cancer. METHODS: A retrospective population-based cohort study, using data from the Clinical Practice Research Datalink, 2007-2012, was conducted. Patients (n = 182 428) with at least one non-insulin antidiabetic drug (NIAD) prescription and aged ≥18 years during data collection, were matched one-to-one to control patients without diabetes. Multivariable Cox proportional hazards models and a new user design were used to estimate the hazard ratio (HR) of pancreatic cancer in incretin users (n = 28 370) compared with control subjects without diabetes and other NIAD-treated patients. Time-dependent adjustments were made for age, sex, lifestyle, comorbidities and drug use. RESULTS: The mean duration of follow-up was 4.1 years for incretin users. Current NIAD use was associated with a fourfold increased risk of pancreatic cancer [HR 4.28, 95% confidence interval (CI) 3.49-5.24]. This risk was almost doubled among current incretin users as compared with control subjects. Incretin use was not associated with pancreatic cancer when compared with control subjects with diabetes (HR 1.36, 95% CI 0.94-1.96); however, the 'new user' design did show an association between incretin use and pancreatic cancer when compared with control subjects with diabetes. In both cohorts with prevalent and incident users of antidiabetic drugs, the risk of pancreatic cancer almost doubled in those who had recently initiated incretin therapy (up to seven prescriptions), whereas this elevated risk dropped to baseline levels with prolonged use. CONCLUSIONS: We found that incretin use was not associated with pancreatic cancer after adjustment for the severity of the underlying Type 2 Diabetes Mellitus (T2DM). The elevated risk of pancreatic cancer in those recently initiating incretin agents is likely to be caused by protopathic bias or other types of unknown distortion. The presence of considerable confounding by disease severity and the lack of a duration-of-use relationship do not support a causal explanation for the association between incretin agents and pancreatic cancer.

Short-term variation in plasma mitotane levels confirms the importance of trough level monitoring.

OBJECTIVE: Mitotane is the drug of choice in patients with adrenocortical carcinoma. The anti-neoplastic effect is correlated with mitotane plasma levels, which render it crucial to reach and maintain the concentration above 14 mg/l. However, mitotane pharmacokinetics is poorly understood. The aim of this study was to investigate the variation in plasma mitotane levels during the day and the influence of a single morning dose. DESIGN: A prospective case-control study was conducted to investigate the variation in plasma mitotane levels. METHODS: Patients who had been treated for at least 24 weeks and had reached the therapeutic plasma level (14 mg/l) at least once were eligible. In the first group, mitotane levels were determined hourly for the duration of 8 h after administration of a single morning dose. In the second group, mitotane levels were assessed similarly without administration of a morning dose. RESULTS: Ten patients were included in this study, and three patients participated in both groups. Median plasma level at baseline was 16.2 mg/l (range 11.3-23.3 mg/l) in the first group (n=7) and 17.0 mg/l (13.7-23.8) in the second group (n=6). Plasma levels displayed a median increase compared with baseline of 24% (range 6-42%) at t=4 after morning dose and a change of 13% (range -14 to 33%) at t=4 without morning dose (P=0.02). CONCLUSION: A substantial increase in mitotane plasma levels was observed in steady-state patients within a period of 8 h after morning dosing. Without morning dose, mitotane curves showed a variable profile throughout the day. This implies that random sampling could yield incidentally high levels. For this reason, we recommend early-morning trough sampling as standard management in monitoring mitotane treatment.

Multiple intravenous doses of paracetamol result in a predictable pharmacokinetic profile in very preterm infants.

AIM: The therapeutic options available to treat neonatal pain are limited, and one alternative for nonopioid systemic treatment is paracetamol. However, pharmacokinetic data from prolonged administration of intravenous paracetamol in neonates are limited. The aim of this study was to present pharmacokinetics after multiple dose of intravenous paracetamol in very preterm infants of <32 weeks' gestation. METHODS: Fifteen very preterm infants received five, six-hourly doses of intravenous paracetamol (7.5 mg/kg). Blood samples were taken to measure paracetamol, glutathione and hepatic function, together with urine samples for paracetamol metabolites. RESULTS: A two-compartment pharmacokinetic model gave the best fit for all individual patients and resulted in a predictable pharmacokinetic profile. The estimated pharmacokinetic population parameters were volume of distribution 0.764 ± 0.225 L/kg, elimination rate constant (ke ) 0.117 ± 0.091/h and intercompartment rate constants k12 0.607 ± 0.734/h and k21 1.105 ± 0.762/h. CONCLUSION: Our study found that multiple doses of intravenous paracetamol resulted in a predictable pharmacokinetic profile in very preterm infants. Increases in postmenstrual age and weight were associated with increased clearance. No evidence of hepatotoxicity was found.

