Evaluation of Hydroxychloroquine as a Perpetrator on Cytochrome P450 (CYP) 3A and CYP2D6 Activity with Microdosed Probe Drugs in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Although polypharmacy is a particular challenge in daily rheumatological practice, clinical research on the effects of hydroxychloroquine (HCQ), a commonly used drug for patients with rheumatic diseases, is sparse on cytochrome P450 (CYP)-mediated metabolism. We have shown that pre-treatment with pantoprazole does not alter HCQ absorption in healthy volunteers. In this paper, we report the effects of a single 400 mg dose of HCQ on specific CYP3A and CYP2D6 substrates in healthy volunteers. METHODS: In the trial, participants were randomized into two groups (HCQ plus a 9-day course of pantoprazole, or HCQ only). As a secondary endpoint, the effects of a single oral dose of HCQ on the exposure of the oral microdosed CYP3A probe drug midazolam (30 µg) and the oral microdosed CYP2D6 probe drug yohimbine (50 µg) were studied in 23 healthy volunteers (EudraCT no. 2020-001470-30, registered 31 March 2020). RESULTS: The exposure of the probe drugs after intake of HCQ compared with baseline values was quantified by the partial area under the plasma concentration-time curve 0-6 h after administration (AUC0-6 h) for yohimbine and the partial AUC2-4 h for midazolam. Under HCQ, yohimbine AUC0-6 h was unchanged, independent of CYP2D6 genotypes and pantoprazole exposure. Midazolam AUC2-4 h was 25% higher on the day of HCQ administration than at baseline (p = 0.0007). This significant increase was driven by the pantoprazole subgroup, which showed a 46% elevation of midazolam AUC2-4 h as compared with baseline (p < 0.0001). The ratio of midazolam to 1-OH-midazolam partial AUC2-4 h significantly increased from 3.03 ± 1.59 (baseline) to 3.60 ± 1.56 (HCQ) in the pantoprazole group (p = 0.0026). CONCLUSION: In conclusion, we observed an increased midazolam exposure most likely related to pantoprazole.

Influence of a Short Course of Ritonavir Used as Booster in Antiviral Therapies Against SARS-CoV-2 on the Exposure of Atorvastatin and Rosuvastatin.

PURPOSE: Early antiviral treatment with nirmatrelvir/ritonavir is recommended for SARS-CoV-2-infected patients at high risk for severe courses. Such patients are usually chronically ill and susceptible to adverse drug interactions caused by ritonavir. We investigated the interactions of short-term low-dose ritonavir therapy with atorvastatin and rosuvastatin, two statins commonly used in this population. METHOD: We assessed exposure changes (area under the concentration-time curve (AUC∞) and maximum concentration (Cmax)) of a single dose of 10 mg atorvastatin and 10 mg rosuvastatin before and on the fifth day of ritonavir treatment (2 × 100 mg/day) in healthy volunteers and developed a semi-mechanistic pharmacokinetic model to estimate dose adjustment of atorvastatin during ritonavir treatment. RESULTS: By the fifth day of ritonavir treatment, the AUC∞ of atorvastatin increased 4.76-fold and Cmax 3.78-fold, and concurrently, the concentration of atorvastatin metabolites decreased to values below the lower limit of quantification. Pharmacokinetic modelling indicated that a stepwise reduction in atorvastatin dose during ritonavir treatment with a stepwise increase up to 4 days after ritonavir discontinuation can keep atorvastatin exposure within safe and effective margins. Rosuvastatin pharmacokinetics were only mildly modified; ritonavir significantly increased the Cmax 1.94-fold, while AUC∞ was unchanged. CONCLUSION: Atorvastatin doses should likely be adjusted during nirmatrelvir/ritonavir treatment. For patients on a 20-mg dose, we recommend half of the original dose. In patients taking 40 mg or more, a quarter of the dose should be taken until 2 days after discontinuation of nirmatrelvir/ritonavir. Patients receiving rosuvastatin do not need to change their treatment regimen. TRIAL REGISTRATION: EudraCT number: 2021-006634-39. DRKS00027838.

