Kazuko Kitamura

Evaluation of skin test reactions in patients with non-immediate type drug eruptions

Skin test reactions were evaluated in 242 patients who appeared to develop delayed type drug eruptions from the clinical course. The patch testing was positive in 62 (31.5%) of 197 patients tested and the intradermal testing in 105 (89.7%) of 117 patients. The positive ratios of intradermal testing were higher in maculopapular (MP), erythema multiforme (EM), and erythrodermic (ED) types than in eczematous (Ecz) type drug eruptions, while those of patch testing were comparatively high in ED, Ecz type, and anticonvulsant‐induced drug eruptions. It is considered that the combination of patch testing and intradermal testing is useful for determination of causative drugs in delayed type drug eruptions.

A PROBABLE ROLE FOR VACCINES CONTAINING THIMEROSAL IN THIMEROSAL HYPERSENSITIVITY

We patch tested 141 patients with 0.05% aq thimerosal and 222 patients with 0.05% aq, mercuric chloride, including 63 children. The frequency of positive patch test reactions to thimerosal was 16.3%. There was a marked preponderance in the young age groups after vaccination, while none of 3h infants (aged 3–48 months) reacted lo thimerosal positive reactions to mercuric chloride were found in 23 (10.4%) of 223 patients. We also sensitized guinea pigs with diphtheria‐pertussis‐tetanus (DPT) vaccine containing 0.01% thimerosal and succeeded in inducing hypersensitivity to thimerosal. From patch testing in humans and animal experiments, it is suggested that 0.01% thimerosal in vaccines can sensitize children, and that hypersensitivity to thimerosal is due to the throsaticylic part of the molecule and correlates with photosensitivity to piroxicam.

Sulfhydryl Drug‐induced Eruption: A Clinical and Histological Study

Sulfhydryl drug‐induced skin eruptions were studied clinically and histologically in 23 patients. In this study, tiopronin, D‐penicillamine, captopril and gold sodium thiomalate were considered to be sulfhydryl drugs, because they have a thiol group or release sulfhydryl compounds. The clinical features included skin eruptions that were maculopapular, erythema mutiforme‐like, eczematous, psoriasis‐like, seborrheic dermatitis‐like, Gibert‐like, lichen planus‐like, and pemphigus‐like. These clinical findings were reminiscent of the wide variety of eruptions seen in cutaneous graft‐versus‐host reactions (GVHR). Histologically, areas of vacuolation and eosinophilic necrosis with a satellite infiltrate of lymphoid cells were seen in the epidermis, and perivascular infiltrates were noted in the dermis. These findings were similar to the histological picture of cutaneous GVHR. In skin tests with sulfhydryl compounds, 19 out of 20 subjects showed positive reactions, and autoantibodies were found in 8 out of 12 subjects tested.

Cutaneous Reactions Induced by Calcium Channel Blocker: High Frequency of Psoriasiform Eruptions

Fifteen cases with cutaneous reactions to calcium channel blockers (Ca‐antagonist), dihydropiridine (including nicardipine, nifedipine, nisoldipine), verapamil, and diltiazem are reported. The patients from Yokohama City University Hospital and affiliated hospitals included 4 males and 11 females with cardiovascular diseases. Their average age was 64.7 (54 to 82) years. They had been taking Ca‐antagonists for an average of 95 days (7 days to 10 years) before they developed dermatitis. The frequency of reactions to Ca‐antagonists was high with diltiazem (5/16: 31.25%) and dihydropyridine (7/16: 43.75%), including nifedipine (4/7), nisoldipine (1/7), and nicardipine (2/7). Stevens‐Johnson syndrome (MCOS) was associated only with verapamil.

Immunohistochemical Study of Graft-versus-Host Reaction (GVHR)-Type Drug Eruptions

Skin biopsies of graft‐versus‐host reaction (GVHR)‐type drug eruptions in the acute phase were compared immunohistochemically with those in the chronic phase and also with non‐GVHR type drug eruptions in the acute phase. Predominance of CD8+ T cells in the epidermal infiltrates, reduction in the number of epidermal OKT6+ dendritic cells (Langerhans cells), and increased expression of HLA‐DR and ICAM‐1 on keratinocytes were observed in the acute phase of GVHR‐type, but not in either the chronic phase of GVHR‐type or the acute non‐GVHR type. These findings were similar to those of previous reports on skin lesions of acute GVH disease (GVHD) seen after bone marrow transplantation.

