Relapses of Immune Thrombocytopenia after the Second and Booster Doses of BNT162b2 Vaccine.

We present here a 65-year-old male patient known for immune thrombocytopenic purpura (ITP) and fluctuating platelet count who experienced a severe exacerbation of thrombocytopenia following BNT162b2 COVID-19 vaccination. One month after the second dose, he presented petechiae and asthenia with isolated thrombocytopenia (platelet count: 3 × 109/L). He recovered after a 4-day course of intravenous corticosteroid treatment and intravenous immunoglobulin therapy. Eight months later, his platelet count was within the normal range, and he received a booster dose of vaccine after premedication with prednisone. Eight days later, his platelet count dropped to 29 × 109/L, but he remained asymptomatic. He received a rescue treatment with prednisone followed by rituximab over 4 weeks, allowing progressive improvement. Our case suggests a strong association between COVID-19 vaccination and the exacerbation of ITP.

Population Pharmacokinetics of Amitriptyline After Intrathecal, Epidural, and Intravenous Administration in Sheep.

BACKGROUND: Amitriptyline (AMI) is a lipophilic, tricyclic antidepressant with analgesic properties that could potentially be used for epidural (EPI) analgesia. However, no pharmacokinetic data are available for AMI in spinal spaces. The objective of this study was to evaluate the spinal disposition and intrathecal (IT) bioavailability of AMI after IT and EPI administration. METHODS: Six Lacaune ewes received 3 consecutive administrations of AMI. They initially received 10 mg of AMI administered intravenously, then 5 mg of AMI administered intrathecally, and 50 mg of AMI injected into the EPI space. Consecutive administrations were separated by intervals of 2 hours. A simultaneous microdialysis technique was used to determine the EPI and IT concentrations of AMI. Population analysis with S-ADAPT software was used to evaluate the pharmacokinetic parameters. RESULTS: Following intravenous administration, the clearance and central compartment (Vc) in plasma were 1.32 L/min and 147 L, respectively. Concentration-time profiles for the IT and EPI compartments were highly variable after transmeningeal diffusion. The IT Vc after IT administration and the EPI Vc after EPI administration were 2.4 and 48.9 mL, respectively. Less AMI transferred from the EPI to the IT space than from the IT to the EPI compartment, with bioavailabilities of 1.3% and 55%, respectively. CONCLUSIONS: Simultaneous population analysis for AMI demonstrated differences in EPI and IT pharmacokinetics following the EPI and IT administration of this drug. The IT bioavailability of AMI after EPI administration is relatively low.

Ex vivo and in vivo diffusion of ropivacaine through spinal meninges: influence of absorption enhancers.

Following epidural administration, cerebrospinal fluid bioavailability of local anesthetics is low, one major limiting factor being diffusion across the arachnoid mater barrier. The aim of this study was to evaluate the influence of absorption enhancers on the meningeal permeability of epidurally administered ropivacaine. Five enhancers known for their ability to increase drug permeability via transcellular and/or paracellular pathways, i.e. palmitoyl carnitine, ethylenediaminetetraacetic acid, sodium caprate, dodecylphosphocholine and pentylglycerol, were tested ex vivo on fresh specimen of meninges removed from cervical to lumbar level of rabbit spine following laminectomy and placed in diffusion chambers. Among them, sodium caprate lead to the best permeability improvement for both marker and drug (440% and 112% for mannitol and ropivacaine, respectively) and was therefore selected for in vivo study in a sheep model using microdialysis technique to evaluate epidural and intrathecal ropivacaine concentrations following epidural administration. Resulting dialysate and plasma concentrations were used to calculate pharmacokinetic parameters. Following sodium caprate pre-treatment, ropivacaine intrathecal maximal concentration (Cmax) was 1.6 times higher (78 ± 16 µg ml(-1) vs 129 ± 26 µg ml(-1), p<0.05) but the influence of the absorption enhancer was only effective the first 30 min following ropivacaine injection, as seen with the significantly increase of intrathecal AUC(0-30 min) (1629 ± 437 µg min ml(-1) vs 2477 ± 559 µg min ml(-1), p<0.05) resulting in a bioavailable fraction 130% higher 30 min after ropivavaine administration. Co-administration of local anesthetics with sodium caprate seems to allow a transient and reversible improvement of transmeningeal passage into intrathecal space.