CYP3A and CYP2C19 Activity Determined by Microdosed Probe Drugs Accurately Predict Voriconazole Clearance in Healthy Adults.

BACKGROUND AND OBJECTIVE: Voriconazole is an important broad-spectrum anti-fungal drug with nonlinear pharmacokinetics. The aim of this single centre fixed-sequence open-label drug-drug interaction trial in healthy participants (N = 17) was to determine whether microdosed probe drugs for CYP3A and CYP2C19 reliably predict voriconazole clearance (CLVRZ). METHODS: At baseline, a single oral microdose of the paradigm substrates midazolam (CYP3A) and omeprazole (CYP2C19) were given to estimate their clearances (CL). Thereafter, a single oral dose of voriconazole was administered (50, 100, 200 or 400 mg), followed by the microdosed probe drugs. RESULTS: The clearances of midazolam (CLMDZ 790-2790 mL/min at baseline; 248-1316 mL/min during voriconazole) and omeprazole (CLOMZ 66.4-2710 mL/min at baseline; 30.1-1420 mL/min during voriconazole) were highly variable. CLMDZ [geometric mean ratio (GMR) 0.586 at 50 mg voriconazole decreasing to GMR 0.196 at 400 mg voriconazole] and CLOMZ (GMR 0.590 at 50 mg decreasing to GMR 0.166 at 400 mg) were reduced with higher voriconazole doses. CLMDZ was linearly correlated with CLVRZ (slope 1.458; adjusted R2 0.528) as was CLOMZ (slope 0.807; adjusted R2 0.898). Multiple linear regression resulted in an adjusted R2 of 0.997 for the relationship CLVRZ ~ log CLOMZ + log CLMDZ using data during voriconazole treatment and an adjusted R2 of 0.997 for the relationship CLVRZ ~ log CLOMZ + log CLMDZ + voriconazole dose, using baseline data for CLMDZ and CLOMZ. CONCLUSION: Microdosed midazolam and omeprazole accurately described and predicted total CLVRZ TRIAL REGISTRATION: EudraCT No: 2020-001017-20, registered on March 5th, 2020. DRKS: DRKS00022547, registered on August 6th, 2020.

Effect of Clarithromycin, a Strong CYP3A and P-glycoprotein Inhibitor, on the Pharmacokinetics of Edoxaban in Healthy Volunteers and the Evaluation of the Drug Interaction with Other Oral Factor Xa Inhibitors by a Microdose Cocktail Approach.

PURPOSE: We assessed the differential effect of clarithromycin, a strong inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein, on the pharmacokinetics of a regular dose of edoxaban and on a microdose cocktail of factor Xa inhibitors (FXaI). Concurrently, CYP3A activity was determined with a midazolam microdose. METHODS: In an open-label fixed-sequence trial in 12 healthy volunteers, the pharmacokinetics of a microdosed FXaI cocktail (µ-FXaI; 25 µg apixaban, 50 µg edoxaban, and 25 µg rivaroxaban) and of 60 mg edoxaban before and during clarithromycin (2 x 500 mg/d) dosed to steady-state was evaluated. Plasma concentrations of study drugs were quantified using validated ultra-performance liquid chromatography-tandem mass spectrometry methods. RESULTS: Therapeutic clarithromycin doses increased the exposure of a therapeutic 60 mg dose of edoxaban with a geometric mean ratio (GMR) of the area under the plasma concentration-time curve (AUC) of 1.53 (90 % CI: 1.37-1.70; p < 0.0001). Clarithromycin also increased the GMR (90% CI) of the exposure of microdosed FXaI apixaban to 1.38 (1.26-1.51), edoxaban to 2.03 (1.84-2.24), and rivaroxaban to 1.44 (1.27-1.63). AUC changes observed for the therapeutic edoxaban dose were significantly smaller than those observed with the microdose (p < 0.001). CONCLUSION: Clarithromycin increases FXaI exposure. However, the magnitude of this drug interaction is not expected to be clinically relevant. The edoxaban microdose overestimates the extent of the drug interaction with the therapeutic dose, whereas AUC ratios for apixaban and rivaroxaban were comparable to the interaction with therapeutic doses as reported in the literature. TRIAL REGISTRATION: EudraCT Number: 2018-002490-22.

