Drug absorption in vitro model: filter-immobilized artificial membranes. 2. Studies of the permeability properties of lactones in Piper methysticum Forst.

The assessment of transport properties of 23 drug and natural product molecules was made using the in vitro model based on filter-immobilized artificial membranes (filter-IAM), assembled from phosphatidylcholine in dodecane, in buffer solutions at pH 7.4. Five of the compounds were lactones extracted from the roots of the kava-kava plant. Experiments were designed to test the effects of stirring (0-600 rpm) during assays and the effects of varying the assay times (2-15 h). The highly mobile kava lactones permeated in the order dihydromethisticin (40)>yangonin (37)>kavain (34)>methisticin (32)>desmethoxyyangonin (26), the numbers in parentheses being the measured effective permeabilities in units of 10(-6) cm/s. By comparison, commercial drugs ranked: phenazopyridine (35)>testosterone (19)>propranolol (13)>ketoconazole (6.3)>piroxicam (2.2)>caffeine (1.7)>metoprolol (0.8)>terbutaline (0.01). In addition to permeability measurements, membrane retention of compounds was determined. Yangonin, desmethoxyyangonin, ketoconazole, and phenazopyridine were more than 60% retained by the artificial membranes containing phospholipids. Stirring during assay significantly increased the observed permeabilities for highly mobile molecules, but had minimal impact on the poorly permeable molecules. The influence of hydrogen bonding was explored by determining permeabilities using filters coated with dodecane free of phospholipids. In the filter-IAM method, concentrations were determined by microtitre plate UV spectrophotometry and by LC-MS. Higher-throughput was achieved with direct UV by the use of 96-well microtitre plate formats and with LC-MS by the use of cassette dosing (five-in-one).

Anxiolytic properties of botanical extracts in the chick social separation-stress procedure.

RATIONALE: The recent growth in sales of natural products labeled as dietary supplements in the United States has renewed scientific interest in the study of the therapeutic effects of multi-component botanical products. OBJECTIVES: This study sought to determine whether botanical extracts derived from the Rutaceae family, Acori graminei, the Magnoliaceae family, Alchemilla vulgaris and Primula veris, which had previously been identified in bioassays as having potential anxiolytic activity, were active in the chick social separation-stress procedure. METHODS: Eight-day-old chicks received IP injections of test articles 30 min before being tested in the presence of two social companions or in isolation for a 3-min observation period. Dependent measures were: a) latency to adopt a ventral recumbent posture to index sedation, b) number of vocalizations to index separation-distress and c) a composite pain score (comprised of footlift frequency and footlift duration in response to 50 microl of 0.10% formalin injected into the plantar surface of the foot) to index stress-induced analgesia. RESULTS: Proprietal extracts NPS00033 from the Rutaceae plant family and NPS00039 (Relora) from the Magnoliaceae plant family screened positive in this chick model without causing sedation. CONCLUSIONS: These results suggest that botanical extracts Relora and NPS00033 may be useful in modulating anxiety states.

Why the U.S. Government is not contributing to the resolution of the nation's drug problem.

When the U.S. Surgeon General suggested looking at the experience of countries that have officially or de facto decriminalized drugs, the administration's reaction was unequivocal: under no circumstances would the decriminalization of drugs be considered. This reaction prevails despite the admission by almost everyone that the so-called "war on drugs" is not merely a failure but a disaster. Had the Surgeon General's suggestion been followed the results would show that decriminalization--judging from the experience of other nations and states within the United States that have decriminalized marijuana--would have few negative consequences and many positive ones, not the least of which would be a lessening of crimes associated with the prohibition of drugs. In the United States the effect might also be to reduce the hidden racist war that takes place nightly in the ghettoes of the nation's underclass.

Development and evaluation of a novel dissolution apparatus for medicated chewing gum products.

A novel dissolution apparatus was developed for medicated chewing gum products. A prototype gum product containing phenylpropanolamine hydrochloride (PPA) was used to evaluate the apparatus. The apparatus consists of a conical Teflon base and a rotating, ribbed Teflon plunger suspended in a dissolution vessel. Parameters evaluated were rotation speed, plunger frequency, medium volume, medium type, medium sampling location, number of plunger ribs, and number of gum pieces. Samples were taken over a 20-min period and samples were analyzed by HPLC. Cumulative percentage released-versus-time profiles were obtained for each parameter evaluated. Statistical analysis of the gum product indicated that the only significant differences occurred at the lowest rotation speed and lowest plunger frequencies. A Level A correlation was found between the in vitro release profile for the 20-rpm and 30-cycles/min plunger frequency and the in vivo chew-out study.

Development and evaluation of enteric-coated penicillamine tablets.

Commercially available 250-mg penicillamine tablets were converted into enteric-coated tablets. Based on in vitro dissolution and disintegration tests, tablets coated with five layers of a cellulose acetate phthalate formulation by a modified pan coating technique were judged to be superior to other coated tablets. These tablets resisted disintegration in simulated gastric fluid over a 4-h period and disintegrated in an average of 21 min in simulated intestinal fluid. Enteric-coated penicillamine tablets were tested in vivo in nine weanling pigs divided into three groups: a negative control group, a test group dosed with enteric-coated penicillamine tablets, and a positive control group dosed with uncoated tablets. The incidence of GI tract bleeding, as determined by daily occult blood tests of the stools, was significantly less in the animals receiving the enteric-coated tablets when compared with the positive control group. The enteric-coated dosage form appeared to decrease GI tract irritation caused by penicillamine. Plasma concentration-time curves for penicillamine in the pigs were similar in shape to those reported in humans. Atypical double peaks occur in both species. Relative bioavailability of the enteric-coated tablet was found to be 67% when compared with the uncoated tablet. This apparent reduction is probably due to a large intrasubject variation in areas under the plasma concentration-time curves and not to a dosage form effect.

Effect of docusate sodium on drug release from a controlled-release dosage form.

This study was designed to determine the effect of a clinically used surfactant, docusate sodium, on the release of chlorpheniramine from a controlled-release dosage form (encapsulated coated pellets). In vivo treatments consisted of the controlled-release capsule alone or with 200 mg of docusate sodium. Plasma chlorpheniramine levels were determined, and the AUC was calculated. No significant difference in AUC values was observed between the two treatments. At a concentration below the CMC, docusate sodium enhanced the in vitro drug release rate. The surfactant exerted a greater effect on the release of the first one-third of the drug contained in nonwax-coated pellets. At the CMC, 0.02% (w/v), docusate sodium rapidly entrapped chlorpheniramine in micelles. The overall enhanced dissolution rate in vivo may have been offset by micellar drug entrapment.