Assessment blood-brain barrier

The Rb-82 generator permits serial studies in the same patient as often as every 10 minutes with 20-60 mCi of Rb-82 for rapid bolus intravenous infusion. Inherent in the administration of high levels of Rb-82 activity is the need for precise flow control from an automated system to deliver the desired amount of radioactivity. The development of the alumina column parameters and the elution protocol as well as the automated microprocessor system controller are presented here. Some of the details of this system have been discussed in earlier publications (15,21). Generator produced Rb-82 is used as a diffusible flow tracer in myocardial perfusion studies and as a nondiffusible tracer in brain studies to assess blood brain barrier permeability changes in patients with brain tumors or Alzheimer s type dementia. 

Di, L., Kerns, E.H., and Carter, G.T. (2008) Strategies to assess blood-brain barrier penetration. Expert Opinion on Drug Discovery, 3, 677-687. 

The following substrates were used to assess blood-brain barrier transport systems L-lysine and L-histidine (basic and neutral amino acid systems, respectively), adenine (purine base), thiamine (vitamin), choline (amine), pyruvate (monocarboxylic acid) and 3-hydroxybutyrate (ketone body). Tracer levels of the C-labelled substrates (Amersham International pic) were added to the perfusate at 0.3-1.2 /iCi/ml together with pH]inulin at l.OjUCi/ml as intravascular marker. Following a net perfusion time of 18.5 s, the animal was decapitated. The brain was rapidly removed, sliced into 2 mm coronal sections and quick-frozen on solid CO2. Each slice was dissected on a freezing... 

The steady-state programmed infusion technique (Pratt, 1985) was used to assess blood-brain barrier integrity and to measure regional brain uptake of glucose in both lead exposure models. 

Bressler J, Clark O Driscoll C (2013) Assessing blood-brain barrier function using in vitro assays. Methods Mol Biol 1066 67-79... 

The study of active transport mechanisms has grown substantially in recent years, with transport proteins such as P-gp, BCRP, and MRP-2 among the most studied [59]. Several types of in vitro assays to assess substrates of transporters have been established these include assays directed toward intestinal and biliary efflux [60]. Assays that measure passive and active transport are also used to assess penetration of the blood-brain barrier. In addition to the assays described above, transfected cell lines that overexpress transporters present in the blood-brain barrier are also employed [61]. 

C.J. Bachmeier, T.J. Spitzenberger, W.F. Elmquist, and D.W. Miller. Quantitative assessment of HIV-1 protease inhibitor interactions with drug efflux transporters in the blood-brain barrier. Pharm Res. 22 1259-1268 (2005). 

Distribution, including accumulation of an absorbed substance, will be the same irrespective of the route of administration. However, distribution and accumulation at the site of apphcation (inhalation, oral, dermal) may depend on the route of administration. In such cases, local accumulation may occur and may be responsible for tissue damage. In these cases, systemic toxicokinetics of the substance may be of limited relevance for the risk assessment. It is generally not cmcial for risk assessment to determine the precise tissue distribution profile for a substance. In certain special cases, however, specific tissue distribution studies may assist or even be essential for the interpretation of available toxicological data. For example, it may be of interest to know whether the substance will cross the blood-brain barrier, the placenta barrier, or will accumulate in specific tissues. 

Feng, M.R. (2002) Assessment of blood-brain barrier penetration In silko, in vitro and in vivo. Current Drug Metabolism, 3, 647-657. 

The recent addition of interferon-P-la and interferon-pib to the therapeutic arsenal for the treatment of MS aims to shut down inflammation at the blood-brain barrier and thereby reduce the rate of relapse and decrease frequency and severity of MS disease symptoms.Both P-interferons have demonstrated benefits in the treatment of patients with established MS, including slowing the progression of physical disability, reducing the rate of clinical relapses, and reducing the development of brain lesions, as assessed by MRI. Several trials have found that interferon-pib (Betaseron) reduced the frequency of relapse by approximately 30% [3-5]. These studies also suggested a trend toward a delay in the progression of disability. Interferon-pia (Avonex) was subsequently found to reduce the frequency of relapse [6-8]. 

Witt, K.A., et al. 2000. Insulin enhancement of opioid peptide transport across the blood-brain barrier and assessment of analgesic effect. J Pharmacol Exp Ther 295 972. 

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