Arnold C. Osterberg

The pharmacology of fenbufen, 3-(4-biphenylylcarbonyl)propionic acid, and 4-biphenylacetic acid, interesting antiinflammatory-analgesic agents.

Fenbufen [3-(4-biphenylylcarbonyl)propionic acid] was shown to be an orally and parenterally effective nonsteroidal antiinflammatory analgetic and antipyretic agent in animals. Like clinically useful drugs (aspirin, phenylbutazine and indomethacin) it has potent antiinflammatory activity in a wide spectrum of laboratory tests in mice, rats, guinea pigs, and dogs and was of particular interest since it appears to have high analgetic efficacy and a long duration of antiinflammatory and analgetic action. While shown to have ulcerogenic potential in rats at toxic doses, it appeared to have a superior margin of gastrointestinal safety in treatment of dogs with urate synovitis. Evidence was also presented to show that BPAA (4-biphenylacetic acid), a metabolite of fenbufen, has a similar profile of antiinflammatory activity, although appearing to produce slightly more gastrointestinal injury. It appears that BPAA may be the agent responsible for at least part of fenbufens pharmacologic effects. The data presented suggest that fenbufen has the potential to be used safely and effectively to provide relief for patients with inflammatory disease.

Method for the measurement of respiration in unanesthetized rats: Effect of selected analgesics and hypnotics

Summary An apparatus and procedure for the measurement of minute volume and respiratory rate in the unanesthetized rat has been described. A change of ±10% or greater from pretreatment minute volume indicates a significant ( P P At equal analgesic dosages, morphine was shown to be quantitatively more depressant to respiration than meperidine or codeine. Sodium phenobarbital was shown to exert a more sustained respiratory depression than methyprylon at a dose producing a comparable degree of locomotor ataxia. Nalorphine administered alone was found to exhibit a moderate respiratory depressant effect regardless of the dosage used, but when given in conjunction with either morphine, meperidine, or codeine a dose-dependent antagonism was observed.

Some pharmacologic properties of thozalinone, a new excitant

Abstract Thozalinone has been shown to possess some pharmacologic actions similar to those of amphetamine and imipramine, but with important differences. It is less toxic than amphetamine, and its margin of safety in mice is greater. The stimulant action does not progress to tremors or convulsions as the dosage is increased. The anorexigenic activity of thozalinone is more pronounced and longer lasting than that of amphetamine. There is no evidence of the development of tolerance. The cardiovascular side effects of thozalinone are minimal, and analeptic actions are absent.

Additions and Corrections- 1-Aryl-3-azabicyclo-[3.1.0]hexanes, a New Series of Nonnarcotic Analgesic Agents

A series of 1-aryl-3-azabicyclo[3.1.0]hexanes was synthesized by hydride reduction of 1-arylcyclopropanedicarboximides. Hydroxyphenyl analogues 20, 22, and 24 were prepared by EtSNa--DMF ether cleavage of the corresponding methoxyphenyl analogues 2m, 2n, and 23, respectively, with the secondary amines 20 and 22 going through the N-formyl intermediate 19 and 21. The p-ethoxy analogue 26 was obtained by O-ethylation of 19, followed by base hydrolysis of the amide 25. The greatest analgesic potency in mouse writhing and rat paw-pain assays was observed for para-substituted compounds. Bicifadine, 1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane (2b), was the most potent member of the series and is presently undergoing clinical trials in man. Analgesic activity of 2b is limited to the (+) enantiomer 2v, which has the 1R,5S absolute configuration as determined by single-crystal X-ray analysis. The N-methyl analogue (27d) of 2b showed significant analgesic potency, whereas the N-allyl (27a), N-(cyclopropylmethyl) (27b), and N-(n-hexyl) (27c) analogues were inactive. Bicifadine (2b) showed a nonnarcotic profile different from analogous azabicycloalkane and 3-phenylpyrrolidine analgesics.