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Intravenous administration of a total dose of more than 200 million IU of penicillin-G led to sensitisation of lymphocytes and formation of specific anti-penicilloyl antibodies of the IgG class. These effects were prevented when the penicillin solution used was freshly prepared and given as a bolus rather than as a slow infusion. The causative antigens seem to be related not to penicilloylated high molecular weight impurities in the penicillin preparations, but to the degradation and/or transformation products of penicillin-G that form when the drug is in solution even if only for a few hours, and not only at room temperature but also at 4 degrees C. Thus penicillin solutions should be freshly prepared and administered from vials containing less than 10 million IU so that bolus doses can be given.

HLA typing of 46 patients with demonstrated penicillin allergy did not show significant correlation of hypersensitivity to the penicilloyl group with any HLA antigens. On the other hand, lymphocytes from penicillin-sensitive patients generated nonspecific cytotoxic cells (e.g., cytotoxic for P 815 mastocytoma mouse cells or chicken red blood cells) when cultured in vitro together with penicillin. Under similar conditions, only some lymphocyte populations from nonpenicillin-sensitive normal individuals showed cytotoxicity. Although family studies are required to demonstrate that differences in the generation of cytotoxic cells by penicillin in nonsensitive populations are due to genetic factors, it is obvious that attempts to achieve primary sensitization in vitro is the most rational approach to a study of Ir genes in man.

A second clinical trial of the compound Ro 6-0787, which is a specific monovalent penicilloyl hapten inhibitor of allergic reactions to penicillin has been conducted by investigators from 9 different European groups in 90 patients allergic to penicillin. The effect of a combined Ro 6-0787-penicillin therapy was considered as clinically successful in the large majority of cases, since treatment with penicillin could be pursued or resumed without allergic manifestation in 42 from 46 cases (91 percent). The effect of Ro 6-0787 alone on acute allergic manifestations after interruption of penicillin therapy was more difficult to evaluate but was nevertheless considered satisfactory in 17 from 26 patients (65 percent). A depression of skin hypersensitivity to PPL and/or penicillin and penicillin derivatives sometimes persisting for weeks and months was obvious in numerous allergic patients submitted to combined Ro 6-0787-penicillin treatment. A depressing effect on antipenicillin antibody titers detected by passive hemaglutination was also manifest in some patients. Failure to suppress allergic manifestations was reported in 11 cases, among which some may have been due to insufficient dosage of inhibiting hapten. The overall tolerance of Ro 6-0787 in allergic patients has been very good. Nevertheless, the major obstacle to a wider general use of Ro 6-0787 at the present time appears to be the occurrence of positive skin reactions to that compound in approximately 5 percent of patients allergic to penicillin. It is not yet ascertained whether the occasional positive skin reactions and urticaria to Ro 6-0787 may have been due to aggregation, or incomplete dissolution of the compound or whether it reflects hypersensitivity to another antigenic determinant. With the reservation that patients with positive skin test to Ro 6-0787 have for the time being to be excluded from combined treatment, this monovalent hapten certainly offers a new possibility to resume and/or pursue penicillin therapy in patients demonstrably allergic to that drug.

Eight patients treated with a total of 220-550 million U penicillin-G developed neutropenia. These cases have been compared with eight patients receiving a similar dose of pencillin-G with no adverse reactions and with eight untreated subjects. All penicillin-treated patients showed raised levels of anti-IgG antibodies and lymphocyte culture stimulation indices. These values were highest in the neutropenia group. Both of the two tests significantly discriminated the three groups. Antineutrophil antibodies could be detected in four of seven neutropenic patients with a staphylococcal-slide-assay while indirect immunofluorescence and microcytotoxicity tests failed to reveal these antibodies. The literature dealing with neutropenias induced by penicillin-G and its congeners is reviewed. We conclude that (1) penicillin-G in doses exceeding a total of 200 million U frequently induces neutropenia, (2) an immune-mediated pathogenesis a highly probable, (3) neutropenia after penicillins is different from two hither-to accepted types of this side effect, (4) sufficiently high amounts of penicillin-G intravenously always induce sensitization against this drug.