• Purine nucleoside analogues
• cladribine
• multiple sclerosis
• subcutaneous
• cost
• drug
• re-discovery
• off-label
• immune suppression
• DMT

Cladribine (CdA), a purine nucleoside analogue (PNA) that targets anti-CD4 and 8 T-cells, has recently been repositioned by Merck as an oral disease-modifying therapy for of highly active relaspe-remitting Multiple Sclerosis (RRMS), available as oral cladribine tablets (Mavenclad 10 mg). Its surplus value in the existing panel of disease-modifying therapy (DMT) for MS like the anti-CD20 B-cell targeting monoclonal antibodies, that is, rituximab (mouse chimeric), ocrelizumab (humanised) and ofatumumab (fully human) of which present data suggest that these are very effective in multiple sclerosis, is curious.1 In this personal viewpoint, we would like to highlight the potentially usefulness of PNA’s available and their limitations.

PNAs are active in chronic lymphocytic leukaemia, hairy cell leukaemia (HCL) and off-label in low-grade lymphomas. Cladribine has been used for HCL since the early 1980s as intravenous therapy.2 Cladribine delivered subcutaneously (SC) appeared to be most convenient in HCL and is considered to have equal efficacy compared with intravenous administration. Oral CdA use has been suggested since the early 1990s by Carson et al 3 were it not that being unstable at acidic pH and is degraded by bacterial nucleoside phosphorylases. Other available PNAs are fludarabine (F-Ara) and clofarabine (CAFdA), which all are deoxyadenosine derivatives that act as antimetabolites that compete with natural deoxynucleosides used for DNA synthesis (figure 1).

All of these PNAs need to be metabolised to exert their cytotoxic …

Correspondence to Dr Hans J C Buiter, Clinical Pharmacology and Pharmacy, Amsterdam University Medical Centres, Amsterdam 1081 HV, The Netherlands; hjc.buiter{at}amsterdamumc.nl