Studies on digitalis. 23. Blood‐brain barrier of digitoxin in humans

Abstract

Summary: Data on the cerebrospinal fluid concentrations of digitoxin in man have been lacking. Aim of the present study was to investigate serum and cerebrospinal fluid concentrations of digitoxin. Eleven patients with normal cerebrospinal fluid composition, normal serum albumin values, normal renal and hepatic function and normal hematologic tests were given a single dose of 0.6 mg digitoxin. Serum and cerebrospinal fluid were collected 16 h after the dose, and assayed by radio-immunoassay, serum digitoxin protein binding was measured with equilibrium dialysis.Mean serum digitoxin concentration was 12.4 ng/ml (SO 2.6) and mean CSF concentration 0.84 ngiml (SO 0.22) giving a CSF/serum ratio of 0.07 (SO 0.03). Serum digitoxin protein binding was 97.4% (SO 0.4) and the calculated CSF/free serum digitoxin ratio was thus 2.94 (SO 1.43).Free serum digitoxin concentrations are more relevant for pharmacologic effect than total serum digitoxin concentrations and also for passage into the central nervous system. Using free drug concentrations the ratio between digitoxin in serum and CSF is lower than reported values for digoxin indicating a higher penetrance of digitoxin into the central nervous system. This corresponds well with the higher lipid solubility of digitoxin. Post mortem studies have shown that concentrations are higher in cerebral tissue than in CSF for digoxin. Determination of CSF concentrations thus probably underestimates the penetrance of digitalis glycosides into the central nervous system, but may serve as a useful indicator of variance among digitalis glycosides.

Real-time analysis of the effects of toxic, therapeutic and sub-therapeutic concentrations of digitoxin on lung cancer cells

“…Digitoxin is a natural occurring cardiac glycoside (CG) (Elbaz et al, 2012a) with a prolonged half-life, a well-established clinical profile, a narrow therapeutic window (Elbaz et al, 2012a), and increased ability to readily cross both the blood brain and the placental barriers (Storstein et al, 1979). Laboratory investigations suggested that digitoxin exhibits high selectivity towards cancer cells when compared to healthy cells (Elbaz et al, 2012a; López-Lázaro et al, 2006) making the drug a viable chemotherapeutic alternative against several types of cancer from leukemia, to pancreatic and lung cancers (López-Lázaro, 2007; Winnicka et al, 2006).…”

A small-molecule lycorine derivative reveals Na+/K+-ATPase α3 as an anti-obesity target

“…2f & 2g ). Digitoxin and oleandrin are reported to be capable of going through blood-brain barrier, but there is no such information available for istaroxime 23,24 . If the brain-localized Na + /K + -ATPase α3 was responsible for the effects we observed above, it is reasonable to surmise that Na + /K + -ATPase inhibitors function as anti-obesity agents only when they can access to the brain.…”

A Novel Cardenolide Glycoside Isolated from Xysmalobium undulatum Reduces Levels of the Alzheimer’s Disease-Associated β-Amyloid Peptides Aβ42 In Vitro

“…More enthusiasm on glycosides can be drawn from the evidence that they could be pluripotent AD treatment agents; they have been reported to additionally inhibit acetylcholinesterase enzymes, which are well-established and characterized AD druggable targets [ 21 ]. Glycosides have the added advantage of being able to penetrate the blood–brain barrier (BBB) [ 22 , 23 ] (>98% of small molecules are not able to penetrate the BBB), a major stumbling block which retards development of AD therapeutics [ 24 ]. In fact, in some studies it has been demonstrated that glycosylation of some compounds has significantly improved their BBB penetration [ 25 , 26 ].…”