Frailty as a Marker for the Plasma Concentrations of Direct Oral Anticoagulants in Older Patients: Results of an Exploratory Study.

BACKGROUND: Frailty makes older adults vulnerable to adverse health outcomes and can modify pharmacokinetics and drug exposure. OBJECTIVE: We aimed to explore the relationship between different frailty assessments and trough plasma concentrations of direct oral anticoagulants in older patients. METHODS: The frailty status of adults aged ≥ 70 years receiving regular direct oral anticoagulant medication was assessed by four different instruments: Fried physical phenotype, Rockwood frailty index, Short Physical Performance Battery, and FRAIL scale. The two performance measures "slow gait speed" and "weak grip strength" were used to build a separate score depending on the number of positive criteria (none, one, two). For each participant, a single steady-state direct oral anticoagulant trough plasma concentration was collected, dose-normalized, and its relationship to the various frailty assessments analyzed. RESULTS: Forty-two participants completed the study, with most using apixaban (n = 22). Dose-normalized apixaban trough concentrations were 2.48-fold higher in frail participants (Fried phenotype) than in robust participants (p = 0.009) and correlated positively with Fried physical phenotype (rs = 0.535, p = 0.010) and negatively with Short Physical Performance Battery (rs = - 0.434, p = 0.044). Compared with participants who met none of the criteria "slow gait speed" and "weak grip strength", apixaban trough concentrations were approximately 1.9-fold higher in participants who were positive for one (p = 0.018) or two (p = 0.013) of these measures. CONCLUSIONS: In this exploratory study, higher levels of frailty on performance-based frailty assessments were associated with higher apixaban exposure in older adults. CLINICAL TRIAL REGISTRATION: German Clinical Trials Register DRKS00016741; registered 20 February, 2019.

Metabolic Effect of Blocking Sodium-Taurocholate Co-Transporting Polypeptide in Hypercholesterolemic Humans with a Twelve-Week Course of Bulevirtide-An Exploratory Phase I Clinical Trial.

Bile acids (BA) play an important role in cholesterol metabolism and possess further beneficial metabolic effects as signalling molecules. Blocking the hepatocellular uptake of BA via sodium-taurocholate co-transporting polypeptide (NTCP) with the first-in-class drug bulevirtide, we expected to observe a decrease in plasma LDL cholesterol. In this exploratory phase I clinical trial, volunteers with LDL cholesterol > 130 mg/dL but without overt atherosclerotic disease were included. Thirteen participants received bulevirtide 5 mg/d subcutaneously for 12 weeks. The primary aim was to estimate the change in LDL cholesterol after 12 weeks. Secondary endpoints included changes in total cholesterol, HDL cholesterol, lipoprotein(a), inflammatory biomarkers, and glucose after 12 weeks. In addition, cardiac magnetic resonance imaging (CMR) was performed at four time points. BA were measured as biomarkers of the inhibition of hepatocellular uptake. After 12 weeks, LDL cholesterol decreased not statistically significantly by 19.6 mg/dL [−41.8; 2.85] (Hodges−Lehmann estimator with 95% confidence interval). HDL cholesterol showed a significant increase by 5.5 mg/dL [1.00; 10.50]. Lipoprotein(a) decreased by 1.87 mg/dL [−7.65; 0]. Inflammatory biomarkers, glucose, and cardiac function were unchanged. Pre-dose total BA increased nearly five-fold (from 2026 nmol/L ± 2158 (mean ± SD) at baseline to 9922 nmol/L ± 7357 after 12 weeks of treatment). Bulevirtide was generally well tolerated, with most adverse events being administration site reactions. The exploratory nature of the trial with a limited number of participants allows the estimation of potential effects, which are crucial for future pharmacological research on bile acid metabolism in humans.

