RESUMO
In France, sickle cell disease (SCD) is the most common rare disease and represents the most prevalent genetic disorder, with 19,800 to 32,400 patients diagnosed in 2016 and 1:714 newborns affected in 2019. SCD is caused by a single mutation in the ß-globin gene, resulting in the production of abnormal hemoglobin (called HbS), chronic hemolytic anemia, and impaired red blood cell rheology. SCD patients face several severe acute and chronic complications, including stroke, acute chest syndrome (ACS), painful vaso-occlusive crisis (VOC), organ failure, and a high risk of infections. As patients' care pathway remains unclear in France, a roundtable advisory board meeting was organized in the country to provide insights into the management of SCD in alignment with clinical guidelines. The meeting brought together a panel of esteemed key opinion leaders (KOLs) in SCD management, encompassing both clinical practice and research. During the meeting, the KOLs discussed clinical practices and their alignment with French guidelines, identifying areas of concordance and discrepancy. They also addressed disparities in SCD clinical practices across regions and medical centers. The KOLs discussed the prophylactic and therapeutic options currently available for SCD patients in France, with a focus on transfusion therapies, especially automated red blood cell exchange (aRBCX). The results of this advisory board meeting provide a valuable platform for gathering expert perspectives on SCD management, clinical practices, guideline alignment, and the potential for contributions to guideline updates.
RESUMO
The effect of three monoclonal digoxin-specific antibodies on total and free digoxin plasma disposition was studied in rats in order to determine the role of affinity constant (Ka) and dose. Thirty minutes after digoxin infusion, administration of a stoichiometrical dose of the ICIO, 6C9 and 9F5 IgG (Ka = 6 10(9), 3.1 10(8) and 2.5 10(7) M-1, respectively) resulted in a plasma digoxin increase linearly related to Ka. The mean free plasma digoxin was 0.6 +/- 0.4, 7.8 +/- 3.3 and 43 +/- 22% respectively after 1C10, 6C9, and 9F5 IgG infusion in comparison to 70 +/- 9% in the control group. When the IgG:digoxin ratio increased from 1 to 5, plasma digoxin Cmax and AUCT also increased as a function of both affinity (Ka) and dose (N), but not linearly. The product of NKa defined an immunoreactivity factor that was well fitted to the digoxin redistribution parameters (Cmax and AUCT) by a Hill equation.
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Digoxina/sangue , Animais , Afinidade de Anticorpos , Especificidade de Anticorpos , Colchicina/imunologia , Digoxina/imunologia , Digoxina/farmacocinética , Relação Dose-Resposta a Droga , Imunoglobulina G/imunologia , Imunoglobulina G/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , TrítioRESUMO
The effect of non-absorbable fat substitutes (sucrose polyester (SPE) and tricarballylate triester (TCTE)) on the enterohepatic circulation of colchicine was studied in the rat. In a first experiment, emulsions of either sunflower oil (SFO), SPE, or TCTE, were introduced into the ligated small intestine and compared to a control group receiving physiological saline. All the groups received colchicine as an intravenous bolus. The plasma levels of colchicine in all groups was not affected, and luminal samples indicated that SPE and TCTE have no influence on the biliary excretion of colchicine (a previous experiment in bile duct-cannulated rats showed that SPE and TCTE, introduced by intragastric tube, have no effect on bile flow rate). In a second experiment, colchicine diluted in bile was mixed with saline or emulsions of either SFO, SPE or TCTE, and introduced into the ligated small intestine. The area under the curve and the maximal plasma concentration of colchicine were reduced when the drug was mixed with SPE or TCTE rather than saline (p < 0.0005). After 150 min, luminal samples were taken and showed significantly higher (p < 0.034) concentrations of colchicine in both SPE and TCTE groups compared to the saline group, indicating a significant inhibition of reabsorption of biliary colchicine. In conclusion, the non-absorbable fat substitutes, SPE and TCTE, did not influence biliary excretion of colchicine but reduced its reabsorption, thus altering its enterohepatic circulation.
Assuntos
Anticolesterolemiantes/farmacologia , Colchicina/farmacocinética , Proteínas Alimentares/farmacologia , Ácidos Graxos/farmacologia , Absorção Intestinal/efeitos dos fármacos , Sacarose/análogos & derivados , Ácidos Tricarboxílicos/farmacologia , Animais , Bile/fisiologia , Radioisótopos de Carbono , Interações Medicamentosas , Emulsões , Circulação Êntero-Hepática/efeitos dos fármacos , Circulação Êntero-Hepática/fisiologia , Substitutos da Gordura , Masculino , Polietilenoglicóis/farmacocinética , Ratos , Ratos Sprague-Dawley , Sacarose/farmacologiaRESUMO
The effect of non-absorbable fat substitutes (sucrose polyester (SPE) and tricarballylate triester (TCTE)) on cyclosporin A (CsA) intestinal absorption was studied in the rat using in situ perfusion and gastric intubation techniques. A first experiment using the recirculating intestinal perfusion model showed that emulsions of either 5% SPE or TCTE significantly reduced (p < 0.0008) CsA absorption, whereas no difference was found between results for saline and 5% olive oil emulsion. In single-pass intestinal perfusion experiments SPE dose-dependently inhibited CsA absorption at SPE concentrations of 0.31% (p < 0.0004) and higher. Using gastric intubation, whole blood CsA concentrations significantly decreased when administered with SPE and TCTE in comparison with olive oil (p < 0.04). These results confirm that the CsA fraction dissolved in the undigested oil phase, constituted by the undigested and nonabsorbed fat substitute, is unavailable for intestinal absorption.
