Elsevier

Brain Research Bulletin

Volume 60, Issue 3, 15 May 2003, Pages 297-306
Brain Research Bulletin

Facilitation of drug entry into the CNS via transient permeation of blood brain barrier: laboratory and preliminary clinical evidence from bradykinin receptor agonist, Cereport

https://doi.org/10.1016/S0361-9230(03)00043-1Get rights and content

Abstract

One novel approach of transporting drugs into the central nervous system (CNS) involves the activation of receptors on the endothelial cells comprising the blood brain barrier (BBB). Recently the selective B2 bradykinin receptor agonist, Cereport (also called RMP-7), has been shown to transiently increase permeability of the BBB. Although initially developed to increase the permeability of the vasculature feeding glioma, recent studies have demonstrated that Cereport also increases the delivery of pharmacological agents across the normal (i.e. nontumor) BBB. In this review paper, we discuss evidence of enhanced CNS delivery of carboplatin, loperamide, and cyclosporin-A, which are accompanied by enhanced chemotherapeutic, analgesic and neuroprotective effects, respectively. These observations suggest feasibility of Cereport as an adjunct therapy to pharmacological treatments that require drug availability in the CNS to exert therapeutic efficacy. Because many potential drugs for CNS disorders normally do not cross the BBB, Cereport-induced transient permeation of BBB stands as an efficacious strategy for enhancing pharmacotherapy.

Section snippets

Introduction: the blood brain barrier (BBB) impedes drug delivery to the central nervous system (CNS)

Progressive CNS diseases are characterized by the continuous deterioration of both cognitive and motor functions leading to prolonged periods of increasing incapacity. Among the most problematic and prevalent neurological disorders are those associated with the loss of specific populations of brain neurons. Today, approximately 12 million people in the United States suffer from such neurological disorders. Estimated costs in the United States of public expenditures and secondary medical

Bradykinin receptor stimulation as a means to enhance drug delivery across the BBB

One approach that has been explored over the past two decades involves the administration of endogenous ligands or their analogs to increase permeability of the BBB by activation of receptors on the endothelial cells comprising the BBB. Brain endothelial cells possess numerous neurotransmitter and peptide receptors on both their luminal and abluminal membrane surfaces 8., 82., 83., 85., 86., 88.. These receptors are coupled to traditional second messenger systems involving calcium fluxes, G

Enhanced delivery of chemotherapeutics into brain tumors and normal brain

The majority of in vivo studies of Cereport have focused on its ability to increase the permeability of the vasculature supplying gliomas to enhance the delivery of hydrophilic chemotherapeutics 28., 61.. An extensive series of autoradiographic studies using the RG2 rat model of glioma, demonstrated that both intravenous 4., 23. and intracarotid infusions 2., 22., 24. of Cereport produce a dose related increase in the permeability of the blood brain tumor barrier (BBTB). The uptake effects

Conclusion

The safe and effective administration of Cereport offers a novel way of facilitating pharmacologic effects in the CNS. The preceeding laboratory and clinical data provide evidence of enhanced chemotherapeutic, analgesic and neuroprotective effects when Cereport is administered in combination with carboplatin, loperamide and CsA, respectively. There are only minimal side effects seen in animals, as well as patients who received Cereport. Consistent among these studies is the indication that

Acknowledgements

The authors express their gratitude to Jeffrey G. Lind who provided expert technical assistance in the final preparation of the manuscript.

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