Cladribine: Mode of Action and Implications for Treatment of Multiple Sclerosis

  title={Cladribine: Mode of Action and Implications for Treatment of Multiple Sclerosis},
  author={Thomas P. Leist and Robert Weissert},
  journal={Clinical Neuropharmacology},
Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system. The inflammation is driven significantly by autoreactive lymphocytes, which recruit cells of the innate immune system such as macrophages that contribute to subsequent tissue damage, ultimately resulting in demyelination and axonal damage that are characteristic in MS lesions. Cladribine (2-chlorodeoxyadenosine [2-CdA]) is a synthetic chlorinated deoxyadenosine analog that is biologically active… 

Current and Emerging Therapies for the Treatment of Multiple Sclerosis: Focus on Cladribine

A recent placebo-controlled, double-blind study of cladribine showed decreased relapse rates, risk of disability progression and MRI measures of disease activity at 96 weeks, but concerns about safety prevented the FDA from approvingcladribine in 2011, so use of clad ribine for treatment of relapsing and remitting multiple sclerosis will remain off-label.

Cladribine: mechanisms and mysteries in multiple sclerosis

The hypothesis that cladribine’s action of benefit is to deplete memory B cells is important: if correct, it implies that selective targeting of this cell population and sparing of other lymphocytes could modify disease activity without predisposing to immunosuppression-related complications.

Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells

Selective B cell cytotoxicity coupled with slow repopulation kinetics results in long-term, memory B cell depletion by cladribine, which may offer a new target, possibly with potential biomarker activity, for future drug development.

Cladribine tablets’ potential role as a key example of selective immune reconstitution therapy in multiple sclerosis

  • A. BoykoO. Boyko
  • Medicine, Psychology
    Degenerative neurological and neuromuscular disease
  • 2018
Clinical benefits of cladribine tablets in these studies include decreased relapse rate and disability progression with large reductions in lesion activity, and protection against brain volume loss, which clearly point to an interesting area of research.

Cladribine Tablets for Relapsing–Remitting Multiple Sclerosis: A Clinician’s Review

Cladribine tablets represent a selective, high-efficacy, oral form of IRT for patients with MS that targets lymphocytes and spares innate immune cells and is associated with a lower monitoring burden than many other DMTs, while short dosing periods can help to improve adherence.

Cladribine tablets for the treatment of relapsing–remitting multiple sclerosis

This article provides an overview of the chemistry, mechanism of action and pharmacological properties of cladribine tablets therapy, and highlights the rationale for its development as an oral treatment for MS.

Effects of cladribine on primary rat microglia and human monocyte-derived dendritic cells Submitted in partial fulfilment of the requirements for the degree DOCTOR OF PHILOSOPHY ( PhD )

Investigation of the effects of CdA on the induction of apoptosis in human monocytes and monocyte-derived immature (ImDC) and mature (mDC) dendritic cells revealed that caspaseindependent apoptosis is induced in DC and suggests cell type specific effects of cdA, which may contribute to the immunomodulatory effects ofCdA in autoimmune diseases.



Development of oral cladribine for the treatment of multiple sclerosis

The need for new MS therapies to improve treatment adherence is discussed, the mechanism of action, existing efficacy and safety data, and the clinical development of oral cladribine are reviewed; the need for continuous risk monitoring for all new potent immunoactive drugs under development is emphasized.

Cladribine for multiple sclerosis: review and current status

  • J. Sipe
  • Medicine
    Expert review of neurotherapeutics
  • 2005
The proposed study will be the first large multicenter randomized controlled clinical trial of oral cladribine in multiple sclerosis, with evidence of efficacy, tolerability and acceptable side effects/toxicity.

Pharmacological Basis for Cladribine Resistance

The purpose of this review was to elucidate and analyse the available data concerning mechanisms of resistance of cladribine with emphasis on recent advances in the characterization of activating and inactivating enzymes in the induction of resistance tocladribine.

Mechanisms of Action for Treatments in Multiple Sclerosis

The potential mechanisms of action of several effective therapies for MS that are currently available or in development are reviewed and the effects of each treatment are described in terms of their actions on key processes in a five-step model of MS pathogenesis.

Central nervous system-directed effects of FTY720 (fingolimod)

Effect of immunosuppressive cladribine treatment on serum leucocytes system in two-year clinical trial in patients with chronic progressive multiple sclerosis.

Results obtained indicate fast and long-lasting decrease of serum leucocyte level and suppressive influence of cladribine treatment on immune processes in multiple sclerosis patients.

The Clinical Pharmacokinetics of Cladribine

Cladribine is a new purine nucleoside analogue with promising activity in low-grade lymphoproliferative disorders, childhood acute myelogenous leukaemia and multiple sclerosis and there is no correlation between the plasma concentration of cladribine and that of the intracellular metabolites.

Emerging therapeutic targets in multiple sclerosis

The application of novel and cutting-edge technologies in the fields of genomics and proteomics is providing a better understanding of the genetic and environmental factors involved in multiple sclerosis susceptibility and progression, as well as the detection of biomarkers for disease activity and response to therapy.