Proposed mechanism of pulmonary gas trapping (PGT) following intravenous perfluorocarbon emulsion administration.

PURPOSE: To investigate various hypotheses and identify the most likely mechanism preventing the complete collapse of test animal lungs at sacrifice subsequent to intravenous injection of certain perfluorocarbon emulsions. PROTOCOL: Literature data were reviewed, experimental data were extracted from completed studies and new data were generated in an attempt to delineate reasons why, in certain animals, lungs fail to collapse normally at necropsy if previously injected with certain perfluorocarbon emulsions. The proposed hypothesis involved gas osmosis through endogenous pulmonary surfactant-liquid bridges (micro-bubbles). RESULTS: The observed effect of incomplete lung collapse upon necropsy was found to correlate with perfluorocarbon vapor pressure. Results indicated that failure to collapse could be attributed to the formation of intra-alveolar micro-bubbles induced by the normal pulmonary elimination of perfluorocarbon vapor. These micro-bubbles result in a phenomenon which could be characterized by the term, pulmonary gas trapping. Reduction of the perfluorocarbon concentration gradient across the bubble films by exposure to a perfluorocarbon vapor-containing atmosphere was found to reduce the effect in-vivo and prevent gas osmosis bubble growth in-vitro. CONCLUSION: Experimental observations are consistent with the proposed theory of perfluorocarbon-related gas osmosis through micro-bubbles that prevent complete lung collapse as observed upon opening the thoracic cavity of test animals.

Food effects on the nighttime pharmacokinetics of Theo-Dur tablets.

A randomized crossover study demonstrated major food effects on the pharmacokinetics of Theo-Dur, two 200-mg theophylline anhydrous sustained-release tablets, as an evening dose. These effects included a higher maximum serum theophylline level and relatively prolonged delay in drug absorption, both significant. The findings, which showed marked individual variation, could be clinically important for patients receiving evening medication.

The United States experience with oral controlled-release morphine (MS Contin tablets). Parts I and II. Review of nine dose titration studies and clinical pharmacology of 15-mg, 30-mg, 60-mg, and 100-mg tablet strengths in normal subjects.

The results of nine US multicenter, sequential crossover, dose titration studies of controlled-release oral morphine (MS Contin 30 mg tablets [MSC], Purdue Frederick, Norwalk, CT) are reviewed in Part I. The studies demonstrated the prolonged analgesic efficacy of the preparation in the treatment of patients with moderate to severe cancer-related pain. Approximately 93% of the patients achieved satisfactory to excellent analgesia on a 12-hour regimen when appropriate dose titration was allowed. The remaining patients were successfully maintained on an 8-hour regimen. The preparation was well-tolerated and comparable in safety to immediate-release oral morphine. In global evaluations, MSC was judged to be significantly (P less than 0.05) more effective, and with significantly (P less than 0.05) fewer side effects than both the prestudy opioid analgesics and 4-hour immediate-release oral morphine. Patients had a broad range of morphine requirements (mean daily MSC dose, 240 mg; range, 60 mg/day to 1800 mg/day); therefore various MSC tablet strengths were developed. Part II presents three studies in which the MSC formulations (15-mg, 60-mg, and 100-mg tablets) were compared to the 30-mg tablet within three randomized, single-dose, two-way crossover, analytically blinded bioavailability protocols, to determine bioequivalence and dose proportionality. The maximum morphine concentration, time of maximum morphine concentration, and area under the plasma morphine versus 12-hour and 24-hour time curve (AUC 0.12; AUC 0.24) were determined in each study. There were no significant differences between the values associated with MSC 1 X 30 mg tablet and 2 X 15 mg tablets (study 1), MSC 2 X 30 mg tablets and 1 X 60 mg tablet (study 2), and MSC 3 X 30 mg tablets and 1 X 100 mg tablet (study 3, values adjusted to dose of 90 mg), except for one marginally significant difference in study 3 (AUC 0.24; P = 0.04) which was not clinically or biopharmaceutically significant. The results showed that MSC 15-mg, 30-mg, 60-mg, and 100-mg dosage strengths are bioequivalent and dose proportional, and, therefore, therapeutically interchangeable. It was concluded that with routine assessment of the patient and adherence to the principles of analgesic dosing, MSC can be successfully used to control cancer-related pain. Furthermore, the availability of various MSC tablet strengths can be expected to facilitate the analgesic management of a patient population with widely differing opioid requirements.

Synthesis and biological properties of some novel heterocyclic homoprostanoids.

In the search for prostaglandin-like structures capable of exerting specific and desirable biological properties, a variety of simple heterocyclic homoprostanoidal derivatives was synthesized from readily available stearic acid derivatives. Compounds 5b and 5e were found to be more than 100 times as potent as PGE1 and PGE2 in a tracheal chain bioassay and, like 6, 9, and 12, inhibited PGE2-induced diarrhea. Derivatives 6 and 7a showed significant PG-synthetase inhibitor activity.

Inhibition of prostaglandin synthetase and carrageenan-induced edema by tricyclic analogs of flufenamic acid.

A group of tricyclic analogs of flufenamic acid were tested for their ability to inhibit both the biosynthesis of prostaglandin and carrageenan-induced inflammation of the rat paw. All had activity greater than phenylbutazone as inhibitors of prostaglandin synthetase, with SK&F 22908 being as active as flufenamic acid. The anti-inflammatory activities of these compounds correlated only to a minor degree with the inhibition of prostaglandin biosynthesis. The data support the position that within this series of compounds inhibition of prostaglandin synthetase and non-steroidal antiinflammatory activity, as well as ulcerogenic liability, may be an expression of different mechanisms.