First-in-human, randomized, double-blind, placebo-controlled, dose escalation trial of the anti-herpes simplex virus monoclonal antibody HDIT101 in healthy volunteers.

HDIT101 is a first-in-class humanized monoclonal antibody recognizing a conserved epitope in glycoprotein B, a target present on the surface of herpes simplex virus 1 (HSV-1) and HSV-2 particles as well as on virus-infected cells. This was a first-in-human, single-center, double-blind, placebo-controlled trial in 24 healthy volunteers, randomized 3:1 (placebo:active) in each of the six dose levels with escalating doses up to 12,150 mg HDIT101. HDIT101 was administered intravenously, to study safety, pharmacokinetics (PKs), and immunogenicity. HDIT101 was well-tolerated in all recipients and no serious or severe adverse events, no infusion-related reactions, and no events suggestive of dose limiting off-target toxicity occurred. The mean serum exposure (area under the curve from zero to infinity [AUC0-∞ ]) of HDIT101 showed a linear increase from 4340 h*µg/ml at a dose of 50 mg to 1,122,247 h*µg/ml at a dose of 12,150 mg. No immunogenic effects following HDIT101 exposure were observed at any of the applied doses. HDIT101 demonstrated the expected PK properties of a monoclonal antibody was well-tolerated, and could be safely administered even at excessively high doses that may be required for treatment of patients with septical HSV spread.

Drug-coated balloons in below-the-knee arteries.

Background: The search for an optimal interventional treatment strategy in infrapopliteal peripheral artery disease remains in the focus of interest. Whether drug-coated balloons (DCB) might enhance interventional outcomes after crural interventions is a matter of debate, as studies yielded conflicting results on DCB safety and efficacy. Patients and methods: We analyzed a retrospective cohort of 75 infrapopliteal DCB interventions performed at our institution in 68 patients with peripheral artery disease in Rutherford category 3 to 6. Results: Despite a high rate of long complex lesions and multi-vessel disease, freedom from clinically driven target lesions revascularization (TLR) after 365 days was 68%. After six months, healing or significant improvement of the ischemic ulcer was observed in 78% of cases. Accordingly, freedom from major amputation and death after 365 days was 82%. Freedom from major amputation and death was 76.2% of cases in patients with diabetes mellitus as opposed to 91.5% in patients without diabetes mellitus (p=0.049). Conclusions: With this real-world analysis we would like to contribute to the ongoing discussion on the benefit and safety of DCB treatment in below-the-knee interventions.

Drug Treatment of Hypercholesterolemia in Older Adults: Focus on Newer Agents.

There is increasing research interest in cholesterol-lowering therapy in older patients. The newer lipid-lowering agents (the proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors evolocumab and alirocumab; the PCSK9 synthesis inhibitor inclisiran, and the adenosine triphosphate-citrate lyase inhibitor bempedoic acid) might also provide more options for the future treatment of older patients. Data analyses of the phase III outcome trials of the PCSK9 inhibitors suggest that their clinical benefits are maintained at older ages and that there is no increased relative risk of adverse events in older patients; however, data from patients aged ≥ 75 years and particularly aged ≥ 85 years are limited, and the trials did not collect information on the frailty status of patients. Frailty is a predictor of adverse outcomes, including mortality, and might help guide therapy decisions. To date, no outcome data are available for cardiovascular endpoints for the low-density lipoprotein cholesterol-lowering drugs inclisiran and bempedoic acid. Except for the risk of gout and tendon rupture with bempedoic acid, which remains to be further characterized in larger populations, the safety profile of the novel lipid-lowering agents in older patients seems favorable. The newer lipid-lowering agents could be added to other lipid-lowering medication or used as an alternative treatment in older patients with documented statin intolerance (as is already recommended in guidelines for the PCSK9 inhibitors), such as myopathy. Especially in older patients needing high-intensity therapy despite polypharmacy or certain comedications, the absence of clinically relevant drug-drug interactions with the PCSK9 inhibitors and inclisiran might be an advantage.

