Azathioprine and chlorambucil: mechanism of action and use in ...

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literature, warfarin is rarely used therapeutically in animals and may be less of a concern in veterinary medicine. Dosage and monitoring Azathioprine (Imuran®, GlaxoSmithKline) is available in 25mg and 50mg tablets and as a sodium salt for injection (50mg vial). The recommended dose for azathioprine in dermatology in humans and dogs is reported to be 1-2.2 mg/kg orally daily, reducing to every other day administration after 1-2 weeks of daily therapy. However, many clinicians advocate the use of a body surface area derived dose rate (50mg/m 2 ) in animals over 20kg. In humans, a new dosing system (Table 3) has been proposed base on pretreatment TPMT activity. While TPMT is a useful indicator of potential risk groups for adverse haematologic effects, the role of TPMT activity in dogs, cats and horses remains unclear so dosing based on TPMT activity in these species is not recommended. Table 3. Proposed new dosing schedule (human) – adapted from Patel, et al. 1 Patient group TPMT activity (U/ml rbcs) Suggested max. dose (mg/kg) No activity (homozygous mutation) < 5 Recommend not using Low activity (heterozygous) 5-13.7 1 Normal activity (homozygous wild type) 13.8-19.5 2.5 High activity (high homozygous) > 19.5 3 Therapeutic response to azathioprine occurs in 6-8 weeks. If a response is not seen, then the azathioprine dose may be increased by 0.5 mg/kg at 4 week intervals with reference to white cell counts and clinical response, but a total dose of 3mg/kg should not be exceeded. 3 If there is no response to treatment after 12-16 weeks, azathioprine should be discontinued. No formal guidelines exist for hematological or biochemical monitoring of azathioprine in dermatology patients in the human or veterinary fields. Baseline complete blood count (CBC) and serum biochemistry panels should be run prior to the initiation of therapy. The author then repeats the CBC at weekly intervals for the first 4 weeks of therapy, then fortnightly to 8 weeks of therapy, monthly to 16 weeks then every 3 months thereafter. Biochemical analysis (with particular reference to liver function testing) is repeated 2 weeks after initiation of therapy, and then if any evidence of gastrointestinal upset, inappetence, fever, malaise or icterus is present. Ideally, urine culture and sensitivity should be performed prior to the initiation of therapy and then every 3 months, due to long term immunosuppression and the risk of occult urinary tract infections (note that this risk is not specific to azathioprine). Chlorambucil History Chlorambucil is a potent alkylating agent used in a range of neoplastic and non-neoplastic dermatological conditions. The development of the alkylating agents, including chlorambucil, have revolutionised cancer chemotherapy. Alkylating agents are derivatives of mustard gas (nitrogen mustards), which were extensively used as chemical warfare agents in both World War I and II. Top secret studies carried out in the early to mid 1940s revealed that when these agents were administered systemically they were highly cytotoxic, with the degree of cytotoxicity positively correlated with the proliferative capacity of the cells – thus nitrogen mustards and their derivatives preferentially killed highly proliferative organs such as the gastrointestinal tract, bone marrow and lymphoid tissues. 37 The first clinical report of nitrogen mustards using in cancer chemotherapy was published by Goodman et. al in 1946, 38 when 67 patients with Hodgkin’s lymphoma, leukaemia and lymphosarcoma were treated with a nitrogen mustard derivative. Significant improvement was seen in a number of patients, but the margin of safety of the drug in these individuals was narrow. Chlorambucil was developed in 1953 by Everett et. al, 39 with the addition of an aryl group to the nitrogen mustard molecule known as bis-(2-chloroethyl)amine, Addition of other active moieties onto this base molecule led to the development of a number of more targeted drugs such as melphalan and cyclosphosphamide. 40 Pharmacology and mechanism of action Alkylation agents exert their effect directly on DNA, RNA and proteins, usually by non specific means. The chlorine groups on the nitrogen mustard facilitate nucleophilic attack of nitrogen to form an imminium ion (R3N). This highly reactive ion undergoes alkylation at N7 of guanine to form a 51
monoalkylated product on the DNA strand. Repetition of this cycle causes cross-linking of DNA. In the case of chlorambucil, two complementary strands of DNA are cross-linked. 41 Cross-linking of DNA prevents separation of DNA strands for transcription and subsequent failure of transcription leads to apoptosis. Chlorambucil can also covalently bond to RNA and proteins through a similar mechanism. 42 Figure 4. Chemical composition of chlorambucil Chlorambucil is considered cell cycle non-specific. Following oral administration, chlorambucil is rapidly and nearly completely absorbed from the gastrointestinal tract. It is highly protein bound in plasma. The major route of metabolism is spontaneous hydrolysis, though chlorambucil is also metabolized in the liver to form phenylacetic acid mustard (active compound). Phenylacetic acid mustard is further metabolized to inactive products which are excreted in the urine and faeces. 43 Indications in Dermatology Human Table 1. Selected dermatologic diseases where chlorambucil has shown to be of benefit Neoplastic disease Pyoderma gangrenosum 44 Cutaneous T cell lymphoma 45, 46 Behçet’s disease Sézary syndrome 46 Necrobiotic xanthogranuloma 49 Cutaneous B cell lymphoma 50 Cutaneous sarcoidosis 51 Non-neoplastic disease Sweet’s syndrome 52 Pemphigus vulgaris 53 Bullous pemphigoid 54 Pemphigus foliaceous 53 Dermatomyositis 55 Veterinary Table 2. Selected dermatologic diseases where chlorambucil may be of benefit Mast cell tumour 56, 57 Discoid lupus erythematosus 22 Feline eosinophilic granuloma complex 58 Systemic lupus erythematosus 22 Pemphigus foliaceous 21, 22 Immune-mediated vasculitis 22 Pemphigus vulgaris 21, 22 Cold agglutinin disease 22 Superficial pemphigus complex 21, 22 Urticaria pigmentosa 56 Bullous pemphigoid 22 ? Cutaneous T cell lymphoma 59 Adverse effects Haematologic Bone marrow toxicity is the most common side effect of chlorambucil therapy. It may be mild and transient, or severe and progressive. Myelosuppression is manifested by anaemia, leukopenia and thrombocytopenia. Leukocyte nadir may take 7-14 days, with recovery from 7-28 days. Severe pancytopenia may take months to years to achieve full recovery. 43 Gastrointestinal Nausea and vomiting are frequent side effects of alkylating agent administration, including chlorambucil. Nausea has been reported within minutes of administration of the drug in humans, but may takes hours or days to become clinically apparent. 42 In general, traditional antiemetics are poorly effective in controlling vomiting with these agents. Intractable nausea and/or vomiting may require hospitalization and symptomatic therapy. A dose reduction should be considered in severe cases. Hepatotoxicity has been documented in humans and animals with alkylating agents, 42, 43, 60 however chlorambucil has a higher safety margin than other alkylating agents (e.g. lomustine) thus fatal hepatoxicity with this drug is rarely reported in the human literature and, to the authors’ knowledge, has not been reported in the veterinary literature. 47, 48 52
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