The pharmacokinetic effect of adalimumab on thiopurine metabolism in Crohn's disease patients.

BACKGROUND AND AIMS: A drug interaction between infliximab and azathioprine has previously been reported in Crohn's disease patients: the concentration of the main active thiopurine metabolites, the 6-thioguanine nucleotides (6-TGN), increased 1-3 weeks after the first infliximab infusion by 50% compared to baseline. The aim of this prospective study was to determine the effect of adalimumab on thiopurine metabolism in Crohn's disease patients, evaluated by 6-TGN and 6-methylmercaptopurine ribonucleotides (6-MMPR) concentration measurement. METHODS: Crohn's disease patients on azathioprine or mercaptopurine maintenance therapy starting with concomitant adalimumab treatment were included. 6-TGN and 6-MMPR concentrations were determined before initiation of adalimumab and after 2, 4, 6 and 12 weeks of combination therapy. The activity of three essential enzymes involving thiopurine metabolism, thiopurine S-methyltransferase (TPMT), hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and inosine-triphosphate pyrophosphatase (ITPase), was evaluated at baseline and week 4. Clinical outcome was evaluated by the Crohn's disease activity index and C-reactive protein concentrations at baseline, week 4 and week 12. RESULTS: Twelve Crohn's disease patients were analyzed. During the follow-up period of 12 weeks the median 6-TGN and 6-MMPR concentrations did not significantly change compared to baseline. TPMT, ITPase and HGPRT enzyme activity did not change either after 4 weeks. In two patients (17%) myelotoxicity was observed within 2-4 weeks, in whom both low therapeutic 6-TGN and 6-MMPR concentrations were found. CONCLUSIONS: In this study in Crohn's disease patients no pharmacokinetic interaction was shown between adalimumab and the conventional thiopurines, azathioprine and mercaptopurine.

Five-year fracture risk estimation in patients with Parkinson's disease.

BACKGROUND: Previous studies have shown that patients with Parkinson's disease (PD) are at increased risk of fractures. However, no specific prediction model for fracture estimation among PD patients is currently available. Therefore, the aim of this study was to develop a simple score for estimating the 5-year osteoporotic and hip fracture risks among patients with PD. METHODS: The U.K. Clinical Practice Research Datalink (1987-2011) was used to identify incident PD patients. Cox proportional-hazards models were used to calculate the 5-year risks of osteoporotic and hip fracture among PD patients. The regression model was fitted with various risk factors for fracture and the final Cox model was converted into integer risk scores. RESULTS: We identified 4411 incident PD patients without a history of osteoporotic treatment. The 5-year risks of osteoporotic and hip fracture were plotted in relation to the risk score. Risk scores increased with age, female gender, history of renal disease and history of dementia. The C-statistic, which is a parameter to test the internal validity of the model, was reasonable for the prediction of osteoporotic fracture (0.69) and hip fracture (0.73). CONCLUSION: In this study, we developed a simple model to estimate 5-year fracture risk among incident PD patients. It may be useful in daily practice after external validation.

Interchangeability of gabapentin generic formulations in the Netherlands: a comparative bioavailability study.

To investigate the so-called "drift" with generic-generic drug substitution, a single-dose, four-way crossover comparative bioavailability study was performed involving 24 healthy subjects and three generic and one branded formulation of a tablet containing 800 mg gabapentin as test medication. The results showed that the 90% confidence intervals (CIs) for the area under the drug concentration-time curve (AUC(0-t)) and for the peak drug concentration (C(max)) were within the acceptance range of 80-125% for all comparisons. The safety profiles of the different gabapentin formulations were comparable. To conclude, all three generic formulations of gabapentin were found to be bioequivalent with the branded formulation and with each other, indicating that the formulations are interchangeable. These results strongly indicate the absence of "drift" with gabapentin generic-generic substitution.

[Conversion disorders]. / Konversionsstörungen.

