Soichi Itoh

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 absorption of ondansetron in rats: an alternative route of drug delivery

Purpose: Ondansetron (OND) is a 5-HT3 receptor antagonist that is used therapeutically for the prevention of nausea and vomiting associated with emetogenic cancer therapy. There is a need for nasal drug delivery in specific patient populations where the use of commercially available intravenous and oral dosage forms may be inconvenient and/or unfeasible. Methods: OND (Zofran Injection, 2 mg/ml) was administered at a dose of 1 mg/kg to male Sprague-Dawley rats intravenously or intranasally (n = 3 in each group). A special surgical procedure was performed to ensure that the drug solution was held in the nasal cavity. OND was injected into the femoral vein for the intravenous group. Blood samples were collected at appropriate times for 60 min. An HPLC method was employed to determine OND in the plasma. Results: The results clearly showed that OND was readily and rapidly absorbed through the nasal mucosa of the rat. The peak plasma level was attained within 10 min. OND was also completely absorbed as the plasma concentration-time profiles for the two routes were comparable. The terminal elimination half-lives were also similar. Conclusions: The nasal administration route for OND is apparently as effective as the intravenous route. If one considers the limitations of delivering OND orally or intravenously to patients undergoing emetogenic cancer therapy, it becomes obvious that the intranasal route is a potential alternative modality to prevent nausea and vomiting associated with such therapy.

Effects of osemozotan, ritanserin and azasetron on cocaine-induced behavioral sensitization in mice

Repeated intermittent administration of psychostimulants causes behavioral sensitization in rodents. Previous studies using serotonin (5-HT) receptor ligands show that the 5-HT system is involved in cocaine-induced behavioral sensitization in rats, but the role of the 5-HT system has not been studied in mice. The present study examined the effects of the 5-HT(1A) receptor agonist osemozotan, the 5-HT(2) receptor antagonist ritanserin and the 5-HT(3) receptor antagonist azasetron on cocaine-induced behavioral sensitization in male ddY mice. Repeated administration of cocaine for 7 days enhanced cocaine-induced locomotor activity, and this sensitization was observed even after withdrawal for 7-14 days. Cocaine-induced behavioral sensitization after a 7-day withdrawal was significantly reduced with the coadministration of osemozotan, ritanserin or azasetron with cocaine repeatedly for 7 days. A single injection of osemozotan or ritanserin before cocaine challenge also reduced repeated cocaine-induced behavioral sensitization. However, none of these ligands inhibited cocaine-induced behavioral sensitization, when each drug was administered for 7 days after repeated cocaine administration. These results suggest that the central 5-HT system plays a role in the development and expression, but not maintenance, of behavioral sensitization in cocaine-treated mice.

Pharmacokinetic and Pharmacodynamic Interactions between Furosemide and Hydrochlorothiazide in Nephrotic Patients

We examined the response of 8 patients with nephrotic syndrome (creatinine clearance 70.4 +/- 16.0 ml/min) to oral furosemide (F; 40 mg) in the absence (control) and in the presence of oral hydrochlorothiazide (HCT; 100 mg). In the 24-hour period after oral F, HCT was shown to increase urine volume and urinary sodium and chloride excretion. Increment was most significant during the 12- to 24-hour period. Enhancement of the diuresis with HCT was associated neither with a significant increase in the area under the curve of plasma F concentration nor an increase in urinary F excretion. Urinary excretion of glucuronidated F, one of the main metabolites of F, however, was decreased with HCT. In summary, HCT significantly enhanced the response to F in nephrotic patients.

The effect of fatty acids on the rectal absorption of acyclovir in rats

Abstract— The enhancing effect of fatty acids on the rectal absorption of acyclovir has been evaluated in rats. Acyclovir proved to be absorbed to the extent of 3 to 9% after oral administration. After rectal administration in the absence of absorption‐promoter, the bioavailability of acyclovir was 37%. Its rectal administration with 4% sodium caprate resulted in enhanced bioavailability (81 ± 3%).

Intestinal absorption of atenolol in rat.

Intestinal absorption characteristics of atenolol (AT) were measured by the plasma concentrations after oral and small intestinal administrations and monitoring its disappearance from in situ intestinal loops in anesthetized rat. Relative AUC of AT after oral administration in rat was 24% as compared to AUC value of intravenous administration. However, relative AUC for small intestinal administration in the anesthetized rat was 76%. Following administration of AT into duodenal, jejunal and ileal loops, AUC calculated from blood levels was 705, 613, and 838μg·min/ml, respectively, and the order was consistent with the absorption rate.Disappearance rate constants were 3-0.5h-1. The result shows that there is no difference in absorption from each segment of intestine. Rat intestinal AT transport showed concentration dependency, especially up to 25μg/ml in the mucosal medium, in an experiment using in vitro everted rat intestinal sac prepared from duodenum, jejunum and ileum.

Release characteristics of indomethacin from commercial suppositories and its rectal absorption in rabbits.

The release rates of indomethacin from 5 kinds of commercially available suppositories were compared by using three different methods, i.e., dialysis cell, membrane diffusion, and cylindrical filter paper.The release from each fatty base by the method of membrane diffusion was about 30% for labeled amount after 120min, and that from each macrogol base was 23%.By dialysis cell method, indomethacin released from macrogol base was about 80% after 120min, whereas that from fatty base was 26-37%. The maximum plasma concentrations of indomethacin after rectal administration of both products A and B composed of macrogol base to rabbits was 31.8μg/ml, and those of products C, D, and E of fatty base were 21.4, 15.0, and 34.7μg/ml, respectively.The in vitro release rate was not concerned in the plasma concentration of indomethacin.It was found that the volume of suppository markedly influenced the rectal absorption, because correlation coefficient between the maximum plasma concentration of indomethacin and the volume of suppository was 0.932.

Release test of drug from rectal capsules by dialysis tubing method.

The release of indomethacin from 3 kinds of rectal capsules was investigated by 2 different dialysis tubing methods, i.e., stationary method and up-and-down motion method. In the case of stationary method, any release rate of indomethacin from rectal capsules was much slower than that from suppositories, and the amount of the release during 2 hrs was within 8% of the labeled amount. The release of the drug from rectal capsule was not improved by the addition of water into the dialysis tubing, or by sinking deeply the dialysis tubing to spread out the contents in rectal capsule. However, by the up-and-down motion of dialysis tubing using disintegration test apparatus, the release rate was 2-3 times higher than that by the stationary method.The data from this experimental condition was well reproducible. The technique could be applied to test the release of drug from both rectal capsule and suppository.