Predicting Hospital Readmissions from Health Insurance Claims Data: A Modeling Study Targeting Potentially Inappropriate Prescribing.

BACKGROUND: Numerous prediction models for readmissions are developed from hospital data whose predictor variables are based on specific data fields that are often not transferable to other settings. In contrast, routine data from statutory health insurances (in Germany) are highly standardized, ubiquitously available, and would thus allow for automatic identification of readmission risks. OBJECTIVES: To develop and internally validate prediction models for readmissions based on potentially inappropriate prescribing (PIP) in six diseases from routine data. METHODS: In a large database of German statutory health insurance claims, we detected disease-specific readmissions after index admissions for acute myocardial infarction (AMI), heart failure (HF), a composite of stroke, transient ischemic attack or atrial fibrillation (S/AF), chronic obstructive pulmonary disease (COPD), type-2 diabetes mellitus (DM), and osteoporosis (OS). PIP at the index admission was determined by the STOPP/START criteria (Screening Tool of Older Persons' Prescriptions/Screening Tool to Alert doctors to the Right Treatment) which were candidate variables in regularized prediction models for specific readmission within 90 days. The risks from disease-specific models were combined ("stacked") to predict all-cause readmission within 90 days. Validation performance was measured by the c-statistics. RESULTS: While the prevalence of START criteria was higher than for STOPP criteria, more single STOPP criteria were selected into models for specific readmissions. Performance in validation samples was the highest for DM (c-statistics: 0.68 [95% confidence interval (CI): 0.66-0.70]), followed by COPD (c-statistics: 0.65 [95% CI: 0.64-0.67]), S/AF (c-statistics: 0.65 [95% CI: 0.63-0.66]), HF (c-statistics: 0.61 [95% CI: 0.60-0.62]), AMI (c-statistics: 0.58 [95% CI: 0.56-0.60]), and OS (c-statistics: 0.51 [95% CI: 0.47-0.56]). Integrating risks from disease-specific models to a combined model for all-cause readmission yielded a c-statistics of 0.63 [95% CI: 0.63-0.64]. CONCLUSION: PIP successfully predicted readmissions for most diseases, opening the possibility for interventions to improve these modifiable risk factors. Machine-learning methods appear promising for future modeling of PIP predictors in complex older patients with many underlying diseases.

Effect of Pantoprazole on the Absorption of Hydroxychloroquinea A Randomized Drug-Drug Interaction Trial in Healthy Adults.

Hydroxychloroquine as a weak basic compound with two amines is strongly enriched in cell compartments with low pH, suggesting that modification of gastric pH by coadministered proton pump inhibitors might reduce its solubility and absorption and thus its efficacy in patients. We addressed this question in a single-center, open-label, randomized, parallel drug-drug interaction trial in healthy adults (EudraCT No. 2020-001470-30). All participants received a single oral dose of 400-mg hydroxychloroquine, and one group additionally received 40 mg of pantoprazole once daily for 9 days dosed to steady state. Whole-blood samples were collected for 72 hours, and hydroxychloroquine was quantified by liquid chromatography-tandem mass spectrometry. Primary endpoints were whole-blood hydroxychloroquine areas under the concentration-time curve from 0 to 72 hours (AUC0-72h ) and peak concentrations (Cmax ). Unpaired 2-sided t-tests of the log transformed pharmacokinetic parameters were performed to compare both groups. Twenty-four participants (12 per group) were included. Hydroxychloroquine AUC0-72h and Cmax did not differ between groups without and with pantoprazole (arithmetic mean; AUC0-72h , 7649 ng/ml • h, and 8429 ng/ml • h, P = .50; Cmax , 448 ng/mL and 451.5 ng/mL, P = .96, respectively). Pantoprazole did not alter hydroxychloroquine absorption, indicating that proton pump inhibitors do not affect its bioavailability.

