The levels of vancomycin in the blood and the wound after the local treatment of bone and soft-tissue infection with antibiotic-loaded calcium sulphate as carrier material.

AIMS: Calcium sulphate (CaSO4) is a resorbable material that can be used simultaneously as filler of a dead space and as a carrier for the local application of antibiotics. Our aim was to describe the systemic exposure and the wound fluid concentrations of vancomycin in patients treated with vancomycin-loaded CaSO4 as an adjunct to the routine therapy of bone and joint infections. PATIENTS AND METHODS: A total of 680 post-operative blood and 233 wound fluid samples were available for analysis from 94 implantations performed in 87 patients for various infective indications. Up to 6 g of vancomycin were used. Non-compartmental pharmacokinetic analysis was performed on the data from 37 patients treated for an infection of the hip. RESULTS: The overall systemic exposure remained within a safe range, even in patients with post-operative renal failure, none requiring removal of the pellets. Local concentrations were approximately ten times higher than with polymethylmethacrylate (PMMA) as a carrier, but remained below reported cell toxicity thresholds. Decreasing concentrations in wound fluid were observed over several weeks, but remained above the common minimum inhibitory concentrations for Staphylococcus up to three months post-operatively. CONCLUSION: This study provides the first pharmacokinetic description of the local application of vancomycin with CaSO4 as a carrier, documenting slow release, systemic safety and a release profile far more interesting than from PMMA. In particular, considering in vitro data, concentrations of vancomycin active against staphylococcal biofilm were seen for several weeks. Cite this article: Bone Joint J 2017;99-B:1537-44.

Determination of trace lithium in human erythrocytes by electrothermal atomic-absorption spectrometry with pyrocoated graphite tubes and integrated platform.

Electrothermal graphite-furnace atomic-absorption spectroscopy with pyrocoated graphite tubes, integrated platform and matrix modification was used to determine submicromolar concentrations of trace lithium in human red blood cells. Matrix-matched samples were used to establish calibration curves for concentrations up to 0.58 microM (addition-calibration method) with satisfactory linearity (r2 > 0.99) and intra- and inter-day variability (CV < 11.4%). The median concentration of trace lithium in the cells of 40 healthy Caucasian volunteers devoid of medical or psychiatric history was 0.23 microM (inter-quartile range 0.20-0.30). The levels of trace lithium in the red blood cells correlated (r2 = 0.83) with plasma concentrations (median 0.13 microM, inter-quartile range 0.11-0.19) measured in the same blood sample. Dietary factors (e.g. consumption of lithium-containing mineral water) affected both levels. The red blood cell/plasma lithium ratio had a median value of 1.57 (inter-quartile range 1.16-2.07), implying that trace lithium is accumulated in erythrocytes. This contrasts with most reports of red blood cell/plasma ratio, measured during therapeutic treatment with lithium, for which the average value is 0.5-0.8, albeit for much higher concentrations of lithium (approx. 500-800 microM). The proposed analytical method has the required sensitivity and accuracy for determination of trace lithium in red blood cells and makes it possible to perform epidemiological studies to assess human exposure to environmental lithium in diet and beverages, and inter-individual variations in trans-membrane and renal lithium kinetics at the submicromolar level.

Determination of trace lithium in biological fluids using graphite furnace atomic absorption spectrophotometry: variability of urine matrices circumvented by cation exchange solid phase extraction.

A graphite furnace atomic absorption spectrometry method has been developed for the quantitative determination of submicromolar endogenous concentration of lithium in human plasma and urine using pyrolitically-coated graphite tubes in combination with ammonium nitrate matrix modification. This latter treatment could not completely abolish the interferences caused by the matrix, notably in urine samples. The variability of the urinary matrices required an additional standardization procedure by solid-phase extraction on strongly acidic cation exchange cartridges. Matrix-matched samples were used for the establishment of calibration curves with the addition-calibration method. Calibration curves were linear up to 0.72 mumol/l (1.0 > r2 > 0.99). The described method enables accurate measurements of trace-lithium in biological samples at concentrations down to 0.03 mumol/l with intra- and inter-day variabilities < 10%. The method was applied to the determination of trace-lithium levels in urine and plasma samples from healthy individuals enabling the calculation of its fractional excretion (FeLi) (median range 17.3%), a value which reflects the functional capacity of the kidney to reabsorb sodium and water at the proximal tubular portion of the nephron. This sensitive method can thus be used as an investigative and diagnostic tool in various renal pathophysiological conditions, in clinical research, and may also be applied to studies on the trace-lithium status of population in connection with psycho-affective disorders.