Assuntos
Ciclosporina/farmacocinética , Gorduras Insaturadas na Dieta/farmacologia , Ésteres/farmacologia , Ácidos Graxos/farmacologia , Sacarose/análogos & derivados , Ácidos Tricarboxílicos/farmacologia , Animais , Ciclosporina/administração & dosagem , Ciclosporina/química , Absorção Intestinal/efeitos dos fármacos , Intubação Gastrointestinal , Masculino , Azeite de Oliva , Perfusão , Óleos de Plantas/química , Ratos , Ratos Sprague-Dawley , Solubilidade , Sacarose/farmacologiaRESUMO
The effect of non-absorbable fat substitutes (sucrose polyester (SPE) and tricarballylate triester (TCTE)) on [3H]digitoxin intestinal absorption was studied in the rat using a small intestine in-situ perfusion technique. The effect of SPE and TCTE was compared with that of sunflower oil, oleic acid, and saline. After 120 min perfusion, 5% SPE emulsion significantly reduced (P < 0.001) digitoxin absorption compared with all other treated groups. Five per cent TCTE emulsion had a less marked effect than SPE (P = 0.0002) and did not differ from sunflower oil. No difference was found between saline and 5% oleate emulsion, which did not reduce digitoxin absorption compared with other treated groups (P < 0.02). When taurocholic acid and lipase were added, results for the saline-, TCTE-, and SPE-treated groups were similar to those above, but the sunflower oil-treated group showed significantly enhanced (P < 0.01) digitoxin absorption. Thin-layer chromatography of the lipid phases showed hydrolysis of sunflower oil in the presence of taurocholic acid and lipase, but not of TCTE or SPE. The inhibitory effect of the non-absorbable fat substitutes on digitoxin absorption could be related to drug sequestration by the persistent oil phase constituted by the undigested and then unabsorbed fat substitutes. That part of digitoxin dissolved in the undigested oil phase is consequently unavailable for intestinal absorption.
Assuntos
Gorduras Insaturadas na Dieta/farmacologia , Proteínas Alimentares/farmacologia , Digitoxina/farmacocinética , Ácidos Graxos/farmacologia , Absorção Intestinal/efeitos dos fármacos , Sacarose/análogos & derivados , Ácidos Tricarboxílicos/farmacologia , Animais , Substitutos da Gordura , Masculino , Perfusão , Ratos , Ratos Sprague-Dawley , Sacarose/farmacologia , TrítioRESUMO
The disposition of colchicine-specific Fab fragments and the effect of Fab fragment administration on the disposition of colchicine were studied in anaesthetized bile duct-cannulated rats. One group of rats (n = 6) received a 125I-Fab dose of 38 mg kg-1 i.v. The plasma disposition was characterized by a volume of distribution of 179 +/- 48 mL kg-1, total body clearance of 1.02 +/- 0.07 mL min-1 kg-1, t1/2 alpha of 0.17 +/- 0.03 h and t1/2 beta of 1.3 +/- 0.3 h. Fab fragments were in part excreted by the renal route (15.6 +/- 6% of the Fab dose), while biliary excretion was a minor route (< 2% of the Fab dose). Two other groups of rats received 15 micrograms kg-1 colchicine (n = 6) or 15 micrograms kg-1 colchicine plus 38 mg kg-1 colchicine-specific Fab fragments (n = 6) by intravenous infusion. Pharmacokinetics of colchicine was markedly altered in the Fab-colchicine-treated rats. In this group, distribution volume and total body clearance of colchicine were decreased by factors of 22 and 10, respectively, compared with the values in the colchicine-treated group and were very similar to those of Fab fragments. An 80% reduction of cumulative biliary excretion of colchicine was observed in Fab-colchicine-treated rats (P < 0.01). The fraction of colchicine dose excreted by the urinary route was 38 +/- 6.9 and 9 +/- 0.7% respectively in Fab-colchicine- and colchicine-treated groups (P < 0.01). These data show that during Fab treatment, colchicine followed the elimination kinetics of Fab fragments.(ABSTRACT TRUNCATED AT 250 WORDS)