Ropivacaine (total and unbound) and AGP concentrations after transversus abdominis plane block for analgesia after abdominal surgery.

BACKGROUND: The goal of this study was to assess the safety of single bolus dose of ropivacaine (ROP) followed by continuous infusion through transversus abdominis plane block catheter. The aim was to determine ROP absorbed from the infusion site, changes in protein binding after surgery, and clinical determinants of adverse effects. METHODS: Twelve patients undergoing laparotomy, received bilateral transversus abdominis plane block under ultrasound guidance using a 20-mL bolus of 0.5% ROP followed by 10 mL/h of 0.2% ROP infusion for 48 hours. Serial blood samples were drawn presurgery and to 48 hours postbolus. Plasma concentrations of total and unbound ROP were measured by high performance liquid chromatography with ultraviolet detection. Alpha-1 acid glycoprotein concentrations were measured by enzyme-linked immunosorbent assay. Patients were monitored for any signs or symptoms of central nervous system and chorionic villus sampling toxicity. RESULTS: After the bolus dose, the mean (±SD) peak plasma total (bound plus unbound) ROP concentration (Cmax) was 2.1 (±0.8) mg/L and unbound ROP concentration was 0.04 (±0.02) mg/L. During the infusion phase, total ROP concentration continued to rise to a mean (±) Cmax of 3.3 (±1.6) mg/L, and the peak unbound concentration was 0.06 (±0.0) mg/L. No patients showed symptoms of ROP toxicity or unacceptable QTc intervals. CONCLUSIONS: Although the total ROP concentrations approached or exceeded reported neurotoxicity thresholds, no patients had unbound ROP concentrations approaching the unbound toxicity threshold, nor showed any signs or symptoms of toxicity. This result was consistent with changes in protein binding to alpha-1 acid glycoprotein after surgery.

A historical perspective of the glycosphingolipids and sphingolipidoses.

Glycosphingolipids are a polysaccharide chain between 1 and 40 carbohydrate residues long glycosidically linked to ceramide (a long-chain aliphatic amino-alcohol or sphingoid) that is embedded in the cell plasma membrane with the carbohydrate moiety on the outside. The sphingoid imparts rigidity to the membrane and the carbohydrate tails protect the cell surface and have functions in relation to cell adhesion, growth, regulation, differentiation, cell interaction, recognition and signalling. They provide adhesion sites for pathogens and change during oncogenic transformation. Ceramide is also a component of sphingomyelin. Glycosphingolipids are degraded by lysosomal hydrolysis. The sphingolipidoses are a series of diseases in which mutations affecting the enzymes catalysing the last 11 steps of this process causing abnormal compounds proximal to the metabolic block to accumulate intralysosomally. Thus, they are a sub-group of the lysosomal storage diseases. The degradation of sphingolipids containing three or less carbohydrate residues requires a sphingolipid activator protein and mutations affecting these proteins also cause abnormal glycosphingolipid storage. With one exception (Fabry disease, which is X linked) the sphingolipidoses are inherited autosomally. The phenotypic manifestations of the individual sphingolipidoses are variable although the more severe variants are usually the better known. They have generally been regarded as untreatable but notable therapeutic advances are being made by enzyme replacement therapy and regulating the rate of glycosphingolipid synthesis by inhibiting UDP-glucose-N-acylsphingosine D-glucosyl transferase (CerGlcT), which is the first reaction on the pathway of glycosphingolipid synthesis. The compounds used are N-alkylated iminosugars whose glucose and galactose stereochemistries inhibit CerGlcT. Prenatal and carrier state diagnosis, genetic counselling and the abortion of affected foetuses are reducing the incidence of some of the most severe sphingolipidoses in certain high-incidence populations.