Pharmacokinetics and anaesthetic effects of propofol‐PM: a novel water soluble propofol formulation
Notice bibliographique
Résumé
We have investigated the use of amphiphilic diblock copolymers of poly (N-vinyl-2-pyrrolidone) and poly-(d,l-lactide), PVP-PLA, to dissolve propofol inside micelles (30–60 nm) – Propofol-PM. We compared the pharmacokinetics (PK) of propofol in blood and plasma when administered as 1% Diprivan and as three 1% solutions reconstituted from Propofol-PM 7, 10 and 12% respectively. We also undertook a preliminary pharmacodynamic (PD) study. Forty male Sprague–Dawley rats (325 ± 10 g) were randomly allocated to one of eight groups (five rats/group). Ten rats were used for each of the four propofol formulations: five rats for the collection of whole blood and five for plasma. The rats were anaesthetised with isoflurane and both jugular veins exposed. Isoflurane was then discontinued. When the animals responded to a hind paw pinch, they received propofol 10 mg.kg (1 ml.kg over 1 min) via the jugular vein. Blood samples were collected at 1, 3, 5, 7.5, 10, 15, 30, 60 and 75 min after injection. A PK model was constructed using nonmem software. Animal weight, sample matrix (blood or plasma) and propofol formulation (Diprivan, Propofol-PM 7, 10 and 12%) were evaluated as model covariates. In a separate small PD study, the times of the recovery endpoints (leg withdrawal, first movement, righting) were compared for the four propofol formulations. All experiments were conducted in accordance with guidelines from the Canadian Council on Animal Care and the Use of Laboratory Animals, and a certificate of conformity granted. The optimal PK model had two compartments and incorporated sample matrix and propofol formulation as dichotomous covariates (Fig. 1). Sample matrix was applied to all structural parameters. An influence of propofol formulation was observed for all structural model parameters (excluding distributional clearance) but only when plasma was used as the sample matrix. The effect of formulation was not apparent when whole blood concentrations of propofol were measured. The average model predicted profiles. Error bars show ± 1 SD. The whole blood PK of Propofol-PM did not differ from that observed with Diprivan. We observed lower propofol concentrations in plasma samples after Propofol-PM administration than after Diprivan but the quantity of the copolymer in the Propofol-PM formulations did not influence the PK. Although there was no statistically significant difference in any of the recovery endpoints, the number of animals in the PD study was small (n = 4–6 per formulation) and there was a high degree of variability. Hence, the PD study was likely underpowered to detect small differences and must be regarded as preliminary.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».