Intact plasma quantification of the large therapeutic lipopeptide bulevirtide.

Bulevirtide is a first-in-class entry inhibitor of the hepatitis B and hepatitis delta virus blocking the sodium/bile acid co-transporter NTCP, and was recently approved for the treatment of hepatitis D as a priority medicine (prime) in an accelerated assessment by the European Medicines Agency. It is a very large lipopeptide comprising 47 amino acids in its sequence and a myristoylation at the N-terminus. For support of clinical development, we established highly sensitive plasma quantification assays using 100 µL of plasma, spanning concentrations of 0.1 to 100 ng/mL and 1 to 1000 ng/mL with the option to measure ten-fold diluted samples up to 10,000 ng/mL. Quantification was performed with UPLC-MS/MS measurements after extraction with protein precipitation. Both assays were fully validated according to the pertinent guidelines of the FDA and EMA, including incurred sample reanalyses and cross-validation using clinical study samples. Graphical abstract.

Disease-dependent variations in the timing and causes of readmissions in Germany: A claims data analysis for six different conditions.

BACKGROUND: Hospital readmissions place a major burden on patients and health care systems worldwide, but little is known about patterns and timing of readmissions in Germany. METHODS: We used German health insurance claims (AOK, 2011-2016) of patients ≥ 65 years hospitalized for acute myocardial infarction (AMI), heart failure (HF), a composite of stroke, transient ischemic attack, or atrial fibrillation (S/AF), chronic obstructive pulmonary disease (COPD), type 2 diabetes mellitus, or osteoporosis to identify hospital readmissions within 30 or 90 days. Readmissions were classified into all-cause, specific, and non-specific and their characteristics were analyzed. RESULTS: Within 30 and 90 days, about 14-22% and 27-41% index admissions were readmitted for any reason, respectively. HF and S/AF contributed most index cases, and HF and COPD accounted for most all-cause readmissions. Distributions and ratios of specific to non-specific readmissions were disease-specific with highest specific readmissions rates among COPD and AMI. CONCLUSION: German claims are well-suited to investigate readmission causes if longer periods than 30 days are evaluated. Conditions closely related with the primary disease are the most frequent readmission causes, but multiple comorbidities among readmitted cases suggest that a multidisciplinary care approach should be implemented vigorously addressing comorbidities already during the index hospitalization.

Using the Causal Inference Framework to Support Individualized Drug Treatment Decisions Based on Observational Healthcare Data.

When healthcare professionals have the choice between several drug treatments for their patients, they often experience considerable decision uncertainty because many decisions simply have no single "best" choice. The challenges are manifold and include that guideline recommendations focus on randomized controlled trials whose populations do not necessarily correspond to specific patients in everyday treatment. Further reasons may be insufficient evidence on outcomes, lack of direct comparison of distinct options, and the need to individually balance benefits and risks. All these situations will occur in routine care, its outcomes will be mirrored in routine data, and could thus be used to guide decisions. We propose a concept to facilitate decision-making by exploiting this wealth of information. Our working example for illustration assumes that the response to a particular (drug) treatment can substantially differ between individual patients depending on their characteristics (heterogeneous treatment effects, HTE), and that decisions will be more precise if they are based on real-world evidence of HTE considering this information. However, such methods must account for confounding by indication and effect measure modification, eg, by adequately using machine learning methods or parametric regressions to estimate individual responses to pharmacological treatments. The better a model assesses the underlying HTE, the more accurate are predicted probabilities of treatment response. After probabilities for treatment-related benefit and harm have been calculated, decision rules can be applied and patient preferences can be considered to provide individual recommendations. Emulated trials in observational data are a straightforward technique to predict the effects of such decision rules when applied in routine care. Prediction-based decision rules from routine data have the potential to efficiently supplement clinical guidelines and support healthcare professionals in creating personalized treatment plans using decision support tools.

