Ashraf Traboulsi

Enhancement of the Systemic and CNS Specific Delivery of L-Dopa by the Nasal Administration of Its Water Soluble Prodrugs

AbstractPurpose. To study the utility of the nasal route for thesystemic delivery of L-dopa using water soluble prodrugs of L-dopa and toexamine if this delivery method will result in preferential delivery to theCNS. Methods. Several alkyl ester prodrugs of L-dopa wereprepared and their physicochemical properties were determined. Invitro hydrolysis rate constants in buffer, rat plasma, rat brainhomogenate, rat CSF, and rat nasal berfusate were determined by HPLC. Invivo nasal experiments were carried out in rats. Levels of L-dopa anddopamine in plasma, CSF, and olfactory bulb were determined using HPLCmethod with electrochemical detection. Results. All the prodrugs showed improved solubility andlipophilicity with relatively fast in vitro conversion in ratplasma. Absorption was fast following nasal delivery of the prodrugs withbioavailability around 90%. Dopamine plasma levels did not changesignificantly following nasal administration of the butyl ester prodrug.Olfactory bulb and CSF L-dopa concentration were higher following nasaldelivery of the butyl ester prodrug compared to an equivalent intravenousdose. Conclusions. Utilization of water soluble prodrugs ofL-dopa via the nasal route in the treatment of Parkinsons disease may havetherapeutic advantages such as improved bioavailability, decreased sideeffects, and potentially enhanced CNS delivery.

Nasal administration of albuterol: an alternative route of delivery

The use of metered‐dose inhalers for the delivery of albuterol, a β2‐selective adrenergic agonist, is associated with drawbacks, especially in children and the elderly. This investigation was designed to assess the effectiveness of albuterol delivered intranasally and to compare this delivery route with intratracheal and intravenous delivery. Three parameters of pulmonary function (peak maximal expiratory flow, maximal expiratory flow at 50% vital capacity, and total lung capacity) in anaesthetized, artificially ventilated guinea pigs were used to determine the degree of protection produced by albuterol against bronchoconstrictor responses provoked by acetylcholine. The heart rate was also measured. Although intranasal albuterol induced a slower protective action during the very initial phase of absorption, the drug was shown to be equally effective when administered either intranasally or intratracheally. In contrast, despite a significant effect initially in the case of intravenous albuterol, its ability to influence pulmonary function faded rather rapidly. No statistically significant differences in heart rate could be detected among the different treatment groups. In conclusion, intranasal albuterol may offer an alternative to metered‐dose inhalers for the treatment of acute bronchospasm and for prevention of exercise‐induced asthma, especially for children and the elderly.