Whole-blood pharmacokinetics and metabolic effects of the topical carbonic anhydrase inhibitor dorzolamide.

Following a single-dose, open-label, pilot pharmacokinetic study in six subjects, the systemic pharmacokinetics and metabolic effects of dorzolamide after topical ocular administration were investigated in a double-blind, randomised, placebo-controlled study in 12 healthy volunteers. The subjects received a controlled diet on the 5 days before treatment initiation and throughout the study. For 14 days, a bilateral q.i.d. regimen of 3% dorzolamide, consisting of approximately 7.7 micrograms per day (21.3 mumol) dorzolamide hydrochloride, or placebo was given. Blood and urine electrolytes and acid-base profiles were measured 1 day prior to treatment and on days 1, 7 and 14 of treatment, and 24-h urine samples were collected daily. Topically applied dorzolamide was slowly taken up in erythrocytes and eliminated with a half life of approximately 120 days. Compared to the pre-study values, no significant treatment effect was observed in either the daily profiles or the 14-day cumulative sodium, potassium and citrate excretions. Two other volunteers given acetazolamide (125 mg q.i.d.) and assessed with the identical set of observations demonstrated marked metabolic changes. In spite of the prolonged and marked inhibition of carbonic anhydrase in red blood cells by dorzolamide, clinically significant metabolic and renal effects were not observed. The ocular tolerability profile was acceptable to all subjects.

Renal sodium handling in patients with untreated hypertension and white coat hypertension.

Renal tubular sodium handling was investigated prospectively in 48 normotensive subjects, 53 untreated hypertensive patients, and 13 patients with white coat hypertension using endogenous trace lithium as a marker of proximal sodium reabsorption. A 12-hour daytime ambulatory blood pressure recording was performed in all patients to confirm the diagnosis of hypertension. Patients were included in the white coat hypertension group if their office blood pressure was above 160/90 mm Hg but the mean value of their 12-hour ambulatory recording was lower than 140/90 mm Hg. All participants were studied on their normal diet and ate salt freely. Fractional excretions of sodium (FENa), lithium (FELi), and potassium (FEK) were measured simultaneously before blood pressure recording. FENa was significantly higher in hypertensive patients (0.84 +/- 0.05%, P < .05) than in normotensive control subjects (0.60 +/- 0.06%), and FELi was comparable in the two groups (15.4 +/- 0.65% in hypertensive patients and 17.0 +/- 0.9% in control subjects). However, the relation between FENa and FELi was significantly different in normotensive subjects and hypertensive patients (P < .001), so that for a given increase in FENa a smaller increase in FELi was observed in hypertensive patients. In addition, the ratios of urinary lithium to sodium and urinary potassium to sodium were significantly reduced in hypertensive patients, suggesting an increased proximal reabsorption of sodium. Similar alterations in renal tubular sodium handling were observed in patients with white coat hypertension. These results suggest that an increased sodium reabsorption in the proximal tubule may contribute to the maintenance of hypertension and that white coat hypertension might represent a prehypertensive state.

Fractional excretion of trace lithium and uric acid in acute renal failure.

The early distinction between prerenal azotemia, characterized by an avid proximal tubular sodium reabsorption, and ATN, in which proximal tubule function is depressed, remains an important but difficult clinical task. Indices of acute renal failure based on urinary sodium excretion may be helpful but have several limitations, among which is the use of diuretics. The effectiveness of the fractional excretion of uric acid (FEUA) and that of endogenous lithium (FELi) in the diagnosis of acute renal failure has been evaluated in an unselected group of 46 patients, 28 with prerenal azotemia and 18 with ATN. In the entire group, FELi concurred with the clinical diagnosis in 78% of the patients, whereas the fractional excretion of sodium (FENa) and FEUA were in agreement in only 63 and 50%, respectively. FELi was more sensitive to identify hemodynamic renal failure, because 93% of prerenal failure patients had a low FELi, contrasting with a low FEUA in only 68% and a low FENa in 75%. The major reason for the discrepancy between FENa and FELi was the administration of diuretics. In both acute renal failure groups, FENa was higher in the subgroups receiving diuretics. In contrast, diuretic therapy had no effect on FELi in either group. These results suggest that FELi is more accurate than either FENa or FEUA for distinguishing prerenal azotemia from ATN. The superiority of FELi appears especially relevant in patients treated with the usual diuretics.