Preventing gastrointestinal complications of NSAIDs. Risk factors, recent advances, and latest strategies.

In the United States, gastrointestinal complications induced by nonsteroidal anti-inflammatory drugs (NSAIDs) cause more than 100,000 hospitalizations and an estimated 16,500 deaths annually. Because serious gastrointestinal events can occur without warning, prevention measures must not rely on warning signs alone. This article discusses the epidemiology of NSAID-induced toxic episodes, reviews the risk factors for these occurrences, and offers strategies for minimizing the risk among long-term NSAID users.

Pharmaceutical care of postoperative nausea and vomiting: balanced scorecard for outcomes.

Using the balanced scorecard to measure outcomes, a multidisciplinary team worked to improve antiemetic therapy and decrease postoperative nausea and vomiting. Patient satisfaction measures were nausea and pain scales (10 cm, nonnumbered, visual analog). The quality measure was number of vomiting episodes. Cost measures were length of postoperative stay and antiemetic requirement. Institutional learning was assessed by spread of prescribing changes beyond the first cohort of patients. Intervention subjects were providers of general anesthesia in two cohorts of patients (60 and 346) undergoing laparoscopic cholecystectomy. Outcome assessment revealed low nausea and vomiting scores throughout the study, and antiemetic use decreased 50%. There were no deteriorations in pain scores or length of stay. Balanced scorecard measurements suggest no adverse unintended outcomes consequent to changes in prescribing behavior. Balanced scorecard processes assisted consensus among pharmacists, nurses, and physicians that may have accelerated behavioral changes.

Subcutaneous microdialysis in rats correlates with carbamazepine concentrations in plasma and brain.

Microdialysis simplifies the measurement of pharmacokinetics in pharmacodynamically relevant tissues. Microdialysis permits serial measurements of unbound drug concentration. The objective of the present work was to study rats to correlate plasma carbamazepine pharmacokinetics with subcutaneous and brain tissues. Microdialysis probes were inserted into the jugular vein, the brain, and subcutaneous tissue in Sprague-Dawley rats. After receiving single doses of carbamazepine, 12 mg/kg i.p., pharmacokinetic sampling occurred simultaneously from three microdialysis sites. Microdialysis sampled unbound carbamazepine and carbamazepine-10, 11-epoxide concentrations. Concentrations measured in brain, subcutaneous, and plasma correlated with each other. Except where differences were anticipated, pharmacokinetic parameters, including half-life and time to maximum concentration, were the same regardless of measurement site. The present study suggests microdialysis may allow pharmacokinetic measurements in peripheral physiological spaces that are surrogates for the pharmacologically relevant tissue.

Carbamazepine pharmacokinetics-pharmacodynamics in genetically epilepsy-prone rats.

Carbamazepine produces dose-related anticonvulsant effects in epilepsy models including the genetically epilepsy-prone rat (GEPR) model and the rat maximal electroshock model. Dose-response relationships are quantitatively different among the models. Against electroshock seizures in Sprague-Dawley rats the ED50 dose is 7.5 mg/kg whereas the ED50 against audiogenic seizures in severe seizure GEPRs (GEPR-9s) is 3 mg/kg. In contrast, the ED50 in moderate seizure GEPRs (GEPR-3s) is 25 mg/kg. The present study was designed to ascribe dose-response differences among the three rat strains to pharmacokinetic or pharmacodynamic factors. After systemic carbamazepine, pharmacokinetic studies revealed differences in area under the concentration-vs.-time curve. In other experiments, carbamazepine-induced serotonin release from hippocampus was used as a pharmacodynamic marker. In a concentration-controlled design using intracerebral microdialysis, hippocampal carbamazepine infusions produced similar concentration-response relations for the three rat strains. These data support the hypothesis that dose-response differences among the three rat strains are primarily pharmacokinetic in nature.

Pharmacokinetic model of ascorbic acid in healthy male volunteers during depletion and repletion.

PURPOSE: To develop a new pharmacokinetic model for ascorbic acid (vitamin C) since no previously published model describes ascorbic acid absorption and disposition over a broad physiologic range of doses and plasma concentrations. METHODS: A new model was developed through exploratory simulations. The model was fitted to pharmacokinetic data obtained from seven healthy volunteers who underwent ascorbic acid depletion then gradual repletion. Concentrations of ascorbic acid were measured in plasma and urine. Final pharmacokinetic model parameter estimates were obtained using nonlinear regression analysis. RESULTS: The new model included saturable absorption, distribution and renal tubular reabsorption parameters. The model described ascorbic acid concentrations in plasma, cells, and urine during depletion and gradual repletion phases with a residual error less than 15%. CONCLUSIONS: The model was useful for obtaining a new understanding of the likely causes for the complex concentration-time profile observed during gradual repletion. At doses of 200 to 2500 mg per day, the plateau in pre-dose concentrations is largely due to apparent saturation of tissue uptake and less a function of oral bioavailability and renal excretion than previously thought.

Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance.

Determinants of the recommended dietary allowance (RDA) for vitamin C include the relationship between vitamin C dose and steady-state plasma concentration, bioavailability, urinary excretion, cell concentration, and potential adverse effects. Because current data are inadequate, an in-hospital depletion-repletion study was conducted. Seven healthy volunteers were hospitalized for 4-6 months and consumed a diet containing <5 mg of vitamin C daily. Steady-state plasma and tissue concentrations were determined at seven daily doses of vitamin C from 30 to 2500 mg. Vitamin C steady-state plasma concentrations as a function of dose displayed sigmoid kinetics. The steep portion of the curve occurred between the 30- and 100-mg daily dose, the current RDA of 60 mg daily was on the lower third of the curve, the first dose beyond the sigmoid portion of the curve was 200 mg daily, and complete plasma saturation occurred at 1000 mg daily. Neutrophils, monocytes, and lymphocytes saturated at 100 mg daily and contained concentrations at least 14-fold higher than plasma. Bioavailability was complete for 200 mg of vitamin C as a single dose. No vitamin C was excreted in urine of six of seven volunteers until the 100-mg dose. At single doses of 500 mg and higher, bioavailability declined and the absorbed amount was excreted. Oxalate and urate excretion were elevated at 1000 mg of vitamin C daily compared to lower doses. Based on these data and Institute of Medicine criteria, the current RDA of 60 mg daily should be increased to 200 mg daily, which can be obtained from fruits and vegetables. Safe doses of vitamin C are less than 1000 mg daily, and vitamin C daily doses above 400 mg have no evident value.