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Abstract

The effects of an intravenous (i.v.) injection of the bradykinin analog RMP-7 (100 ng/kg) were assessed in normal dogs and dogs with focal, radiation-induced brain lesions. A dose of 20 Gy was delivered to a point 0.75 cm from a removable interstitial 125I source; parameters relating to blood flow and permeability were quantified using computed tomography 2-8 weeks after irradiation. Blood flow-related endpoints included regional cerebral blood flow (rCBF), mean transit time of blood and vascular volume, while endpoints related to permeability included blood-to-brain transfer constant (Ki), brain-to-blood transfer constant and plasma volume. In unirradiated brain, an i.v. bolus of RMP-7 administered through the left cephalic vein induced a rapid and transient hypotension and a statistically significant increase in vascular volume; no alterations in any parameter related to permeability were observed. After irradiation, changes in rCBF after RMP-7 depended upon time after exposure, effects presumably due to changing morphology in the irradiated tissues. In the radiation lesions, significant increases in Ki were observed 5 minutes after injection of RMP-7, but those increases were not related to time after irradiation or alteration in blood flow-related parameters. Our results showed that RMP-7 selectively increased permeability in already damaged vasculature without affecting the extent or volume of radiation-induced vasogenic edema. These data suggest that RMP-7 may provide an effective means to enhance the delivery of compounds to an already compromised brain while not exacerbating the potential adverse effects of pre-existing vasogenic edema.

A Historical Review of Brain Drug Delivery

“…Intra-arterial RMP-7 caused no BBBD in normal brain in humans [212], which is consistent with an abluminal expression of the BK receptor. Intravenous administration of RMP-7 caused no BBBD in dogs [213] or rats [214]. Intravenous RMP-7 did not increase the clinical efficacy of carboplatin in a RCT of malignant glioma [215].…”

Blood-brain barrier permeability following conventional photon radiotherapy – A systematic review and meta-analysis of clinical and preclinical studies

“…, 27 (55%), investigate BBB disruption in rats [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] , [77] . In addition, eleven (22%) studies use mice [12] , [78] , [79] , [80] , [81] , [82] , [83] , [84] , [85] , [86] , [87] , five involve rabbits [88] , [89] , [90] , [91] , [92] , two include dogs [93] , [94] , two describe monkeys [95] , [96] , one article studied the effects of RT on the BBB in sharks [97] and one in pigs [98] .…”

Pharmacological Modulation of Blood–Brain Barrier Permeability by Kinin Analogs in Normal and Pathologic Conditions

“…Radiation therapy is part of the standard treatment paradigm for CNS tumors [ 57 ]. The short-term effects of prior radiotherapy on the BBB opening induced by Labradimil have been investigated in normal and focal-irradiated dog brains [ 58 ]. Results showed that a single, early i.v.…”