Classification, diagnostic and therapeutic problems are central to the disease concept of conversion disorders, which are based on the presentation of psychosocial suffering by means of pseudoneurological symptoms without an organic cause. The nosological status in the current diagnostic and statistical manual of mental disorders (DSM-IV) and international classification of diseases (ICD-10) is disputed. Prevalence rates ranging from 0.3 % in the general population to 50 % in high risk clinical samples underline the relevance. Traumatic experiences play a major role in the pathogenesis. High rates of comorbid mental disorders, the danger to end in a chronic course, a high secondary illness gain and a somatic illness concept complicate psychotherapeutic approaches which are clearly indicated. Clinical experiences and open studies indicate that both psychodynamic as well as cognitive-behaviour therapies are effective.

Risk of fracture in patients with Parkinson's disease.

UNLABELLED: The aim of the study was to determine fracture risk in incident Parkinson's disease (PD) patients. This study showed that fracture risk assessment may be indicated among patients with PD, in particular when they have recently used selective serotonin re-uptake inhibitors or high-dose antipsychotics, or have a history of fracture, falling, low body mass index (BMI) or renal disease. INTRODUCTION: PD is a movement disorder associated with falling and detrimental effects on bone. Both are recognized risk factors for fracture. Therefore, the aim was to determine fracture risk in incident PD patients stratified by treatment, severity, duration of disease and related comorbidities. METHODS: We conducted a retrospective cohort study using the UK General Practice Research Database (1987-2011). Each PD patient was matched by age, sex, calendar time and practice to a control patient without history of PD. RESULTS: We identified 4,687 incident PD patients. Compared to controls, a statistically significant increased risk was observed for any fracture (adjusted hazard ratio [AHR], 1.89; 95 % confidence interval [CI], 1.67-2.14), osteoporotic fracture (AHR, 1.99; 95 % CI, 1.72-2.30) and hip fracture (AHR 3.08; 95 % CI, 2.43-3.89). Fracture risk further increased with history of fracture, falling, low BMI, renal disease, antidepressant use and use of high-dose antipsychotics. CONCLUSION: This study showed that incident PD patients have a statistically significant increased risk of fracture. Therefore, fracture risk assessment may be indicated among PD patients, who, besides the general risk factors for fracture, like increasing age and female gender, have recently used selective serotonin re-uptake inhibitors or high-dose antipsychotics or have a history of fracture, falling, low BMI or renal disease.

Prevalence of potential drug-drug interactions in cancer patients treated with oral anticancer drugs.

BACKGROUND: Potential drug-drug interactions (PDDIs) in patients with cancer are common, but have not previously been quantified for oral anticancer treatment. We assessed the prevalence and seriousness of potential PDDIs among ambulatory cancer patients on oral anticancer treatment. METHODS: A search was conducted in a computer-based medication prescription system for dispensing oral anticancer drugs to outpatients in three Dutch centres. Potential drug-drug interactions were identified using electronic (Drug Interaction Fact software) and manual screening methods (peer-reviewed reports). RESULTS: In the 898 patients included in the study, 1359 PDDIs were identified in 426 patients (46%, 95% confidence interval (CI)=42-50%). In 143 patients (16%), a major PDDI was identified. The drug classes most frequently involved in a major PDDI were coumarins and opioids. The majority of cases concerned central nervous system interactions, PDDIs that can cause gastrointestinal toxicity and prolongation of QT intervals. In multivariate analysis, concomitant use of more drugs (odds ratio (OR)=1.66, 95% CI=1.54-1.78, P<0001) and genito-urinary cancer (OR=0.25, 95% CI=0.12-0.52, P<0001) were risk factors. CONCLUSION: Potential drug-drug interactions are very common among cancer patients on oral cancer therapy. Physicians and pharmacists should be more aware of these potential interactions.

Transplacental transfer of remifentanil in the pregnant ewe.

BACKGROUND AND PURPOSE: While remifentanil can be used either during labour or fetal surgery, more should be known about the transplacental transfer of this opioid. The aim of this study was to investigate the placental transfer and haemodynamic effects of remifentanil after i.v. administration to pregnant ewes. EXPERIMENTAL APPROACH: Seven pregnant ewes received a continuous infusion of remifentanil (0.33 µg·kg⁻¹·min⁻¹) for 1 h, and maternal and fetal arterial blood samples were drawn at regular intervals during and up to 1 h after the discontinuation of the infusion. Haemodynamic parameters were monitored continuously. Blood gas samples were drawn at baseline and once during the infusion. KEY RESULTS: Peak maternal remifentanil plasma levels of 4.0 ± 0.9 ng·mL⁻¹ (mean ± SD) and peak fetal plasma levels of 0.4 ± 0.3 ng·mL⁻¹ were obtained. Remifentanil plasma levels dropped rapidly after the discontinuation of the infusion. The continuous infusion of remifentanil did not result in significant maternal or fetal haemodynamic changes. CONCLUSIONS AND IMPLICATIONS: Remifentanil rapidly passes through the placenta of pregnant ewes and although remifentanil concentrations stay significantly lower in the fetus compared with those in the mother, remifentanil can be detected in significant amounts in the fetus.

