[In vivo distribution and pharmacokinetics of multiple effective components contained in Panax notoginseng saponins after intratympanic administration].

OBJECTIVE: To investigate in vivo distribution and pharmacokinetics of ginsenoside Rb1 (Rb1), ginsenoside Rg1 (Rg1 ) and sanchinoside R1 (R1) after intratympanic administration (IT) or intravenous administration (IV) of Panax notoginseng saponions (PNS) solution, and provide a novel route for delivering traditional Chinese medicine (TCM) to the brain. METHOD: The guinea pigs were employed as experimental animal. Perilymph (PL), cerebrospinal fluid (CSF), brain tissue and plasma were collected periodically after IT and IV of PNS solution. The concentrations of Rb1, Rg1 and R1 were measured by high performance liquid chromatography (HPLC), and statistic program DAS was applied to the calculation of pharmacokinetic parameters. The self-defined weighting coefficients based on area under curve (AUC) of each component were created to obtain the holistic pharmacokinetic profiles of PNS. The integrated pharmacokinetic parameters were then calculated from non-compartmental model analysis. RESULT: Rb1, Rg1 and R1 diffused through the round window membrane into PL of the inner ear, and then transported to the brain after IT of PNS solution. However, the pharmacokinetic parameters showed significant differences between the three components. Based on the self-defined AUC weighting coefficients integration approach, the holistic pharmacokinetic profiles of PNS were obtained, from which the integrated pharmacokinetic parameters were calculated. The C(max) in CSF and brain tissues following IT were respectively 1.5 and 0.4-fold higher than those following IV. After IT, the AUC in CSF and brain tissues increased by 0.5 and 1.2 times compared with IV. Furthermore, the C(max) and AUC in plasma following IT were respectively 45.9% and 33.1% lower than those following IV. CONCLUSION: This novel intra-cochlear administration might serve as a potential and promising alternative to TCM delivery with enhanced brain-targeted efficiency.

Plasma and cerebrospinal fluid endogenous digoxin-like immunoreactivity in patients with aneurysmal subarachnoid haemorrhage.

Recent evidence indicates the presence of naturally occurring digitalis-like compounds in mammals, collectively known as either digitalis-like (DLF) or ouabain-like (OLF) factors, presumed to be endogenous hormones regulating the biological activity of the NA+/ K(+)-ATPase and its isoforms. This substance has been postulated to enhance renal tubular sodium excretion and to increase peripheral vascular resistance. Digoxin-like immunoreactive substance (DLIS) was observed in plasma of some patients with spontaneous subarachnoid haemorrhage (SSAH). Accumulating evidence suggests the central nervous system as a site of synthesis, but also as a site of hypertensinogenic action of endogenous cardioglycosides. The present study intends to establish the ratio of the DLIS in plasma to that in cerebrospinal fluid (CSF) in patients with SSAH and to investigate possible connection of this substance with development of arterial vasospasm. A prospective analysis of DLIS levels was performed on plasma and CSF samples obtained in 40 patients who had suffered a recent SSAH. DLIS levels were determined by the fluorescence polarisation immuno-assay method immediately after the admission to the Ward, and again seven days later. The comparison of CSF and plasma DLIS levels did not show statistically significant differences between the results--neither for the first (Z = 0.530; P = 0.591) nor for the seventh day after the disease onset (Z = 0.448; P = 0.654). Three possible hypothetical explanations of these results are offered: a) substance determined by digoxin immuno-assay has no essential likeness to digoxin; b) loss of the haemato-encephalic barrier integrity enabling free substance exchange between plasma and central nervous system; c) digoxin-like substance production within the central nervous system. Further, comparison of DLIS plasma levels (7th day from onset of SSAH) with angiography results showed that patients with multiple vasospasm had essentially higher plasma DLIS levels compared to patients with no vasospasms (Z = 2.59; P = 0.0097). The amount of extravasated blood, assessed on the basis of cranial CT scanning, was also connected with higher plasma DLIS levels (X2 = 3.29; P = 0.0305). The enhanced arterial narrowing which occurs in SSAH may be in part mediated by increased digitalis-like factor activity.