Dexamethasone significantly attenuates sub-arachnoid hemorrhage-induced elevation in cerebrospinal fluid citrulline and leukocytes.

AIM: Cerebral vasospasm is a leading cause of death and disability following aneurysmal subarachnoid hemorrhage (SAH). Nitric oxide (NO) is a potent mediator of vasodilation, and citrulline is a known contributor to NO production. The leukocytosis inflammatory response can increase vasoconstrictive compounds that may also contribute to vasospasm. Dexamethasone is a glucocorticosteroid commonly administered after SAH, which may alter the production of leukocytes and citrulline. The goal of this project was to study the effects of dexamethasone on leukocytosis, citrulline, and angiographic vasospasm. METHODS: Experimental SAH was induced in 18 New Zealand white rabbits. Intravenous dexamethasone was administered to one group (N.=9) at 2 mg/kg/day. A placebo group (N.=9) was given a saline infusion with otherwise identical procedures. CSF citrulline, leukocytes, protein, and glucose, as well as plasma citrulline were measured at baseline and 3 days post-SAH in a blinded fashion. Basilar artery angiography was performed at baseline and repeated 3 days post-SAH. RESULTS: The change in CSF citrulline from day 0 to day 3 was significantly lower in the dexamethasone group compared to controls (P=0.002). The change in CSF white blood cells was also significantly lower (P=0.005). There was no significant change in plasma citrulline levels or angiographic vasospasm. CONCLUSION: Dexamethasone significantly decreases CSF citrulline and CSF leukocytosis after experimental SAH. It is possible this could lead to a relative vasoconstriction and vasodilation, respectively. These processes could cancel-out opposing effects of dexamethasone on cerebral vasospasm, partially contributing to the recognized, multifactorial, inconsistent effects of glucocorticoids on vasospasm.

Contribution of differences in plasma binding of propranolol to ethnic differences in sensitivity. Comparison between Chinese and Caucasians.

Chinese are more sensitive to the beta-blocking and hypotensive effects of propranolol than Caucasians. To determine the contribution of ethnic differences in the plasma binding of propranolol to the differences in sensitivity, 8 Caucasians (22.8 +/- 1.5 yr) and 8 Chinese (31.8 +/- 2.1 yr) were studied following single doses of 0, 10, 20, 40 and 80 mg propranolol orally. The binding of propranolol in plasma was determined by equilibrium dialysis after addition of 300 mg racemic propranolol to the plasma. The concentrations of free and bound (+) and (-)-propranolol were determined by stereospecific high performance liquid chromatography (HPLC). Dosage had no influence on the plasma binding of either enantiomer. The unbound fractions of both (-)-propranolol (16.06 +/- 0.79% vs 12.41 +/- 0.93%, P < 0.05) and (+)-propranolol (17.73 +/- 0.81% vs 14.33 +/- 0.89%, P < 0.01) were greater in Chinese than Caucasians, respectively. In both groups, the ratio of unbound (-) to (+)-propranolol was less than 1 (P < 0.01) and was greater in Chinese (0.91 +/- 0.01 vs 0.88 +/- 0.01) (P < 0.01), implying that in Chinese less isomers of both types were bound and there was a greater unbound proportion of the pharmacologically active (-)-propranolol which may contribute to their increased sensitivity to propranolol. It is demonstrated that ethnic differences in stereoselective protein binding may be an important variable in interindividual determinants of drug response.

Simultaneous determination of codeine and its seven metabolites in plasma and urine by high-performance liquid chromatography with ultraviolet and electrochemical detection.

A sensitive and selective high-performance liquid chromatography method has been developed for the measurement of codeine and its seven metabolites, norcodeine, morphine, normorphine, codeine-6-glucuronide, morphine-6-glucuronide, morphine-3-glucuronide and norcodeine glucuronide, in plasma and urine. The compounds were recovered from plasma and urine using solid-phase extraction with C18 cartridges and separated on a reversed-phase C8 column with a mobile phase consisting of 77% buffer (5 mM sodium phosphate monobasic and 0.70 mM sodium dodecyl sulfate, pH 2.35) and 23% acetonitrile. Codeine, norcodeine, codeine-6-glucuronide, norcodeine glucuronide and morphine-3-glucuronide were detected by ultraviolet detection at 214 nm, with a detection limit of 0.02 nmol/ml for each compound in plasma. Morphine-6-glucuronide, normorphine and morphine were monitored by electrochemical detection at 350 mV, with a detection limit of 0.003 nmol/ml for each compound in plasma. The assay showed good reproducibility and accuracy using external standardization. The recovery and inter-day variation for all compounds in plasma samples were 63.40-77.90% and 3.49-16.77% (R.S.D.) and while in urine were 64.98-90.13% and 2.93-9.96% (R.S.D.), respectively.