J.M. Scherrmann

Elimination of Paraquat

1 There is a striking discrepancy between the efficacy of the kidneys, haemodialysis and haemoperfusion in removing paraquat from the body and the poor prognosis of paraquat poisoning even when the blood and urine concentrations (which are good indices of concentrations in lung and other tissues) are very low. 2 Extracorporeal elimination techniques have been used world-wide in paraquat poisoning. Do they remove paraquat effectively? Certainly. Do they increase the survival rate? Probably not. The reason being that when these techniques of elimination are initiated, potentially lethal concentrations of paraquat have already been attained in the highly vascular tissues of vital organs and in pneumocytes. 3 The data presented here suggest that the successful treatment of paraquat poisoning will not be achieved by modification of toxicokinetics.

Colchicine disposition in human leukocytes after single and multiple oral administration

Inasmuch as leukocytes were reported to be an active pharmacologic compartment, colchicine disposition was determined in plasma, granulocytes, and mononuclear cells in healthy volunteers after 1 mg oral single and multiple doses. After the single dose, maximal colchicine concentration was observed at 1 hour in plasma and 47 hours later in leukocytes. This delay was confirmed by the slow accumulation of colchicine by lymphocytes in culture. In the multiple‐dose study, mean granulocyte colchicine concentration (20 to 53 ng/109 cells) were twofold higher than in mononuclear cells (9 to 24 ng/109 cells). Mean predicted colchicine multiple‐dose granulocyte and mononuclear cell concentrations were 2.5‐fold and ninefold higher, respectively, than those measured. After the last dose, colchicine decreased, with half‐life values between 41 and 46 hours for leukocytes and 49 hours for plasma. This study validates leukocytes as a microcompartment whose kinetics correlates with colchicine biologic effects.

Effects of mode of inhalation of carbon monoxide and of normobaric oxygen administration on carbon monoxide elimination from the blood

1 The half-life of carbon monoxide (CO) in blood was studied retrospectively in 26 fire victims and in 19 cases of CO poisoning. Normobaric oxygen therapy was administered via mechanical ventilation in 19 fire victims, and by facial mask to the rest of the casualties. 2 Arterial pH was significantly lower (P < 0.05) and PaO2 significantly greater (P<0.01) in the mechanically ventilated fire victims compared to the spontaneously breathing fire victims. 3 The blood CO half-lives were 91 ± 38 min for the 26 fire victims and 87±40 min for the 19 pure CO intoxica tions. 4 The blood CO half-lives were 92 ± 40 min for the 19 mechanically ventilated fire victims and 87 ± 37 min for the 26 spontaneously breathing subjects. 5 We conclude that the elimination of CO from blood was a slow process with no significant effects on the blood CO half-life of either the cause of the CO poisoning or the mode of normobaric oxygen therapy. These data suggest that enhancement of the elimination of carbon monoxide by normobaric oxygen in both pure CO poisoning and fire victims is more difficult to achieve and more complex than has previously been reported.

La colchicine : données récentes sur sa pharmacocinétique et sa pharmacologie clinique

Resume La colchicine est surtout prescrite dans le traitement de la crise de goutte mais son indication a ete etendue a dautres maladies inflammatoires, comme la maladie periodique. Deux proteines jouent un role majeur dans sa pharmacocinetique, la tubuline, recepteur intracellulaire specifique de la colchicine qui conditionne sa demi-vie delimination sanguine et la P-glycoproteine, pompe de detoxication cellulaire qui regule sa distribution tissulaire et son elimination biliaire et renale. Ladministration de colchicine repose sur des regles empiriques fondees sur un compromis entre efficacite et apparition des effets secondaires. Recemment, la determination de ses concentrations plasmatiques par radio-immunologie a permis de definir ses parametres pharmacocinetiques. Son absorption par voie orale est tres variable (de 24 a 88% de la dose administree), sa distribution est tres importante (7 l/kg) alors que la liaison a lalbumine est moderee; son elimination est principalement hepatique et sa demi-vie delimination varie de 20 a 40 heures. Lors de son administration reiteree, le niveau dequilibre est atteint en 8 jours avec des concentrations variant de 0,3 a 2,5 ng/ml pour des posologies de lordre de 1 mg/j. Letude des relations pharmacocinetiques-pharmacodynamiques montre que les effets de la colchicine ne sont pas correles aux concentrations plasmatiques mais a celles du compartiment intraleucocytaire. Lapparition deffets secondaires nest pas rare, notamment lorsquelle est associee a des medicaments capables dinteragir avec le cytochrome P450 et/ou la P-glycoproteine, provoquant alors une diminution de la clairance hepatique et/ou renale. Le suivi therapeutique de la colchicine lors de ces circonstances permettrait de prevenir lapparition de ces effets secondaires.

Applications of a blood-brain barrier technology platform to predict CNS penetration of various chemotherapeutic agents. 1. Anti-infective drugs.

Except for a few well-documented CNS therapeutics, quantitative data on blood-brain barrier (BBB) permeation is incomplete, unreliable or nonexistent and this is a major impediment in BBB modeling. Furthermore, only the passive diffusion component is generally taken into account. Three techniques of modeling (in vivo, in vitro and in silico) were set up and compared. The in silico predicted permeation of 287 anti-infective drugs has been faced to clinical observations. Good correlations were observed between in vitro permeability coefficients, influx transfer coefficients from in vivo studies and Pe scores from the computational model. High Pe score values are associated with an increase of reported CNS side effects.