Cyclosporin A in Fat Emulsion Carriers: Experimental Studies on Pharmacokinetics and Tissue Distribution

Abstract: In the commercially available intravenous formulation of Cyclosporin A (Sandimmun®), polyoxyethylated castor oil (Cremophor®EL) is used as a solubilizing agent. We have recently reported that the acute nephrotoxic effect of this preparation was alleviated by replacing Cremophor®EL with a soybean oil-based fat emulsion in a rat model. To further explore the potential of fat emulsions as carriers for cyclosporin A, data on the in vivo pharmacokinetics and tissue distribution are required. In this study in pigs, the pharmacokinetics of soybean oil-cyclosporin A was compared to that of Sandimmun®. The two formulations seemed bioequivalent, as there were no significant differences in the systemic clearances, volumes of distribution or elimination half-lives. Moreover, the tissue distributions of soybean oil-cyclosporin A and Sandimmun® were compared in rats. These studies also included two additional lipid-based carriers: one based on iodized ester of poppy seed oil and the other on a liposomal preparation. The tissue distributions were found to be similar regardless of the carriers used. Fat emulsion carriers seem to offer possibilities for preparing better tolerated intravenous formulations of cyclosporin A while maintaining the same characteristics concerning pharmacokinetics and tissue distribution.     

Resurfacing difficult wounds: selective use of the posterior tibial flap

The posterior tibial flap is a type C fasciocutaneous flap from the medial calf with the posterior tibial vascular bundle as its pedicle. Most of the skin perforators, 1 to 3 in number, can be found in the middle third of the leg, with an average diameter of 0.8 mm and an average length of 22 mm. The posterior tibial artery ranges between 1.5 and 2.0 mm in diameter, although it is absent in 8 percent of limbs. Since the saphenous nerve is taken with the flap, this is an innervated flap. The flap can be transferred as a free flap or a pedicled flap. The reversed-flow pedicled flap has an average pedicle length of 8 cm. The posterior tibial flap is a reliable, large, thin, innervated flap and can be raised with the patient supine. Case reports are presented of six patients who received a free flap transfer and of one patient who received a reversed-flow pedicled flap. There were two cases of heel ulcerations, two crushed hands, one chronic ulceration and osteomyelitis of the tibia, one burn contracture of the neck, and one salvage flap for diabetic gangrene of the hand.     

Blood flow variation and energy metabolism in the gastric mucosa following 7．5％ hypertonic saline resuscitation

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Normothermic renal artery perfusion: A comparison of perfusates

Hypothermia and preservative perfusates have been used to decrease ischemic renal injury. This study was performed to identify the preservative function of perfusates independent of the effects of hypothermia. Rats underwent 45 minutes of renal ischemia. Rectal and renal parenchyma temperatures were monitored and maintained within 1° C of normal. Perfusates were University of Wisconsin solution (UW), Euro-Collins solution, normal saline solution, and Ringer's lactate solution. A nonperfused ischemic control and a nonischemic control group were also evaluated. Parameters evaluated included serum creatinine and blood urea nitrogen levels, renal ischemic injury grade, renal weight, and gross appearance of the injured kidney. Rats treated with UW solution were found to have a significantly lower creatinine, blood urea nitrogen, and injury grade than the other three perfused groups. The external gross appearance of the UW-treated kidneys was normal, whereas that of the other groups demonstrated moderate to severe injury. Although the mean right/left renal weight difference of the UW-treated group was lower than that of the other three groups, this was not statistically significant. Under normothermic conditions in rats, UW solution affords significant renal protection from ischemia. Euro-Collins, normal saline, and Ringer's lactate solutions display no significant protective effect.Presented at the Twentieth Annual Meeting of the Peripheral Vascular Surgery Society, New Orleans, La., June 10, 1995.     

A comparison of arterial and venous flaps.

The survival rate and elastic properties of the anterior abdominal skin flap in Sprague-Dawley rats were studied in three groups of animals. In group 1 where the flaps were supplied by a normal artery, arterial flaps (1A) had better survival rate and elastic properties than venous flaps (1B). In group 2, where the flaps were supplied by an artery with diminished perfusion pressure, the arterial flaps (2A) still had slightly better results than venous flaps (2B). However, in group 3 where the flaps were supplied by a vein, venous flaps (3B) had better results than arterial flaps (3A).     

