Granica sigurnosti za intravaskularna kontrastna sredstva: tjelesna težina, površina ili toksikokinetički pristup?

The margin of safety of a drug is defined as the ratio between toxicity in animals and safety in humans. For intravascular contrast media, the margin of safety is traditionally the ratio between LD50 and diagnostic dose, both doses being based on bodyweight. The shift to surface area dramatically reduces this margin to unacceptable values. Toxicokinetics, which relates systemic exposure associated with early toxic signs in animals to plasma level in man, seems the most accurate and predictive criterion.Granica sigurnosti lijeka određena je kao odnos između toksičnosti u životinja i sigurnosti za čovjeka. Za intravaskularna kontrastna sredstva granica sigurnosti je poznati odnos između LD50 vrijednosti i dijagnostičke doze, gdje su obje doze temeljene na tjelesnoj težini. Transformacija vrijednosti na površinu značajno smanjuje granicu sigurnosti do neprihvatljivih vrijednosti. Toksikokinetika, koja povezuje sistemsko izlaganje povezano sa ranim znakovima toksičnosti u životinja i s količinama u plazmi čovjeka, čini se, najtočniji je i najpredvidljiviji kriterij

Potent trophic activity of spermidine supramolecular complexes in in vitro models

AIM: To test the growth-promoting activity of the polyamine spermidine bound to various polymeric compounds in supramolecular complexes. METHODS: A thiazolyl blue cell viability assay was used to determine the growth-promoting potency of spermidine-supramolecular complexes in a human skin fibroblast cell line exposed to spermidine and different spermidine-supramolecular complexes that were obtained by combining spermidine and polyanionic polymers or cyclodextrin. Reconstituted human vaginal epithelium was exposed to a specific spermidine-supramolecular complex, i.e., spermidine-hyaluronan (HA) 50, and cell proliferation was determined by Ki-67 immunohistochemical detection. Transepithelial electrical resistance and histological analysis were also performed on reconstituted human vaginal epithelium to assess tissue integrity. RESULTS: The effect of spermidine and spermidine-supramolecular complexes was first tested in skin fibroblasts. Spermidine displayed a reverse dose-related mode of activity with mmol/L growth inhibition, whereas 30% stimulation over basal levels was detected at μmol/L and nmol/L levels. Novel spermidine-supramolecular complexes that formed between spermidine and polyanionic polymers, such as HA, alginate, and polymaleate, were then tested at variable spermidine concentrations and a fixed polymer level (0.1% w/v). Spermidine-supramolecular complexes stimulated the cell growth rate throughout the entire concentration range with maximal potency (up to 80%) at sub-μmol/L levels. Similar results were obtained with spermidine-(α-cyclodextrin), another type of spermidine-supramolecular complex. Moreover, the increased expression of Ki-67 in the reconstituted human vaginal epithelium exposed to spermidine-HA 50 showed that the mode of action behind the spermidine-supramolecular complexes was increased cell proliferation. Functional and morphological assessments of reconstituted human vaginal epithelium integrity did not show significant alterations after exposure to spermidine-HA, thus supporting its safety. CONCLUSION: Spermidine found in spermidine-supramolecular complexes displayed potentiated regenerative effects. Safety data on reconstituted human vaginal epithelium suggested that assessing spermidine-supramolecular complex efficacy in atrophic disorders is justified

Is administration of gadolinium‐based contrast media to pregnant women and small children justified?

The use of gadolinium‐based contrast media in pregnant or lactating women has been discouraged at many radiology departments due to the lack of knowledge of the risks for the fetus and the unwillingness to expose neonates to unnecessary drugs. In the present review the current literature and present guidelines regarding the use of gadolinium‐based contrast media have been reviewed to validate the justification for their administration to pregnant or lactating women and small children. J. Magn. Reson. Imaging 2011;. © 2011 Wiley‐Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86793/1/22413_ftp.pd

Tossicità nell'animale e sicurezza nell'uomo

Fino ai primi anni '80, le indagini epidemiologiche condotte sulle reazioni avverse ai mezzi di contrasto iodurati uroangiografici iniettati per via endovenosa, non erano riuscite a stabilire una correlazione significativa fra l'incidenza delle reazioni e il tipo e/o la dose del composto somministrato. Di conseguenza si era ritenuto che nello scatenamento delle reazioni avverse sistemiche il ruolo delle caratteristiche farmaco-tossicologiche delle diverse molecole iodurate fosse trascurabile rispetto ai fattori di rischio individuali. Studi più recenti hanno tuttavia messo in luce che con i composti non-ionici il rischio di reazioni avverse gravi è circa sei volte inferiore al rischio che si ha con i composti ionici. Questi risultati clinici confermano i dati derivati da studi sugli animali, che hanno evidenziato come i composti non-ionici abbiano un margine di sicurezza da due a tre volte superiore rispetto agli ionici. Alla luce di questi dati è stato riesaminato il valore predittivo degli studi preclinici per la sicurezza dell'impiego clinico dei mezzi di contrasto iodurati. Appare in questo senso utile un approccio «interspecies scaling», possibile grazie al fatto che il comportamento farmacocinetico di questi composti è ormai ben conosciuto ed estremamente semplice sia nell'uomo che nell'animale. </jats:p