Disease relevance of Cereport

• Autoradiographic studies in rat models further demonstrated that labradimil increases the permeability of the BBB in gliomas [1].
• These data indicated that Cereport infused with ACV enhances both the penetration and efficacy of this drug in the treatment of an experimental HSV-1 infection of the rat brain [2].
• These data offer fundamental information regarding the effects of Cereport on delivery of chemotherapeutic agents to brain tumors and provide new insight into receptor-mediated permeability of the blood-brain tumor barrier [3].
• METHODS: For biodistribution studies, Fischer rats bearing intracerebral implants of the F98 glioma received i.v. or i.c. injections of 300 or 500 mg/kg body weight (b.w.) of BPA with or without i.c. infusion of 1.5 microg/kg b.w. of Cereport [4].
• METHODS: In 43 chemotherapy naïve patients, 26 glioblastoma multiforme (GBM) + 17 anaplastic astrocytoma (AA), median age 45 years, MRI responses to intravenous cereport and carboplatin were assessed at baseline, then at 2 monthly intervals [5].

Psychiatry related information on Cereport

• Intravenous administration of a combination of Cereport and loperamide produced a significant analgesic effect (2-fold increase in response times) when animals were tested on a hotplate apparatus [6].

High impact information on Cereport

• In vitro studies demonstrate that labradimil has a longer half-life than bradykinin and selectively binds to bradykinin B2 receptors, initiating typical bradykinin-like second messenger systems, including increases in intracellular calcium and phosphatidylinositol turnover [1].
• Initial proof of principle studies using electron microscopy demonstrated that intravenous labradimil increases the permeability of the BBB by disengaging the tight junctions of the endothelial cells that comprise the BBB [1].
• Cereport, infused intravenously via the jugular vein, was shown to increase [(14)C]ACV uptake in both the HSV-1-infected and -uninfected rat brain by approximately two- to threefold, correlating with enhanced efficacy of ACV in various brain compartments [2].
• The purpose of the present study was to determine if the efficacy of boron neutron capture therapy (BNCT) could be improved by either Cereport (RMP-7) mediated modulation of blood-brain barrier (BBB) permeability or hyperosmotic mannitol-induced BBB disruption using boronophenylalanine (BPA) as the capture agent [7].
• Rats that received intracarotid BPA with Cereport had an MeST of 86 days with 36% long-term survivors, which was very close to that of rats that had hyperosmotic mannitol-induced disruption of the BBB (85 days with 25% long-term survivors) [7].

Chemical compound and disease context of Cereport

• Intra-arterial Cereport (RMP-7) and carboplatin: a dose escalation study for recurrent malignant gliomas [8].
• PURPOSE: To determine the pharmacokinetics of adaptively dosed carboplatin when administered in combination with the bradykinin agonist, lobradimil (RMP-7, Cereport), to pediatric patients with brain tumors [9].
• Thus, while the data support the use of Cereport as adjunctive therapy in the treatment of glioma patients, they also warn that the use of dexamethasone may reduce delivery of chemotherapeutic agents to brain tumors, even when special pharmacologic measures are employed to enhance delivery [10].

Biological context of Cereport

• A subsequent experiment established that a major factor responsible for the lack of an effect with the co-infusion paradigm was tachyphylaxis to Cereport during the 15 min infusion, for a progressively diminished response to Cereport occurred over that time frame, as plasma levels of carboplatin were rising [11].
• This effect was related to the dose of Cereport in the phase I study (AUC values 104-133% of target, Spearman rank correlation coefficient = 0.71, P < 0.001) [12].

Anatomical context of Cereport

• At the physical level we demonstrate that Cereport modifies the tumor vasculature in several important ways, including transient 1) reductions in interstitial fluid pressure within the tumor, 2) increases in pore size of the vasculature, and 3) increases in total vascular surface area [13].
• METHODS: HBMEC grown on transwell membranes were exposed to Cereport [14].

Associations of Cereport with other chemical compounds

• An analysis of the time course of analgesia revealed a graded onset of analgesia which peaked at 30 min, maintained asymptote at 60 min, and began to diminish by 120 min following Cereport and loperamide administration [6].
• Cereport was also tested in combination with the chemotherapeutic drugs carboplatin, vinorelbine, gemcitabine and carmustine to determine if Cereport could enhance the survival benefit beyond that provided by chemotherapy alone [15].
• Cyclic AMP-specific phosphodiesterase 3 (PDE3) inhibitor rolipram (10 micromol/L) abolished Cereport effects, while cGMP-specific PDE5 inhibitor, zaniprast (50 micromol/L) enhanced by 31% (p < 0.05) the effect of 0.1 nmolL Cereport [14].

Analytical, diagnostic and therapeutic context of Cereport

• Survival studies in rodent models of both gliomas and metastatic tumours in the brain demonstrate that the enhanced uptake observed with the combination of labradimil and water-soluble chemotherapeutics enhances survival to a greater extent than achieved with chemotherapy alone [1].
• Intravenous infusions of the bradykinin agonist Cereport (labradimil, formerly RMP-7) enhance delivery of concomitantly administered hydrophilic chemotherapeutic agents to solid tumors [13].
• Animals were pretreated with vehicle, CsA alone (1 mg/kg, a low dose without either immunosuppressive or neuroprotective effects, or 10 mg/kg, a high dose that produces both immunosuppression and neuroprotection), or CsA (1 mg/kg) in combination with Cereport (9 microg/kg) [16].
• After treatment, animals received a 15-min intracarotid infusion of Cereport (4.5 micrograms/kg) and a bolus of [14C]carboplatin [10].

References