Pharmacotherapy in paediatric heart failure: a Delphi process.

BACKGROUND: Little evidence exists to support pharmacotherapeutic strategies for heart failure management in paediatrics. A recent Europe-wide survey suggests that this translates into substantial variability in clinical practice. OBJECTIVE: To conduct a formal discussion among an expert group of paediatric cardiology physicians on controversial aspects regarding the pharmacotherapy of children heart failure, facilitate consensus, and highlight areas of agreement and disagreement. METHODS: A two-round modified Delphi process was conducted between July and August 2015. Topics addressed were predominantly selected from the results of a previous Europe-wide survey. Fourteen statements were presented for discussion grouped under three categories; Angiotensin-converting-enzyme-inhibitors: Considerations for optimal dosage; Angiotensin-converting-enzyme-inhibitors for the management of CHDs; Neurohumoral antagonists for the management of dilated cardiomyopathy-related heart failure. RESULTS: A total of 13 paediatricians dedicated to cardiology from across Europe and the United States of America completed the study; of them, 92% had a working experience in the field of more than 10 years and were working in a specific paediatric cardiology unit. Agreement on the acceptance/rejection of 11 statements was achieved. Results show agreement on the importance of a set of topics relevant to the standardisation of the therapy as well as consensus upon specific therapeutic attitudes. CONCLUSIONS: We have found areas of common thinking and motivation, which can provide a means of triggering scientific collaboration. Our results might also contribute to disseminate available paediatric evidence and promote reducing unjustified variability in everyday practice. Until solid evidence is available, other research methods can contribute to advancing the goal of safe and effective paediatric heart failure pharmacotherapy.

Predicting Stereoselective Disposition of Carvedilol in Adult and Pediatric Chronic Heart Failure Patients by Incorporating Pathophysiological Changes in Organ Blood Flows-A Physiologically Based Pharmacokinetic Approach.

Chronic heart failure (CHF) is a systemic low perfusion syndrome resulting from impairment in the pumping function of the heart. The decrease in blood supply to body organs can potentially affect the pharmacokinetics (PK) of the drugs being administered. Carvedilol is administered as a racemic mixture and undergoes extensive stereoselective first pass metabolism. For such a drug, the pathophysiological changes occurring in CHF can have a profound impact on PK, and thus the resulting pharmacodynamic response, of both enantiomers. The aim of the current work was to predict stereoselective disposition of carvedilol after incorporating the pathophysiological changes in CHF into a whole-body physiologically based PK model using Simcyp, and to scale that model to pediatric CHF patients on a physiologic basis to investigate whether the same changes in the adult model can also be adopted for children. The developed model has successfully described PK of carvedilol enantiomers in healthy adults and in patients after the incorporation of reduced organ blood flows, as seen by the visual predictive checks and the calculated observed/predicted ratios for all PK parameters of interest. In contrast to adults, pediatric patients up to 12 years of age were better described without the reductions in organ blood flow, whereas older pediatric patients were better described after incorporating organ blood flow reductions. These findings indicate that the incorporated blood flow reductions in the adult model cannot be directly adopted in pediatrics, at least for the young ones; however, to draw definite conclusions, more data are still needed.

Pharmaceutical care of an adolescent with type 1 diabetes. / Wie betreuen wir als Apotheker einen Jugendlichen mit Diabetes mellitus Typ 1? Ein Beispiel aus der klinischen Praxis.

This article describes the pharmaceutical care of an adolescent with type 1 diabetes mellitus, who took part in the DIADEMA study. Diabetes was diagnosed for three years and his baseline HbA1c-value was 9.3 %. In the DIADEMA study adolescents received pharmaceutical care provided by community pharmacists in addition to usual care provided by diabetologists and diabetes educators. Patients in the intervention group received monthly scheduled visits with the community pharmacists and on-demand telephone calls. Fundamental contents of the pharmacistá¾½s interventions were in particular self-monitoring of blood glucose, prevention of acute and long-term diabetes complications and conscientious consumption of alcohol. Furthermore difficulties in individual insulin therapy and current life conditions were addressed.

Diabetes Stewardship ­ Pharmaceutical care of adolescents with type 1 diabetes mellitus provided by community pharmacists. / Pharmazeutische Betreuung von Jugendlichen mit Diabetes mellitus Typ 1 Zeit für "Diabetes Stewardship"?