PENICILLIN AND CEPHALOSPORIN—INDUCED RASH IN GUINEA PIGS

Guinea pigs primed for delayed type hypersensitivity (DH) to antibiotics such as penicillin G (PCG), carbenicillin (CBPC), sulbenicillin (SBPC), ampicillin (ABPC), cephalexin (CEX), cephalothin (CET) and cephazolin (CEZ) by immunization in mycobacterial adjuvant developed a generalized rash (GR) and flare‐up of previous test sites when challenged peritoneally with high doses of specific antigen. The GR was delayed in time, and histologically characterized by dilated and compacted small vessels and leucocytic infiltrations into the upper dermis. Animals immunized with CEX or CET developed a strong GR despite the absence of detectable antibodies.

Cross-reactivity between sensitivity to thimerosal and photosensitivity to piroxicam in guinea pigs

Piroxicam (PXM) is a nansteroidal anti‐inflammatory drug which may induce a photosensitive eruption shortly after administration. We examined whether animals sensitized to thimerosal developed a photosensitivity to PXM. Male Hartley strain guinea pigs were sensitized to thimerosal, thiosalicylate and PXM separately. The open patch test was used lo evaluate sensitization to each drug and cross‐reactions between the drugs. Animals sensitized to thimerosal exhibited positive patch test thimerosal to thiosalicylate and positive path test reactions to PXM. Both those sensitized to thiosalicylate and to PXM showed positive patch test reactions to PXM. This study demonstrated that thimerosal induces cross‐sensitivity to PXM in vivo and that the common active components among these compounds may be thiosalicylate.

Generalized rash induced by sulfhydryl drug in guinea pigs--a comparative study on it with cephalothin-induced rash in guinea pigs.

Adverse reactions produced by sulfhydryl compounds with active thiol groups have generally formed a distinctive pattern in man when they are viewed as a class. It has been reported that cutaneous SH‐induced drug eruptions have a wide variety of clinical presentations; histologically, they show a pattern of eosinophilic necrosis and/or satellite necrosis similar to that seen in cutaneous graft vs host reactions.

A cross-reaction between piroxicam-photosensitivity and thiosalicylate hypersensitivity in lymphocyte proliferation test

We examined the cross-reaction between photosensitivity to piroxicam (PXM) and contact sensitivity to thiosalicylate (TOS) by a lymphocyte proliferation test (LPT) in guinea pigs. The lymph node cells (LNCs) plus peritoneal exudate cells (PECs) from guinea pigs contact-sensitized with TOS remarkably cross-proliferated to PXM under UVA (4 J/cm2) irradiation. On the other hand, the PXM-photosensitized LNCs+PECs also cross-proliferated to TOS. From these results, the reciprocal cross-reaction between TOS-hypersensitivity and PXM-photosensitivity was reconfirmed by the in vitro LPT, indirectly indicating that the PXM-photosensitivity is a cell (probably T cell)-mediated PXM photoallergy in its nature. The TOS-primed LNCs+PECs did not cross-proliferate to UVA (4 J, 180 J or 500 J/cm2)-pretreated PXM (UVA-PXM) although it is supposed to contain several photoproducts of PXM. Furthermore, the TOS-primed LNCs developed a remarkable proliferative cross-response to the PECs pulsed with PXM under UVA (4 J/cm2) irradiation (photo-PXM-modified PECs), but not to the PECs pulsed with PXM or UVA-PXM. Therefore, it is presumed that the cross-reactive molecule, which is easily formed from PXM under UVA irradiation, is unstable, and that the formation of complete antigen by the generation of this molecule and its photobinding needs the coexistence of PECs, PXM and UVA irradiation at the same time in the culture.

Piroxicam has at least two epitopes for contact photoallergy

We have demonstrated previously in guinea pigs that the induction of photocontact sensitivity to piroxicam (PXM) also induces a state of cross-reactive contact hypersensitivity to two compounds having structurally related elements, thimerosal (TMS) and thiosalicylate (TOS). The present study was conducted to determine whether oral administration of TOS would desensitize guinea pigs previously photosensitized with PXM. At the same time, the spectrum of reactivities against these compounds and against tenoxicam (TXM) which resembles only piroxicam was assessed by appropriate sensitizing and eliciting protocols. As expected, animals photosensitized to PXM developed reactivities against all four compounds, PXM and TXM (photosensitivity) and TMS and TOS (contact sensitivity). By contrast, photosensitization with TXM induced cross-reactivity only against PXM. Moreover, the induction of contact sensitivity against TMS or TOS induced photosensitive cross-reactivity to PXM, but not to TXM. Finally, the oral administration of TOS produced a transient desensitization only for TMS and TOS. These results suggest that photosensitization with PXM induces two distinct reactivities. The first reactivity cross-reacts with TMS and TOS and is suppressible with orally administered TOS. The second cross-reacts only with TXM and is not suppressible with oral TOS. We conclude that PXM acquires at least two distinct immunogenic epitopes when exposed to UVA irradiation.