2,4-dinitrochlorobenzene (DNCB) has recently received considerable interest as an alternative in th

Fråga: 2,4-dinitrochlorobenzene (DNCB) has recently received considerable interest as an alternative in the treatment of human immunodeficiency virus (HIV) infection.

Background information is required.

Sammanfattning: While there is a well documented theoretical support for the idea of trying DNCB in HIV-infected individuals due to the immunostimulatory effect of the compound there are no clinical effects that today can be used to encourage a widespread use of the compound outside controlled clinical trials. Several severe side effects have been reported and it appears particularly risky to allow an uncontrolled use of this substance. Recently, reported clinical trials are preliminary and inconclusive, and controlled clinical trials are needed to evaluate the effect of the compound. Knowledge about basic pharmacokinetics is also insufficient. Further studies are needed to clarify the degree of absorption metabolism and potential interaction with other drugs.

Svar: DNCB has been used for many years as a chemical in the processing of colour photographs. Its potency as a contact allergen has been exploited for medical purposes to induce a type three hypersensitivity reaction.

MECHANISM OF ACTION: DNCB is applied topically and is bound to collagen to form a haptene (1). After transport to local lymphnodes via Langerhans dendritic cells from the epidermis, TH1 helper cells are activated. The TH1 cells secrete interferon gamma, interleukin 2 and tumour necrosis factor beta, thereby suppressing an antibody response and stimulating a delayed type hypersensitivity reaction. The TH2 cells, which are involved in stimulating IgE mediated hypersensitivity reactions, are not stimulated by DNCB. The delayed type hypersensitivity reaction to DNCB can be demonstrated by a second application of DNCB, not necessarily on the same skin spot as the primary sensitizing exposure to the compound. A dose of one per cent of the sensitizing dose is usually sufficient to elicit response. This secondary response is enhanced by interleukin2 (2). Exposure to DNCB increases CD4+ as well as CD8+ T-lymphocytes (3).

DOSE RESPONSE RELATIONSHIPS: The primary as well as the secondary application of DNCB needs to be made over sufficiently large area of approximately one square centimeter or larger (4). However, for areas exceeding one square centimeter, it is the concentration rather than the total dose that is critical for eliciting a response (5). It has been hypothetized that the exposure of each individual of Langerhans cell must reach a critical level in order for a response to occur. Similar dose response patterns have been obtained in experimental animals as well (6). Females appear to require lower doses than males to elicit a response (7). The dose used to elicit the primary response is ordinarily 0.1 ml of a two per cent solution which corresponds to approximately 10 umol.

PHARMACOKINETICS: In one paper pharmacokinetic properties of DNCB are cited without giving either the source or providing primary data. It is stated that the half-life is four hours and that the percentage excreted unchanged in urine is 53 (8).

CLINICAL APPLICATIONS OTHER THAN HIV-INFECTION: Treatment with DNCB has been tried in autoimmune diseases as well as viral and tumour diseases because adequate treatment effect on these diseases is presumed to depend on a strong cellular immune response. The generally most successful area of application has been to alopecia reata (8). Other diseases have been tried such as treatment of warts (9), certain cases of malignant melanoma (10) and in squamous papilloma (11).

USE IN HIV-INFECTION: The use of DNCB in the treatment of HIV/AIDS has recently been reviewed (12). The idea behind DNCB treatment is to stimulate TH1 helper cells which are lost due to the HIV-infection by specific stimulation with DNCB resulting in not only in a proliferation of cells involved in the DNCB response but also in an increased production of interleukin 2 which may stimulate other populations of TH1 T-lymphocytes (12). Another motivation for the use of DNCB is that the drug has been proposed to be effective in the treatment of condyloma accumunatum which is caused by another virus: papilloma virus (13). From one research group, two papers have been published (14,15) both of which are mainly descriptive and should be characterized as pilot studies. In none of these studies are there any significant changes in viral parameters. The number of CD8+ lymphocytes and the number of CD56+ T-cells (natural killer cells) were increased in the second study. A subgroup analysis of HIV-RNA content in serum suggested that patients with low concentrations of HIV-RNA experienced an increase in HIV-RNA levels while those with a high content pretreatment experienced a decrease in HIV-RNA concentrations. It should be noted that such an effect is to be expected as the classical regression towards the mean effect described by Galfor in the 19:th century.

SIDE-EFFECTS: There are several case studies of mainly cutaneous side-effects due to DNCB. In one HIV-infected patient, too frequent dosing of DNCB resulted in a severe skin reaction with sharply demarcated eruptions at the site of application (16). In another case of uncontrolled use of DNCB, erythema multiforme was observed (17). One case study describes rechallenge confirmed urticaria, and in this paper two other cases of urticaria are cited (18). In the literature there is some debate concerning the potential for inducing tumours with DNCB because the substance fails the Ames test (24,25). Because animal study with very high doses have been performed in mice and rats without an increased incidence of tumours there is little solid evidence for carcinogenicity. Another effect of DNCB is that it inhibits glutathione-S-transferase and thereby depletes cells of glutathione which is essential for the handling of free radicals intracellularly (19,20,21). The concentrations required for glutathione depletion must, however, exceed 2.5 umol/l both measured as inhibition of glutathione-S-transferase (20) or as T-cell receptor mediated stimulation by anti CD3 monoclonal antibodies which cause calcium mobilization intracellularly and tyrosine phosphorylation in proteins (21). It is not likely that this effect will appear on local application of DNCB in cells other than those very close to the area of application since the dose of DNCB is comparatively small as calculated above. For reference list, see 11538.