Diminished in vitro antibacterial activity of oxacillin against clinical isolates of borderline oxacillin-resistant Staphylococcus aureus.

Since it is unknown whether ß-lactam antimicrobial agents can be used effectively against borderline oxacillin-resistant Staphylococcus aureus (BORSA) with oxacillin MICs ≥4 mg/L, the in vitro bactericidal activity and pharmacodynamic effect of oxacillin against clinical BORSA isolates was evaluated. Time-kill experiments with oxacillin were performed and the results compared with those obtained with vancomycin, daptomycin and linezolid against BORSA with oxacillin MICs ≥4 mg/L and BORSA with oxacillin MICs ≤2 mg/L. Furthermore, the effect of ß-lactamase production and plasmid profile analysis were taken into account to clarify responses to oxacillin. Oxacillin killing activity was attenuated against BORSA compared with ATCC 29213 since the pharmacodynamic parameters revealed that the potency of oxacillin was markedly reduced (c. ten-fold) against BORSA with oxacillin MICs ≥4 mg/L. pBORa53-like plasmid-containing BORSA with oxacillin MICs ≤2 mg/L showed markedly more regrowth. In conclusion, oxacillin was non-effective in the eradication of either (i) BORSA with oxacillin MICs ≥4 mg/L or (ii) ß-lactamase-hyperproducing BORSA (MICs ≤2 mg/L). Further investigation into ß-lactam dosing strategies against different BORSA strains is warranted in order to avoid possible therapy failure.

[Requirements regarding compounded pharmaceutical preparation]. / Eisen aan de magistrale bereiding van geneesmiddelen.

Picking the wrong container with raw material in making compounded pharmaceutical preparation is one of the threats to patient safety. The question is whether there still is a place for this type of medication in pharmacotherapy. This case raises three questions: is there a therapeutic rationale for this therapeutic agent, how far should we go in individualizing pharmacotherapy and what are the pharmaceutical prerequisites for this kind of compounding? Once there is an agreement about the need for this product, the focus is on the need for implementation of Good Manufacturing Practice (GMP) rules in community pharmacies. Alternatively, this type of individualized therapy should be stopped.

Glycopyrrolate for sialorrhea in Parkinson disease: a randomized, double-blind, crossover trial.

BACKGROUND: Sialorrhea affects approximately 75% of patients with Parkinson disease (PD). Sialorrhea is often treated with anticholinergics, but central side effects limit their usefulness. Glycopyrrolate (glycopyrronium bromide) is an anticholinergic drug with a quaternary ammonium structure not able to cross the blood-brain barrier in considerable amounts. Therefore, glycopyrrolate exhibits minimal central side effects, which may be an advantage in patients with PD, of whom a significant portion already experience cognitive deficits. OBJECTIVE: To determine the efficacy and safety of glycopyrrolate in the treatment of sialorrhea in patients with PD. METHODS: We conducted a 4-week, randomized, double-blind, placebo-controlled, crossover trial with oral glycopyrrolate 1 mg 3 times daily in 23 patients with PD. The severity of the sialorrhea was scored on a daily basis by the patients or a caregiver with a sialorrhea scoring scale ranging from 1 (no sialorrhea) to 9 (profuse sialorrhea). RESULTS: The mean (SD) sialorrhea score improved from 4.6 (1.7) with placebo to 3.8 (1.6) with glycopyrrolate (p = 0.011). Nine patients (39.1%) with glycopyrrolate had a clinically relevant improvement of at least 30% vs 1 patient (4.3%) with placebo (p = 0.021). There were no significant differences in adverse events between glycopyrrolate and placebo treatment. CONCLUSIONS: Oral glycopyrrolate 1 mg 3 times daily is an effective and safe therapy for sialorrhea in Parkinson disease. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that glycopyrrolate 1 mg 3 times daily is more effective than placebo in reducing sialorrhea in patients with Parkinson disease during a 4-week study.