Impact of pantoprazole on absorption and disposition of hydroxychloroquine, a drug used in Corona Virus Disease-19 (Covid-19): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Primary objective: Evaluation of the effect of the proton pump inhibitor (PPI) pantoprazole on the absorption of hydroxychloroquine (HCQ). Secondary objectives: • Evaluation of the relationship between HCQ concentrations in whole blood, plasma and intracellular concentrations in target cells - peripheral blood mononuclear cells (PBMCs). • Evaluation of HCQ as a potential perpetrator in drug-drug interactions at the level of cytochrome P450 (CYP) 3A4 and CYP2D6 (major drug metabolizing enzymes). TRIAL DESIGN: Single centre, open-label, parallel group, two-arm, phase I drug-drug interaction trial. PARTICIPANTS: Healthy volunteers (18-60 years old) are treated in the Clinical Pharmacological Trial Center of Heidelberg University Hospital, Germany. INTERVENTION AND COMPARATOR: • Participants are randomized in a group to either receive a nine-day course of pantoprazole, or to a control group without pantoprazole. All participants receive a single dose of HCQ 400 mg. • Additionally, CYP3A4 and CYP2D6 phenotyping with microdosed probe drugs is performed using midazolam and yohimbine as enzyme activity markers, respectively. MAIN OUTCOMES: Primary endpoint: Area under the curve (AUC)0-72 h and maximum concentration (Cmax) of a single oral dose of 400 mg HCQ with and without pantoprazole (changes in these two values describe relevant aspects of exposure to HCQ with and without administration of pantoprazole). Secondary endpoints: • AUC2-4 h, AUC0-6 h and Cmax of midazolam and yohimbine. • Correlation of HCQ concentrations in whole blood with concentrations in plasma and peripheral blood mononuclear cells (PBMC). RANDOMISATION: Participants are assigned to treatment groups by using a randomisation list (1:1, block size = 4) and consecutive enrolment. BLINDING (MASKING): The trial is an open-label trial, participants and investigators are not blinded. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total number of 24 participants (12 per group) are planned to be randomised. TRIAL STATUS: Protocol version 2.1 dated 24/04/2020, first patient first visit. April 30th, 2020, recruitment ongoing, anticipated end of study June 30th, 2020. TRIAL REGISTRATION: EudraCT Number: 2020-001470-30 , registered on 31 March 2020 German Clinical trials register number / International Clinical Trials Registry Platform: DRKS00021573, registered on 27 April 2020 FULL PROTOCOL: The full trial protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full trial protocol. The trial protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Characterization of hospitalized cardiovascular patients with suspected heparin-induced thrombocytopenia.

BACKGROUND: Little is known about heparin-induced thrombocytopenia (HIT), a pro-thrombotic, potentially life-threatening immune-mediated reaction to heparin exposure, in conservative and interventional cardiovascular medicine. HYPOTHESIS: The 4T score, validated for prediction of HIT in surgical patients before, is also suitable for assessing HIT probability in cardiovascular patients with unclear thrombocytopenia. METHODS: A total of 403 consecutive patients from our Department of Cardiology, Angiology and Pneumology in whom a HIT screening test was performed between 2009 and 2016 were identified. All 72 patients with a positive screening test were subjected to a functional confirmation test (heparin-induced platelet activation test, HIPA), resulting in 23 patients with serologically confirmed HIT (positive screening test, positive HIPA) and 49 patients with nonconfirmed HIT (positive screening test, negative HIPA). RESULTS: The 4TScore had a sensitivity of 82.6% and a specificity of 28.6% in our patients, suggesting that it might not sufficiently predict the clinical probability of HIT in cardiovascular patients. In both confirmed and nonconfirmed HIT, intrahospital mortality was high without a significant difference (30% in confirmed HIT vs 43% in nonconfirmed HIT). Bacteremia was more often found in patients with nonconfirmed HIT, suggesting infection as a frequent differential diagnosis of thrombocytopenia in these patients (49% vs 17%, P = 0.0185). CONCLUSION: HIT screening should be initiated in cardiovascular patients with unclear thrombocytopenia despite a low 4Tscore in order to distinguish patients requiring alternative anticoagulants from those with other causes such as infections. Further research is needed to specify the risk profile for HIT in cardiovascular patients.