Effects of Nitrite Exposure on Acid–Base Balance, Respiratory Protein, and Ion Concentrations of Giant Freshwater Prawn Macrobrachium rosenbergii at Low pH

Macrobrachium rosenbergii that had been exposed individually for 24 h to 0 (control), 2, 5, 10 mg/L nitrite-N (nitrite as nitrogen) at 4.3 and 7.7 pH levels were examined for hemolymph nitrite-N, oxyhemocyanin, protein, acid–base balance, ion concentrations, and ammonia-N (ammonia as nitrogen) excretion. Hemolymph oxyhemocyanin, protein, pH, HCO₃ ⁻ , TCO₂, osmolality, and ion concentrations were inversely related to ambient nitrite-N concentration and were lower at pH 4.3. However, hemolymph nitrite-N, PO₂ and PCO₂ levels, and ammonia-N excretion were directly related to ambient nitrite-N, and were higher at pH 4.3. Ambient nitrite-N and pH level interacted to cause changes in hemolymph nitrite-N, oxyhemocyanin, protein, PO₂, and pH levels. It is concluded that for M. rosenbergii following nitrite exposure, the incorporated nitrite causes a decrease of pH and an increase of PO₂ in the hemolymph where it reduces oxyhemocyanin level; disturbs nitrogen excretion, ion regulation, and respiratory gas exchange; and may lead to a decrease of oxygen-carrying capacity, which are affected more at low pH. Received: 31 August 1996/Accepted: 9 July 1997     

Fluorescence polarization immunoassay and HPLC assays compared for measuring monoethylglycinexylidide in liver-transplant patients.

We compared fluorescence polarization immunoassay (FPIA, x) and HPLC (y) for measuring monoethylglycinexylidide (MEGX) concentrations in 119 serum samples from 61 liver-transplant donors and recipients. The correlation between the two methods was y = 1.48 micrograms/L + 0.8x (r = 0.89). The bias (mean difference) was 12 micrograms/L (0.055 mumol/L) through the MEGX concentration range measured (0-250 micrograms/L, 0-1.136 mumol/L). We observed a major difference between the two methods in samples from four recipients and one donor. Cross-reactivity in FPIA with lignocaine and two of its metabolites (glycinexylidide and 2,6-xylidine) was < 3%. Samples with high bilirubin concentrations (> 200 mumol/L) required dilution before assay of MEGX by FPIA. Although there was an increase in apparent MEGX concentrations in some samples with increased bilirubin concentrations, the relationship was not constant. Increased plasma concentrations of cholesterol and triglyceride resulted in relatively small increases in apparent MEGX concentrations.     

Different effects of intracellular and extracellular TEA on voltage-dependent K currents of acutely isolated hippocampal CA1 neurons.

Tetraethylammonium (TEA) effects on K currents were examined on either side of the membrane of hippocampal CA1 neurons by means of whole-cell voltage-clamp recording and intracellular perfusion. Recording media contained ion channel blockers to allow the selective activation of voltage-dependent K currents which consisted of a rapidly decaying component (A-current) and a delayed component. Voltage protocols were applied to separate the A-current from the delayed component. Results show that 10 mM extracellular TEA suppressed 50 +/- 11% (S.D., n = 4) of the delayed current at different levels of depolarization but had little effect on the A-current. In contrast 10 mM TEA applied by intracellular perfusion suppressed the A-current by 42 +/- 10% (S.D., n = 4) in addition to inhibiting the delayed currently 55 +/- 15% (S.D., n = 4). Both the intracellular and extracellular actions of TEA on K currents showed no voltage- nor time-dependency. The results suggest that voltage-dependent transient current (A-current) is mediated through a separate group of ionic channels distinct from those that sustained the delayed current. Furthermore, the asymmetrical effects of intracellular and extracellular TEA on the transient current are similar to those described for the A-current in molluscan neurons. This observation supports the notion that the structure of the ion channel mediating the A-current is closely conserved across different species.