Diabetes mellitus Type 1 is one of the most common diseases in childhood. Severe, secondary diseases like hypertension or blindness are results of micro- and macrovascular complications caused by insufficient glycaemic control. Especially adolescent patients with type 1 diabetes have a lower adherence rate. The DIADEMA trial proved that community pharmacist in collaboration with diabetologists and diabetes advisors can have a positive impact on the therapy of adolescents with type 1 diabetes. This article highlights and explains which components of the pharmacist intervention caused the preferable adjustments and improved the insulin therapy of the patients.

[PHARMAGRIPS: structured pharmaceutical counseling in the self-medication of the common cold. A randomised controlled study (RCT)]. / PHARMAGRIPS: Pharmazeutische Beratung in der Selbstmedikation des grippalen Infekts. Eine randomisierte kontrollierte Studie (RCT).

Many minor ailments are treated in Germany by self-medication. Most drugs dispensed by pharmacy staff are those for the common cold, general pain and gastrointestinal disorders. Whilst pharmacists express their need for further training in counseling on side effects, interactions and contraindications, they tend to receive feedback from patients to the effect that the drugs used have not worked. From July to October 2013 we carried out a prospective, single-blind, quasi-randomised controlled study on the effect of training on structured pharmaceutical advice in self-medication of the common cold (PHARMAGRIPS Study). Using a controlled, interventional study design we investigated whether it is possible to improve the pharmaceutical counseling in self-medication within a short time, by using an appropriate teaching method. The counseling should be made in a systematic way and refer to evidence-based content in order to avoid incorrect advice. We enrolled 86 pharmacists and assigned them randomly into the study protocol. Of those, 56 completed the study as planned and were analysed. In this study, we reviewed the structure of the average pharmaceutical consultation and added evidence-based content from the Cochrane Reviews on common cold. We then integrated this structured consultation in a methodical modem training program consisting of e-learning and live classes which we evaluated scientifically. For this purpose, we conducted telephone interviews with the participating pharmacists by using standardized case report forms. The case report forms contained the questions that the participants were supposed to ask. For every question asked, the participant received a certain amount of points, 18 in total. The training was stated to be successful at the primary endpoint when an improvement of at least 3.5 out of 18 points was achieved on average. The secondary endpoints were related to various aspects of the interview process (medical history, limits of self-medication, evidence-based drug selection and integration of customer input in the consultation interaction). The training group improved in the primary endpoint by an average of 5.93 points (p < 0.001) and compared to the control group significantly in all secondary endpoints, with one participant managing to achieve the full score. The participants recognized the importance and practical relevance of the exercise in a short time and were able to implement even integrate complex content in their consultations and to give the customer appropriate advice.

[Dextromethorphan abuse in adolescents: what can the pharmacists do?]. / Dextromethorphan-Missbrauch bei Jugendlichen: Wie kann sich der Apotheker verhalten?

In Germany, dextromethorphan (DXM) is used as OTC cough and cold medication. Overdose, however, can cause psychotropic side effects and is therefore abused among adolescents. To better control the drug by the pharmacist, a pilot was undertaken to monitor drug selling of DXM in German retail pharmacies. Over a 6-month period, pharmacies documented the request of DXM preparations. These data were compared to abuse cases of the German regulatory agency, the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), an analysis of the 2010 annual sales statistic from the IMS OTC and information about DXM products from drug abuse websites. Especially the young DXM buyers in German retail pharmacies showed characteristics similar to those people from the BfArM abuse data file: They were male and used the DXM product Hustenstiller-ratiopharm. Hustenstiller-ratiopharm has well-directed instructions for DXM abuse in the internet. However, the 2010 annual sales statistic from the IMS OTC report identified Wick MediNait as the product with highest sales numbers whereas Hustenstiller-ratiopharm" was of less importance indicating DXM abuse is limited to a small part of the DXM user population.

Evaluating usability of and satisfaction with mHealth app in rural and remote areas-Germany GIZ collaboration in Bosnia-Herzegovina to optimize type 1 diabetes care.