Electrocardiographic and hemodynamic effects of intravenous infusion of bupivacaine, ropivacaine, levobupivacaine, and lidocaine in anesthetized ewes.

BACKGROUND AND OBJECTIVES: Neural blockade techniques are associated with a risk of acute cardiac toxicity after accidental intravenous (IV) injection of local anesthetics. The aim of this study was to compare electrocardiographic (ECG) and hemodynamic (HEM) effects induced by IV infusion of local anesthetics in an anesthetized ewe model. METHODS: Thirty-two anesthetized ewes received IV bupivacaine (BUPI), ropivacaine (ROPI), or levobupivacaine (S-BUPI) at an equimolar dose, or lidocaine (LIDO) at a 3-fold higher rate (n = 8 in each group). RR, PR, QRS, and QT intervals (QTc), changes (Delta) in systolic and diastolic arterial pressure (SAP and DAP), and in myocardial contractility (dP/dt), were assessed every 30 seconds for 7 minutes. From main ECG variables (RR, PR, QRS, QT), we proposed to use multiple correspondence analysis and hierarchical ascending classification to explore the structure of statistical dependencies among those measurements, and to determine the different patterns of ECG and HEM changes induced by infusion of BUPI, ROPI, S-BUPI, and LIDO. RESULTS: Graphic representation of multiple correspondence analysis associated BUPI with the most pronounced modifications in ECG and HEM variables, followed by in decreasing order ROPI, S-BUPI, and LIDO. Comparisons of clusters identified by hierarchical ascending classification confirmed this classification for ECG variables. Ventricular tachycardia occurred only in the BUPI group. CONCLUSIONS: In our anesthetized ewe model, high dose IV infusion of BUPI induced the most marked changes in RR, PR, QRS, QT, QTc intervals, DeltaSAP, and DeltadP/dt. ROPI altered ECG variables less than BUPI but more than S-BUPI. LIDO was associated with the smallest changes.

Epidural, intrathecal and plasma pharmacokinetic study of epidural ropivacaine in PLGA-microspheres in sheep model.

BACKGROUND: Microparticulate local anesthetics-loaded delivery systems are known to provide a controlled release of drug and to reduce systemic toxicity resulting from transient high plasma concentrations. The aim of this study was to evaluate epidural, intrathecal and plasma pharmacokinetics of ropivacaine following epidural administrations of repeated boluses or infusions and to compare them with the epidural administration of polylactide-co-glycolide ropivacaine-loaded microspheres. METHODS: In the first step, the epidural and intrathecal pharmacokinetics was evaluated in 3 Lacaunes ewes, receiving epidural continuous infusion of ropivacaine with increasing doses (20, 50 and 100mg/h). Then, six animals received an epidural administration of ropivacaine-loaded microspheres (500 mg), three others received ropivacaine in epidural bolus (30 mg) followed by infusion (2mg/ml during 6h), and the last three animals received three successive epidural boluses of ropivacaine (50mg) at 2h interval. A simultaneous microdialysis technique was used to measure epidural and intrathecal concentrations of ropivacaine. RESULTS: After epidural administration of ropivacaine-loaded microspheres, Cmax in plasma was around 100 ng/ml while epidural and intrathecal Cmax of ropivacaine were close to 600 and 150 microg/ml, respectively. The ratios of intrathecal to epidural AUC (AUCit/AUCepi) for bolus administration, bolus+infusion administration, and for microspheres were 13.4+/-2.4; 14.1+/-6.1 and 33.9+/-22.6%, respectively. This suggested that administration of ropivacaine as microspheres increased the transmeningeal passage of ropivacaine in comparison to other administration regimens. CONCLUSIONS: Epidural administration of ropivacaine-loaded microspheres led to the sustained levels of ropivacaine in the intrathecal space compared to the boluses of ropivacaine solution. Moreover, epidural administration of microspheres resulted in the highest efficiency in intrathecal uptake of ropivacaine compared to administration in solution.