The practicality of the Congo Red test,or is your vagotomy complete?

The use of Congo Red testing for adequacy of vagotomy in a variety of clinical situations is described. Its intraoperative use is presented for the first time, thus allowing the surgeon immediate documentation of the completeness of his vagotomy and hopefully averting incomplete vagotomy, the single most common cause of ulcer recurrence after vagotomy-pyloroplasty.     

Serotonin as an inhibitor of gastrin

A dose of exogenous serotonin (0.1 mg/kg/min) previously described to cause maximal acid inhibition, was infused into six chronically awake dogs and significantly inhibited acid output. Integrated basal gastrin output was inhibited from a mean of 232.6 pg-min/ml to 31.6 pg-min/ml (p < 0.05) by serotonin infusion. Antral explantation significantly increased gastrin levels from a mean control level of 163 +/- 71.1 pg/ml to a mean of 991.0 +/- 663.4 pg/ml (p < 0.05). These elevated gastrin levels were then not significantly inhibited by serotonin. The effect of serotonin on gastrin output has not previously been documented. Whereas acid inhibition was uniformly achieved, serotonin inhibited basal gastrin output (integrated gastrin output) but not a stimulated level of gastrin output. Serotonin may be an important 'enterogastrone', and its release may play a role both in acid inhibition and in preventing ulcer disease.     

Population pharmacokinetics of cefazolin in critically ill children infected with methicillin-sensitive Staphylococcus aureus

ObjectivesCefazolin is one of curative treatments for infections due to methicillin-sensitive Staphylococcus aureus (MSSA). Both growth and critical illness may impact the pharmacokinetic (PK) parameters. We aimed to build a population PK model for cefazolin in critically ill children in order to optimize individual dosing regimens.MethodsWe included all children (age < 18 years, body weight (BW) > 2.5 kg) receiving cefazolin for MSSA infection. Cefazolin total plasma concentrations were quantified by high-performance liquid chromatography. A data modelling process was performed with the software MONOLIX. Monte Carlo simulations were used in order to attain the PK target of 100% fT _{> 4 × MIC}.ResultsThirty-nine patients with a median (range) age of 7 (0.1–17) years and a BW of 21 (2.8–79) kg were included. The PK was ascribed to a one-compartment model, where typical clearance and volume of distribution estimations were 1.4 L/h and 3.3 L respectively. BW, according to the allometric rules, and estimated glomerular filtration rate (eGFR) on clearance were the two influential covariates. Continuous infusion with a dosing of 100 mg/kg/day to increase to 150 mg/kg/day for children with a BW < 10 kg or eGFR >200 mL/min/1.73m² were the best schemes to reach the PK target of 100% fT _{> 4 × MIC}.ConclusionsIn critically ill children infected with MSSA, continuous infusion seems to be the most appropriate scheme to reach the PK target of 100 % fT _{> 4 × MIC} in children with normal and augmented renal function.     

Binding of a new vinca alkaloid derivative,S12363, to human plasma proteins and platelets. Usefulness of an erythrocyte partitioning technique

Summary The interactions of S12363 with human plasma proteins have been investigatedin vitro by an erythrocyte partitioning technique that allows a quantitative estimation of the plasma and erythrocytes binding. S12363 was 85–95% plasma-bound and 97–98% blood-bound. The main binding protein in plasma was alpha-acid glycoprotein, with a binding constant of 0.6·10⁶ M^–1, accounting for 70% of total S12363 in plasma. Owing to extensive binding to platelets (40–50% of total blood amount), S12363 was mainly distributed in the non plasma blood compartment, with blood-to-plasma concentrations ratio of 1.2–1.4. These results indicate that,in vivo, the fraction of blood S12363 available for tissue diffusion, i.e., the free drug fraction in blood, should depend on both alpha₁-acid glycoprotein concentration in plasma and blood platelet count.     

Influence of age on mortality of colon surgery

The geriatric population continues to grow and surgical decision making is often confused by the effect of aging. This study is part of an ongoing effort to determine surgical risk in the elderly population and to identify the significant factors affecting outcomes which could be used to plan surgical procedures. Records of 163 patients over 70 years of age with elective or emergency surgery (133 patients and 30 patients, respectively) were reviewed. There were 17 deaths. All deaths in a cohort of patients under 70 were examined as well. Ninety-five variables were explored to seek differences between groups. The patients who died, independent of age, were similar. Patients over 70 years of age who died differed from the survivors in many ways, both physiologically and in terms of disease state. Survivors were younger; did not have congestive heart failure; had better hepatic, renal, and pulmonary function; less extensive involvement if malignant disease was present; and fewer postoperative complications. If these factors were removed and only apparently normal physiologic characteristics considered, there were no differences in mortality between the patients over 70 years of age and younger patients. Age was less of a factor than physiologic status.     

