Pharmacoscintigraphic and pharmacokinetic evaluation on healthy human volunteers of sustained-release floating minitablets containing levodopa and carbidopa.

In this study, scintigraphic and pharmacokinetic studies were conducted on 10 healthy, fed volunteers. Two concepts of sustained-release floating minitablets--Levo-Form 1 (matrix) and 2 (coated)--were evaluated and compared to the marketed product Prolopa HBS 125. All the floating forms were radiolabelled with (111)In in order to evaluate their gastric residence time using gamma-scintigraphy. It was shown that the three formulations offered almost the same mean gastric residence time, which was about 240 min. Prolopa HBS 125 and Levo-Form 2 presented intragastric disintegration, which can lead to a more pronounced "peak & valley" effect on the plasma concentration-time profile of levodopa. In contrast, the plasma concentration-time profile of levodopa following the administration of Levo-Form 1 was more evenly distributed. Moreover, Levo-Form 1 provided the lowest variations between men and women in terms of AUC and C(max) values. Finally, when the same amount of inhibitors of extracerebral dopa decarboxylase--carbidopa and benserazide--had been administrated, the mean AUC, C(max) and T(max) values obtained for benserazide were lower than those obtained for carbidopa.

Deposition of nacystelyn from a dry powder inhaler in healthy volunteers and cystic fibrosis patients.

The aim of this study was to compare, using gamma scintigraphy, the lung deposition of a novel mucoactive agent, Nacystelyn (NAL), administered as a dry powder inhaler (DPI) in six healthy volunteers, six adult patients with cystic fibrosis (CF), and six children and adolescents patients with CF. The correlation between in vitro and in vivo results was also tested. It was first demonstrated that the method of labeling of NAL with 99mTc was reliable as tested by three in vitro methods (multistage liquid impinger, multistage cascade impactor, and 2-stage glass impinger). The deposition of unlabeled NAL, labeled NAL, and the radiolabel was similar in all stages of each device. Furthermore, the fine particle fraction (FPF) was the same on all apparatuses. The mean lung deposition obtained in volunteers was 27.5 +/- 13.5%. The results are approximately three times higher than the results obtained previously in healthy volunteers with NAL metered-dose inhalers (MDIs). As expected, the lung deposition observed in patients with CF was lower, e.g., 23.5 +/- 7.0% for adults and 16.5 +/- 5.9% for children and adolescents. A significant correlation was found between lung deposition and both the patient weight (p < 0.02) and height (p < 0.04). Surprisingly, the peripheral:central (P:C) ratio was similar for the three populations, indicating that the presence of mucus in moderately ill patients with CF does not modify the lung distribution of NAL. The FPF measured in vitro was similar to that obtained in volunteers but higher than that found in both patient populations. The DPI formulation of NAL developed will probably improve patient compliance and comfort in future clinical trials and postmarketing use of the drug.

Scintigraphic visualization of intrathecal liposome biodistribution.

BACKGROUND: Liposomes containing local anaesthetics have been administered intrathecally and in the epidural space. Poor attention has been given to the pharmacokinetics of liposomes as drug carriers. Therefore, we observed the biodistribution of liposomes after intrathecal injection in rats by scintigraphic imaging during 24 h. METHODS: We administered 99mTc-labeled multilamellar (MLV) and small unilamellar vesicles (SUV) of defined size and volume dispersities into the cerebrospinal fluid at the lumbar level. Those vesicles were free of contamination by radiolabeled colloids as visualized by light and electron microscopy and of neurotoxic products from phosphatidylcholine hydrolysis and peroxidation, both during the preparation process and after 24 h incubation in cerebrospinal fluid at 37 degrees C in vitro. RESULTS: SUV immediately diffused from the lumbar site of injection to the head and were cleared between 1 and 24 h after injection. MLV were cleared more slowly from the spinal space and appeared in the head region 1 h after injection where they accumulated up to 24 h. These differences were explained in terms of vesicle sizes and volumes. SUV with 0.05 micron diameters were rapidly absorbed into the blood through the arachnoid granulations. In contrast, particles larger than the upper size limit of the arachnoid granulations permeability (+/- 8 microns) could accumulate in the head with a slow elimination rate. CONCLUSION: This difference in clearance from the intrathecal space outlines the importance of defining the size of the liposomes, the distribution of a tracer or a drug inside the liposomal preparation, the chemical stability and the absence of toxic degradation products of liposome formulations before clinical use.

Intragastric positioning of two concurrently ingested pharmaceutical matrix dosage forms.

A triple nuclide scintigraphic technique is presented for the precise and lasting intragastric monitoring in man of two concurrently ingested hydrophilic matrix pharmaceutical forms. After in vitro testing of various labels, ion exchange resin-coupled 201T1- and 111In-oxinate were selected for their release characteristics. 99mTc-pertechnetate oral solution was used to selectively delineate the stomach. This technique was validated on healthy volunteers. It allowed measurement of the effects on gastric residence time of galenic parameters (size, density of matrices), as well as of physiological parameters such as subject posture.

Disinfectants prepared in a hospital pharmacy--assessment of their microbiological purity and antimicrobial effectiveness.

The microbial contamination and antimicrobial effectiveness of seven topical disinfectants prepared at the hospital pharmacy were studied. These products were controlled throughout storage and use. The manufacturing routine investigated was able to deliver larger batch sizes and quality products that allowed increased storage time. The formulations chosen by the pharmacists were effective against bacteria for their intended uses. For chloramine only, loss of effectiveness required reduced storage time. No significant modification in the microbial quality of these products was observed during use in our hospital.

Modulation of inflammatory reactions by surgical trauma: lack of relationship with corticosteroid secretion.

The effect of surgery on inflammation was studied in male Wistar R/A rats using the carrageenin-induced edema model. Swelling of the paw was measured in standardized arbitrary units 2, 4, and 6 hr after a subcutaneous injection of carrageenin iota in the subplantar region of the right hind limb. It was significantly depressed in rats submitted to laparotomy (5.0 +/- 0.4, 8.0 +/- 1.0, 13.7 +/- 1.9) when compared with controls simply anesthetized with ether (6.2 +/- 0.5, 15.5 +/- 1.2, 23.7 +/- 0.6) (p less than 0.001 at 4 and 6 hr). This inhibition lasted for at least 24 hr and was also observed after amputation, although in these experiments, the difference between operated animals and controls was not significant. Alterations of the inflammatory cellular infiltrate were studied using polyurethane sponges soaked with carrageenin lambda implanted subcutaneously in control animals and rats undergoing laparotomy or amputation. The total number of cells recovered from these sponges 5 hr after implantation was smaller in operated rats (2.9 +/- 0.4 x 10(6) cells after laparotomy, 3.1 +/- 1.0 x 10(6) cells after amputation) when compared with controls (11.1 +/- 1.9 x 10(6) cells and 10.3 +/- 1.3 x 10(6) cells) (p less than 0.001 for laparotomy and p less than 0.005 for amputation). The inhibitory effect of operative trauma was not abolished by bilateral adrenalectomy performed 12 days before laparotomy. In rats, surgical trauma induces a depression of remote inflammatory reactions. This phenomenon is not related to increased corticosterone levels.