Background: Type 1 diabetes mellitus (T1DM) management in children and adolescents requires intensive supervision and monitoring to prevent acute and late diabetes complications and to improve quality of life. Digital health interventions, in particular diabetes mobile health apps (mHealth apps) can facilitate specialized T1DM care in this population. This study evaluated the initial usability of and satisfaction with the m-Health intervention Diabetes: M app, and the ease of use of various app features in supporting T1DM care in rural and remote areas of Bosnia-Herzegovina with limited access to specialized diabetes care. Methods: This cross-sectional study, performed in February-March 2023, evaluated T1DM pediatric patients who used the Diabetes: M app in a 3-month mHealth-based T1DM management program, along with their parents and healthcare providers (HCPs). All participants completed self-administered online questionnaires at the end of the 3-month period. Data were analyzed by descriptive statistics. Results: The study population included 50 T1DM patients (children/parents and adolescents) and nine HCPs. The mean ± SD age of the T1DM patients was 14 ± 4.54 years, with 26 (52%) being female. The mean ± SD age of the HCPs was 43.4 ± 7.76 years; all (100%) were women, with a mean ± SD professional experience of 17.8 ± 8.81 years. The app was reported usable in the domains of ease-of-use and satisfaction by the T1DM children/parents (5.82/7.0), T1DM adolescents/young adults (5.68/7.0), and HCPs (5.22/7.0). Various app features, as well as the overall app experience, were rated positively by the participants. Conclusion: The results strongly support the usability of mHealth-based interventions in T1DM care, especially in overcoming care shortage and improving diabetes management and communications between HCPs and patients. Further studies are needed to compare the effectiveness of apps used to support T1DM management with routine care.

Digital health in pharmacy education: Elective practical course integrating wearable devices and their generated health data.

The widespread adoption of wearable devices (wearables) for monitoring vital signs, including blood pressure and glucose levels, has experienced a considerable surge in recent times. This surge has led to the generation of a substantial amount of health data, accessible to pharmacists during patient consultations as the healthcare sector advances in digitalization. To enhance the digital competencies of future pharmacists required by the rapidly changing digital health landscape, the Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich Heine University (HHU) Duesseldorf has developed an innovative elective practical course aimed to bolster pharmacy students' competencies in handling wearables and the health data generated. The three-week practical elective course employed wearables FreeStyle Libre® 3 (Continuous Glucose Monitoring, CGM) and Aktiia (Cuffless Blood Pressure Monitoring). The hands-on activities allowed participants to obtain and interpret wearable-generated health-related data and acquainted them with simulated patient cases. Final-year pharmacy students' subjective assessments before and after the course depicted the increased knowledge and competence regarding analysing wearables data.

Exploring research and education opportunities in digital health for pharmacy, medicine and other health disciplines: Insights from a multinational workshop.

Digital healthcare has rapidly evolved during and in the post-COVID pandemic era, expanding the roles and responsibilities of community pharmacists. Services like telepharmacy, e-prescriptions, remote medication therapy management, and digital monitoring of chronic conditions, have evolved into everyday routine pharmacy practices. Pharmacists are at the forefront and the most accessible healthcare professionals for patients and are increasingly pivotal in providing comprehensive patient care, including digital patient care services. To ensure that future generations of pharmacists are digitally competent, it is crucial that digital health education is provided to pharmacy students. Furthermore, fostering high-quality multidisciplinary research, particularly in collaboration with medicine and other health disciplines, is essential for advancing the digital health skills of the future pharmacy workforce. Despite the growing use of digital health technologies, there are significant between-country differences in digital health education, the clinical settings in which digital health technologies are used, and their implementation in day-to-day practice. This commentary summarizes key insights from the International Digital Health Workshop held at the University of Sydney in November 2023. To help ensure pharmacists are included as participants in future digital health research, recent advances in digital health education and interprofessional research projects across three universities from far-off world regions were presented. Participants discussed a possible collaborative, interprofessional, and international research project on chronic disease prevention using digital health technologies. The need for interdisciplinary digital health curricula was highlighted in the workshop discussions, specifically tailored to address the knowledge requirements of pharmacists and other healthcare professionals.

[Pharmacist's requirements for evidence-based self-medication guidelines]. / Bedarf von Pharmazeuten an evidenzbasierten Leitlinien für die Selbstmedikation.