Complex interventional iliocaval recanalization due to plasmacytoma and cystic echinococcosis.

Post-thrombotic syndrome is common after iliofemoral vein thrombosis. Conservative therapy, mainly limited to compression and anticoagulation therapy, might not be sufficient in controlling symptoms. Interventional recanalization of the chronically occluded iliac veins is an evolving method, promising rapid relief of symptoms. Here, we present two cases of complex interventions in one patient with preceding pelvic radiotherapy due to a plasmacytoma and in another patient in whom a cava wedge resection had been performed because of cystic echinococcosis in the liver.

Renal sympathetic denervation therapy in the real world: results from the Heidelberg registry.

INTRODUCTION: Renal sympathetic denervation (RDN) is a novel treatment option in patients with treatment-resistant arterial hypertension. A subset of recently published randomized and non-randomized trials indicates that RDN leads to sustained lowering of blood pressure (BP) under controlled study conditions. However, registry data that allow evaluation of safety and efficacy in a real-world setting are largely missing. METHODS: Sixty-three consecutive patients with treatment-resistant hypertension underwent RDN with the radiofrequency-based Symplicity™ catheter. As part of our prospective registry, treatment efficacy and safety were monitored after 3, 6, and 12 months. RESULTS: At 6 months follow-up, office systolic BP significantly improved by 19 + 23 mmHg as compared to baseline, while diastolic BP values reduced by 6 + 13 mmHg (p < 0.05). One year after RDN, office BP levels further improved (26 + 25 mmHg in systolic BP and 9 + 13 mmHg in diastolic BP, respectively), even though 19 patients had reduced the number and/or dosage of antihypertensive agents. The response rate, defined as reduction of office systolic BP of ≥ 10 mmHg, was 73% after 6 months. Baseline BP was the only significant predictor of blood pressure response, whereas no correlation was found between the number of ablation points and the individual changes in office blood pressure. Interestingly, patients with challenging renal anatomy profited somewhat less from the procedure than those with "normal" renal anatomy. Procedure related adverse events occurred in three patients (4.7%) and were limited to vascular access complications. CONCLUSIONS: RDN with the Symplicity™ system is safe and effective in patients with treatment-resistant hypertension also in a real-world setting.

Reduced exposure variability of the CYP3A substrate simvastatin by dose individualization to CYP3A activity.

This study aimed to demonstrate that the dose of a CYP3A substrate (simvastatin) can be adapted individually on the basis of CYP3A activity as assessed by midazolam metabolic clearance. In 18 healthy participants individual CYP3A activity was quantified using midazolam metabolic clearance both alone and during CYP3A inhibition with 40 mg ritonavir. Thereafter, simvastatin acid exposure was determined after a simvastatin standard dose (40 mg) and doses adapted to individual CYP3A activity at baseline and during CYP3A inhibition. Interindividual variability of CYP3A activity and simvastatin acid AUC0-24 was large and both correlated (r(2) = 0.745, P < .001). The adapted simvastatin doses ranged from 25 to 80 mg and their administration reduced simvastatin variability fivefold. Despite the low adapted simvastatin dose of 12 mg during CYP3A inhibition with ritonavir, exposure increased (point estimate of 4.2 [90% CI: 3.15-5.61]) probably caused by additional OATP1B1 inhibition. CYP3A activity-based dose adaptation can be used to reduce interindividual variability in simvastatin exposure.