Blood-to-Brain Transfer of Various Oxicams: Effects of Plasma Binding on Their Brain Delivery

Purpose. The objective of this work was to assess the influence of binding to plasma proteins and to serum on the brain extraction of four antiinflammatory oxicams. Methods. The brain extraction of isoxicam, tenoxicam, meloxicam and piroxicam was investigated in rats using the carotid injection technique. Blood protein binding parameters were determined by equilibrium dialysis using human serum, human serum albumin (HSA) and alpha-1-acid glycoprotein (AAG) solutions at various concentrations. Results. All oxicams had low values of brain extraction, between 19% and 39% when dissolved in serum, i.e. under physiological conditions. Brain efflux rate constants calculated from the wash-out curves were the same in the absence or presence of serum. Brain efflux was inversely related to the polarity of the oxicams, such that the higher their H-bonding capacity, the lower their brain efflux. The free dialyzable drug fraction was inversely related to protein concentration. However, rat brain extraction was always higher than expected from in vitro measurements of the dialyzable fraction. Conclusions. Except for piroxicam whose brain extraction was partially decreased in the presence of proteins, the serum unbound and initially bound fractions of oxicams both seem available for transfer into the brain. Modest affinities for AAG rule out any related effect. More surprising is the apparent lack of effect on brain transfer of the high-affinity binding to HSA and serum. The enhanced brain uptake of meloxicam in the presence of AAG could be a result of interactions between this globular protein and the endothelial wall.     

Serum binding of indapamide in health and disease: primary role of alpha 1-acid glycoprotein

The serum concentrations of alpha-1-acid glycoprotein (AAG), albumin (HSA), and non-esterified fatty acids (NEFA), and the serum binding of indapamide were measured in four groups of individuals: control (healthy) subjects (N = 24), patients with inflammatory syndrome (N = 28), with hepatic (N = 20) and renal (N = 27) insufficiency. Indapamide serum binding was increased in patients with inflammatory syndrome (82.2 +/- 3.4%, P less than .001), decreased in patients with hepatic insufficiency (72.3 +/- 5.9%, P less than .001) and unchanged in patients with renal insufficiency (77.7 +/- 2.8%) as compared with controls (78.2 +/- 3.1%). A multivariate analysis indicated that these changes were mainly related to concomitant changes in AAG concentration (that explained 63% of intersubject variability in bound/free binding ratio), and to a lesser extent to HSA (that explained only 4% of the variability in the binding). These data show that the free fraction of the acidic drug indapamide in serum is affected by pathologic conditions in which changes in AAG concentration occur and that, unexpectedly, HSA plays a negligible role in the binding.     

Distribution of cyclosporin A between blood cells and plasma of cardiac and renal transplant recipients

The relationship between blood cells and plasma concentrations of cyclosporin A (Cy A) determined by radioimmunoassay, was investigated in 12 heart and 12 kidney transplant recipients. The decision between a linear and nonlinear model was made according to a standardized residuals plot. We observed high blood cells-plasma concentration ratios in the two groups, indicating a high affinity of Cy A for blood cells. The distribution of Cy A between blood cells and plasma was ascribed to a nonlinear saturable model in the two groups. According to our results we have simulated the blood-plasma concentration ratio of Cy A as a function of plasma Cy A concentration and hematocrit.     

Nicanartine Improves in Vitro Resistance of Lipoproteins to Oxidation

Purpose. The aim of this study is to investigate the plasma protein binding of nicanartine and to measure its antioxidant effect on lipoproteins. Methods. The blood binding was studied with an erythrocyte partitioning method and the lipoprotein oxidation with the conjugated dienes method. Results. Nicanartine was 24.7% LDL (low density lipoprotein)-bound and 29.2% AAG (alphal-acid glycoprotein)-bound. Nicanartine delayed but did not stop the oxidation of the three density classes of lipoprotein HDL (high density lipoprotein), LDL, VLDL (very low density lipoprotein). The addition of AAG to LDL in the conjugated dienes method decreased the nicanartine fraction bound to LDL and decreased its antioxidant effect. The decrease of nicanartine LDL-bound fraction and the decrease in antioxidant effect were not parallel. Conclusions. This suggested that (a) AAG-bound nicanartine dissociated to equilibrate the decrease in LDL-bound nicanartine consummed by oxidation, or (b) the oxidation conditions could involve chemical modifications of nicanartine and therefore modify its affinity for AAG.