Due to the removal of many pharmaceuticals from the prescription requirement, self-medication implies an increasing responsibility for pharmacists towards their patients. The application of evidence-based guidelines could be a responsible basis for consulting in pharmacies. Evidence-based guidelines represent the systematically accumulated and evaluated facts (the evidence) of desired and undesired effects of pharmaceuticals in the population. We wanted to find out which interest pharmaceutical professionals have in evidence-based guidelines and which are the exact requirements on their content, deducted from public pharmacies everyday demands. With this purpose, three surveys were conducted between March and August 2012, in which 365, 350, and 486 pharmaceutical professionals participated respectively. The results show that pharmacy staff is very interested in evidence based guidelines. Furthermore, they suggest that the pharmacy staff feel safe with the self-diagnosis of the customer, with the consideration of limits of self-medication, as well as with the selection of the--according to own assessment--appropriate active substance. For the selection of the correct active substance, the following criteria are named: self-security in the counselling, first-hand experiences as well as the wish of the customer. At the same time, it is striking that the most frequent critique the pharmacy staff gets from pharmacy customers is the lack of effectiveness of the selected medication. With that in mind, it is possible that not the appropriate medication was selected, and the chosen criteria as selection method should be replaced by an evidence-based decision. Secondly, the results show that in up to 52% of the cases, depending on the indications, the participating consultants felt less certain to uncertain with regards to possible interactions or contraindications. Also in this context, it is desirable to prepare the existing data in such a practical way, that the pharmacies are able to apply them directly.

Influence of Age, Heart Failure and ACE Inhibitor Treatment on Plasma Renin Activity in Children: Insights from a Systematic Review and the European LENA Project.

BACKGROUND: Plasma renin activity (PRA) has gained relevance as prognostic marker in adults with heart failure. The use of PRA as a clinically meaningful parameter in children and children with heart failure requires a thorough knowledge of the factors that influence PRA to correctly assess PRA levels. We aim to evaluate the influence of age, heart failure and angiotensin-converting enzyme inhibitor (ACEi) on PRA levels in children. METHODS: We conducted a systematic literature search to identify studies on PRA levels in healthy children and in children with heart failure. In addition, we analysed PRA data measured before (n = 35, aged 25 days-2.1 years), 4 hours after (n = 34) and within the first 8 days of enalapril treatment (n = 29) in children with heart failure from the European project Labeling of Enalapril from Neonates up to Adolescents (LENA). RESULTS: Age has a profound effect on PRA levels in healthy children, as PRA levels in the literature are up to about 7 times higher in neonates than in older children. Children with heart failure younger than 6 months showed 3-4 times higher PRA levels than healthy peers in both the literature and the LENA studies. In the LENA studies, the ACEi enalapril significantly increased median predose PRA by a factor of 4.5 in children with heart failure after 4.7 ± 1.6 days of treatment (n = 29, p < 0.01). Prior to treatment with enalapril, LENA subjects with symptomatic heart failure (Ross score ≥3) had a significantly higher PRA than LENA subjects with asymptomatic heart failure of comparable age (Ross score ≤2, p < 0.05). CONCLUSIONS: Age, heart failure and ACEi treatment have a notable influence on PRA and must be considered when assessing PRA as a clinically meaningful parameter. CLINICAL TRIAL REGISTRATION: The trials are registered on the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu). TRIAL REGISTRATION NUMBERS: EudraCT 2015-002335-17, EudraCT 2015-002396-18.

Determination of enalapril and enalaprilat in small human serum quantities for pediatric trials by HPLC-tandem mass spectrometry.

The angiotensin converting enzyme-inhibitor enalapril is the prodrug of enalaprilat and used in the treatment pediatric hypertension and chronic heart failure. Pharmacokinetic data are lacking to provide adequate dosing and for pediatric pharmacotherapeutical trials it is imperative to minimize sample volume. Therefore an HPLC-tandem mass spectrometry (MS) method for the determination of enalapril and enalaprilat in 100 µL of human serum was developed and validated with benazepril as internal standard (IS). After solid-phase extraction, chromatography was performed on a Luna(®) RP-C(18) (2) column with methanol-water-formic acid (65:35:1, v/v/v) as mobile phase and a flow rate of 0.4 mL/min. The MS was set to positive-mode electrospray ionization and multiple reaction monitoring, analyzing the m/z transitions channels 377.3 → 234.2, 349.3 → 206.1 and 425.3 → 351.2 for enalapril, enalaprilat and IS. Calibration curves were linear in the range of 1.61-206 ng/mL (enalapril) and 1.84-236 ng/mL (enalaprilat) with coefficients of determination >0.99. Relative standard deviations of intra- and inter-run precisions were below 7% and relative errors were below 6 ± 7% for both analytes. Also stabilities were acceptable for both analytes. As an application example, concentrations of enalapril and enalaprilat in serum after oral administration of 20 mg enalapril maleat in a healthy volunteer were determined.

Physiologically based pharmacokinetic modeling: methodology, applications, and limitations with a focus on its role in pediatric drug development.

