Comprehensive and up-to-date reviews on the actions and evaluation of analgesics have been published in America by Small, Eddy, Mosettig and Himmelsbach (1938), and by the Committee on Drug Addiction under the chairmanship of White (1941). Fourneau (1938) has discussed much of the older work on the relationship of chemical constitution to analgesic efficiency. Schaumann (1940) has reported on the synthetic compounds derived from 4-phenyl-piperidines synthesized by Eisleb (1941), and by his analysis has illuminated our conceptions of the structural essentials for analgesic activity. He concluded that of the compounds he examined an optimum was reached in ethyl-4-phenyl-l-methylpiperidine-4-carboxylate hydrochloride (pethidine, demerol, dolantin)-a conmpound which has received the recognition of an approved name, pethidine hydrochloride, in the 7th Addendum to the British Pharmacopoeia (1944). Woolfe and Macdonald (1944) have attempted an evaluation of the analgesic activity of this drug, using a simple technique for the measurement of such action in mice. Pethidine already has an extensive clinical literature, and there is reasonable agreement between estimates of its efficiency, relative to other drugs, on mice and men. This paper describes the application of the experimental technique to a large number of pethidine derivatives and related compounds, most of which have been synthesized for the first time by Bergel et al. (1944). Very few of these have been investigated by Schaumann. While no immediate claim for clinical importance can be made for any of the active compounds, except perhaps for iso-pethidine (C 21) (cf. Glazebrook and Branwood, 1945), our pharmacological experience
Summary and ConclusionsMice and rats which are normally resistant to histamine become more susceptible to its lethal action after an injection ofH. pertussis. This so-called sensitization to histamine is not an anaphylactic phenomenon. It is due to the action of a component ofH. pertussis, the histamine-sensitizing factor (HSF), which in some unknown way overcomes the physiological mechanism in rats and mice that makes them more resistant than other species to histamine. Guinea-pigs which appear not to possess this mechanism and are about 200-fold more susceptible, weight for weight, than rats and mice, were not made more sensitive byH. pertussis.After a stated dose of vaccine, sensitization was detectable in 48 hr., reached a maximum in 3–4 days, remained at this level for about 2 weeks and gradually disappeared. The effects of dosage, route of injection, and weight and sex of mice have been examined.The HSF was found in strains ofH. pertussis; it was not found inH. parapertussis, H. bronchisepticusorH. influenzae. It was only slightly affected by heating at 70° C. for 1 hr. but was destroyed at 80° C. in ½ hr. It was destroyed when bacteria were disintegrated by shaking with glass beads, or by grinding after being freeze-dried. It was found in the supernatant fluid of a partially autolysed vaccine.HSF was antigenic. Antisera were prepared in rabbits. Anti-HSF combined with HSF and neutralized its histamine-sensitizing activity. Bacteria treated with antiserumin vitroabsorbed anti-HSF and did not thereafter sensitize mice.Antiserum protected mice passively against the sensitizing action of vaccine, presumably by combining with HSF. After sensitization had developed the sensitive state was not affected by antiserum.Although HSF is an antigen there was no indication that histamine-sensitization was due to its antigenicity.The HSF was differentiated from heat-labile and heat-stable toxin, haemagglutinin, capsular material and agglutinogen.The preparation V 17, which is a small fraction of the disintegrated bacteria, adsorbed on red cell stromata (Pillemeret al.1954) had a high histamine-sensitizing value. Compared with whole bacterial vaccine it caused little production of agglutinin in mice; in rabbits it caused a slower and smaller production of agglutinin and a faster and greater production of anti-HSF. For this reason immune rabbit sera may have a high agglutinin titre and a low anti-HSF value or vice versa. Anti-HSF rabbit serum protected mice against sensitization by V 17.Vaccines could be graded according to their histamine-sensitizing activity. This did not always correspond to their grading by agglutinin production in mice. The relation of HSF to the immunizing antigen ofH. pertussisand the use of histamine-sensitization to indicate the immunizing potency of pertussis vaccines are discussed.We wish to thank Glaxo Laboratories Ltd. for the supply of reference vaccine, and the Whooping Cough Immunization Committee of the Medical Research Council for vaccines and sera.
Crystalline histamine picrate and hydrochloride have been prepared from cotton dust. The melting-points and crystalline structure found are in agreement with those obtained by other workers.The blood histamines in sixty-five card-room workers have been estimated and compared with the figures found in 103 students and eighteen elderly chronic bronchitics. The figures for the three groups are shown in distribution figures, and the card-room workers have, on an average, a higher blood histamine than both groups of controls. It has, however, to be admitted that the differentiation of card-room asthma from other respiratory diseases on the basis of the level of blood histamine cannot be guaranteed in individuals.
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