The concept of physiologically based pharmacokinetic (PBPK) modeling was introduced years ago, but it has not been practiced significantly. However, interest in and implementation of this modeling technique have grown, as evidenced by the increased number of publications in this field. This paper demonstrates briefly the methodology, applications, and limitations of PBPK modeling with special attention given to discuss the use of PBPK models in pediatric drug development and some examples described in detail. Although PBPK models do have some limitations, the potential benefit from PBPK modeling technique is huge. PBPK models can be applied to investigate drug pharmacokinetics under different physiological and pathological conditions or in different age groups, to support decision-making during drug discovery, to provide, perhaps most important, data that can save time and resources, especially in early drug development phases and in pediatric clinical trials, and potentially to help clinical trials become more "confirmatory" rather than "exploratory".

Pediatric cardiovascular drug development and research: integration of modeling and simulation as one future direction.

The integration of the needs of children into the legal drug development process since 1997 in the United States and since 2007 in the European Union has improved health and stimulated innovative approaches in the design of clinical trials and will benefit both current and future populations. According to the US Food and Drug Administration, to date, 394 pediatric labels together with safer medicines and better dosing practices have provided a sound basis for the safer and more effective use of drugs in a pediatric population. This may be measurable with fewer medication errors and perhaps shorter hospital stays in the future. Although relevant data have been generated by clinical trials in pediatric populations, challenges, such as nonefficacy and safety issues, have arisen. Heterogeneity in the physiological maturation and growth processes and differences in the etiology and pathogenesis of disease in patients from birth to 18 years of age may explain these results. The use of cutting-edge technology, such as modeling and simulation of "in silico" pediatric populations, may allow the integration of data from previous trials and experiments into the design of future clinical trials and allow exploration in other areas that have the potential to enhance the outcome of clinical trials in children.

Study design and simulation approach.

Modeling and simulation techniques are a mainstay of clinical drug development and are particularly useful to support clinical trials in children. If a pediatrician wants to use these tools most efficiently, a basic understanding of the principles and methods of classical and novel techniques of modeling and simulation is essential. Key elements comprise the definition and description of terms like deterministic simulation, Monte Carlo simulation, classical "top down" or novel "bottom up" approach, as well as the term "virtual world simulation." The illustrated examples in this chapter from pediatric clinical trials will help to understand and demonstrate these key elements. The importance of the understanding of developmental physiology and pharmacokinetics will become visible when explaining novel "bottom up" approaches like physiologically based pharmacokinetic simulations which also bridge to current research tools from other areas such as systems biology using mathematical models to describe biological systems.

Prevention for pediatric low cardiac output syndrome: results from the European survey EuLoCOS-Paed.

OBJECTIVE: Characterize current hospital practices related to preventive drug therapy for low cardiac output syndrome (LCOS) in children with open heart surgery (OHS) in Europe. METHODS: Web-based questionnaire survey of European hospitals performing OHS in children, conducted between January and August 2009. RESULTS: Responses to the questionnaire were obtained from 90 of 125 hospitals (72.0%) from 31 different countries across the geographical European regions. The majority of hospitals (77.8%) administered preventive drug therapy and primarily targeted patients at risk (63.3%). Twenty-four different drug regimens were reported, involving 17 drugs from seven therapeutic drug classes. Milrinone, dopamine, epinephrine, dobutamine, and levosimendan made up 85.9% of the total drug use. Furthermore, milrinone was reported in 70.7% of all drug regimens and significantly more often in combination with other drugs than monotherapy (Δ20%, 95% CI 4.7-34.1%). Milrinone combination therapy reports included lower bolus but higher maintenance infusion doses than monotherapy reports. The timing of drug regimen administration varied across the full perioperative period, but drug regimens were mostly initiated during surgery and continued postoperatively. CONCLUSION: Although current hospital practices related to preventive drug therapy for LCOS in children with OHS are characterized by a marked variability, only few drugs make up the bulk of prescribing practice with milrinone being most commonly used. Therefore, the survey provides information on which drugs to focus research and establish safe and effective drug use. A unified approach is urgently needed to ensure that children with OHS can benefit from evidence-based care.

[Adverse drug reactions in children]. / Unerwünschte Arzneimittelwirkungen bei Kindern.

Adverse drug reactions (ADRs) are important safety issues in pediatric pharmacotherapy because they can lead to significant morbidity and mortality in this population. It is currently assumed that the incidence of ADRs in children is between 0.6 % and 19.9 % and that between 0.6 % und 6 % of all hospital admissions of children are triggered by ADRs. Underreporting and insufficient documentation of ADRs in children, however, may obstruct the view on the true numbers. Pharmacovigilance centres in some countries are under way to increase the awareness of the problem. Their programs may help to systematically improve reporting and documentation of ADRs. One important goal is to better assess causality between the patients clinical reaction and drug use, because this is the key knowledge to specifically target an effective and safe pharmacotherapy.

Development and evaluation of a physiologically based pharmacokinetic model to predict carvedilol-paroxetine metabolic drug-drug interaction in healthy adults and its extrapolation to virtual chronic heart failure patients for dose optimization.

Purpose: The metabolic drug-drug interactions (mDDIs) are one of the most important challenges faced by the pharmaceutical industry during the drug development stage and are frequently associated with labeling restrictions and withdrawal of drugs. The capacity of physiologically based pharmacokinetic (PBPK) models to absorb and upgrade with the newly available information on drug and population-specific parameters, makes them a preferred choice over the conventional pharmacokinetic models for predicting mDDIs.Method: A PBPK model capable of predicting the stereo-selective disposition of carvedilol after administering paroxetine by incorporating mechanism (time) based inhibition of CYP2D6 and CYP3A4 was developed by using the population-based absorption, distribution, metabolism and elimination (ADME) simulator, Simcyp®.Results: The model predictions for both carvedilol enantiomers were in close agreement with the observed PK data, as the ratios for observed/predicted PK parameters were within the 2-fold error range. The developed PBPK model was successful in capturing an increase in exposures of R and S-carvedilol, due to the time-based inhibition of CYP2D6 enzyme caused by paroxetine.Conclusion: The developed model can be used for exploring complex clinical scenarios, where multiple drugs are given concurrently, particularly in diseased populations where no clinical trial data is available.

EMDIA Case Series-Effective Medication Therapy Management (MTM) for Diabetes Type 2 Patients-A Proof of Concept Study.

Background: A 2016 meta-analysis of pharmaceutical care for patients with diabetes mellitus showed that the following four components were most effective: (a) individual goal setting, (b) sending feedback to the physician, (c) reviewing the medication, and (d) reviewing blood glucose measurements. Methods: To formulate a hypothesis regarding the effect of these four pharmaceutical care components on glycemic control in patients with diabetes mellitus and the feasibility of these components in practice. Ten patients with type 2 diabetes were included in the case series and received medication therapy management over four months. Results: The four care components were feasible in everyday practice and could be implemented within one patient visit. The average visits were 49 and 28 min at the beginning and end of the study, respectively. The glycated hemoglobin values did not change over the study period, though the fasting blood glucose decreased from 142 to 120 mg/dl, and the number of unsolved drug-related problems decreased from 6.9 to 1.9 per patient by the study end. Conclusions: This case series supports the hypothesis that community pharmacists can implement structured pharmaceutical care in everyday pharmacy practice for patients with type 2 diabetes mellitus.

Zidovudine and lamivudine reach higher concentrations in ventricular than in lumbar human cerebrospinal fluid.

OBJECTIVE: For the treatment of HIV-1-related brain disease and for the prevention of the brain becoming a viral reservoir, it is important that antiretroviral agents reach sufficient concentrations in the CNS. To date, human brain pharmacokinetic data are solely derived from lumbar cerebrospinal fluid (CSF) and mostly originate from single samples. DESIGN: We determined concentrations of antiretroviral drugs in serial samples of ventricular CSF and compared these to the concentrations in serum and lumbar CSF of these patients. METHODS: Two treatment-naïve HIV-1-infected patients received external ventricular drainage for obstructive hydrocephalus. Starting with a combination antiretroviral regimen (cART), ventricular CSF, and subsequently lumbar CSF, with parallel serum, was frequently collected. Drug concentrations were determined and CSF-to-serum ratios were calculated. RESULTS: High concentrations, resulting in high CSF-to-serum ratios, were found in the ventricular CSF of the three substances zidovudine, lamivudine and indinavir, whereas this was not observed for stavudine, ritonavir, saquinavir and efavirenz. Concentrations of zidovudine and lamivudine were up to four times greater in CSF from the ventricles than in lumbar CSF of the same patient. The zidovudine concentrations in the ventricular CSF exceeded serum concentrations by a factor of 1.4. CONCLUSION: Unexpectedly high concentrations of some antiretrovirals in the ventricular CSF, the site close to the brain parenchyma where HIV is located, should be considered when the cART regimen is aiming at CNS viral replication.