Blood-Brain Barrier Disruption in the Treatment of Brain Tumors

Neuwelt, Edward A.; Dahlborg, Suellen A.

doi:10.1007/978-1-4615-7255-8_5

Cited by 39 publications

(31 citation statements)

References 138 publications

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“…Alternatively, a change in endoneurial electrolyte concentrations (Myers et al, 1983) or mannitol itself may cause an alteration of the conformation of opioid receptors from an inactive to an active state and/or a change of the excitability or conductive properties ofaxons (Rechthand and Rapoport, 1987;Powell and Myers, 1989). The latter mechanism, however, seems unlikely in our experiments, since (1) the effects of mannitolopioid combinations were completely reversible by naloxone and (2) mannitol given alone had no effect, which is consistent with clinical studies describing mannitol as an essentially inert substance (Neuwelt and Dahlborg, 1989). The fact that mannitol did not further enhance opioid antinociception in inflamed paws is consistent with the notion that opioid agonists have free access to their receptors due to an already deficient perineurial barrier.…”

Section: Discussionsupporting

confidence: 85%

Perineurial defect and peripheral opioid analgesia in inflammation

et al. 1995

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Opioid receptors have been demonstrated on sensory nerves in both inflamed and normal subcutaneous tissue but locally applied opioid agonists produce analgesia in inflamed tissue only. Inflammation confers a disruption of the perineurial barrier that can also be induced deliberately by hyperosmolar solutions. The present study examines at which stage of Freund's adjuvant-induced inflammation peripheral opioid analgesic effects become manifest and whether a perineurial defect contributes to the appearance of such effects. To this end we have monitored the temporal evolution of inflammatory signs (swelling, temperature, hyperalgesia) and of peripheral antinociceptive effects (by the paw pressure test) of mu-, delta-, and kappa-selective opioids. Using horseradish peroxidase histochemistry, the perineurial barrier was assessed in normal and inflamed tissue and following its artificial disruption by hyperosmolar saline and mannitol in vivo. Finally, we sought to elicit analgesia in normal tissue by the concomitant application of mannitol and receptor-selective opioids or by an extremely lipophilic opioid agonist (fentanyl). We found that peripheral opioid antinociception and perineurial leakage occur simultaneously at a very early stage (within 12 hr) of the inflammatory reaction and that both can be mimicked by the administration of hyperosmolar solutions in normal tissue. Fentanyl produced peripheral antinociception in noninflamed tissue that was potentiated by mannitol or inflammation. Our findings demonstrate that the perineurium is a crucial determinant for peripheral opioid analgesia and that the efficacy of locally applied hydrophilic or lipophilic neuromodulatory compounds can be improved dramatically by the concomitant modulation of perineurial permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionsupporting

confidence: 85%

Perineurial defect and peripheral opioid analgesia in inflammation

et al. 1995

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“…infusion: that is, K 1 is transiently increased, as is AUC PL . This method was originally proposed by Rapoport (Rapoport and Thompson, 1973) and has been used extensively by Neuwelt and colleagues (Kroll and Neuwelt, 1998;Neuwelt and Dahlborg, 1989;Neuwelt et al, 1980;Neuwelt et al, 1983). Controversy about the use of this method arose because of differential susceptibility of the normal BBB as compared with the abnormal BTB.…”

Section: Hyperosmolar Blood-brain Barrier Disruption (Hbbbd)mentioning

confidence: 99%

The blood-brain and blood-tumor barriers: A review of strategies for increasing drug delivery

Groothuis¹

2000

Neuro-Oncol

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Drug delivery to brain tumors has been a controversial subject. Some believe the blood-brain barrier is not important, while others believe it is the major obstacle in treatment and have devised innovative approaches to circumvent it. These approaches can be divided into two categories: those that attempt to increase drug delivery of intravascularly administered drugs by manipulating either the drugs or capillary permeability, and those that attempt to increase drug delivery by local administration. Several strategies have been developed to increase the fraction of intravascular drug reaching the tumor, including intraarterial administration, barrier disruption, new ways of packaging drugs, and, most recently, inhibiting drug ef ux from tumor. When given intravascularly, all drugs have a common drawback: the body acts as a sink, and, even in the best situations, only a small fraction of administered drug actually reaches the tumor. A consequence is that systemic toxicity is usually the dose-limiting factor. When given locally, such as into the cerebrospinal uid or directly into the tumor, 100% of an administered dose is delivered to the target site. However, local delivery is associated with variable and unpredictable spatial distribution and variation in drug concentration. The major dose-limiting factor of most local delivery methods will be neurotoxicity. The relative advantages and disadvantages of the different methods of circumventing the blood-brain barrier are presented in this review, and special attention is given to convection-enhanced delivery, which has particular promise for the local delivery of large therapeutic agents such as monoclonal antibodies, antisense oligonucleotides, or viral vectors. Neuro-Oncology 2, 45-59, 2000 (Posted to Neuro-Oncology [serial online], Doc. 99-30, December 14, 1999 IntroductionThe delivery of drugs to brain tumors has long been a controversial problem. In 1977, Vick et al. wrote in an editorial: "We believe that there is compelling evidence to suggest that the 'blood-brain barrier,' as it is generally conceived, is not one of the factors impeding the success of brain tumor chemotherapy." They went on to say that "dosage, route of administration, tumor cell uptake, metabolic fate within tumor cells, and the washout or sink effect of the extracellular space and CSF are the issues that will have to be studied" (Vick et al., 1977). Some clinicians have agreed with Vick et al. (Donelli et al., 1992;Stewart, 1994); however, on the whole, the belief that the BBB 3 and BTB prevent drugs from reaching brain tumors in suf cient concentrations to kill the tumor cells has motivated numerous attempts to increase the amount of drug that reaches the tumor. Many innovative methods have been used to try to increase drug delivery including, most recently, a method in which drugs are infused directly into brain tumors, a method referred to as convection-enhanced delivery (CED) Laske et al., 1997a;Lieberman et al., 1995). This review Neuro-Oncology n J AN UA RY 2 0 00 45Neuro-Oncology

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“…28 Antonijevic et al 24 demonstrated that the injection of 0.5 M mannitol into rat plantar subcutaneous paw tissue was without ill effect. The hypertonic solution of mannitol did not induce an inflammatory cell infiltrate when the tissues were examined histologically.…”

Section: Discussionmentioning

confidence: 99%

Anesthetic Efficacy of a Combination of 0.5 M Mannitol Plus 36.8 mg of Lidocaine With 18.4 μg Epinephrine in Maxillary Infiltration: A Prospective, Randomized, Single-Blind Study

Younkin

Reader

Drum

et al. 2014

Anesthesia Progress

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The purpose of this prospective, randomized, single-blind study was to determine the anesthetic efficacy of lidocaine with epinephrine compared to lidocaine with epinephrine plus 0.5 M mannitol in maxillary lateral incisor infiltrations. Forty-one subjects randomly received 2 maxillary lateral infiltrations consisting of a 1.84-mL solution of 36.8 mg lidocaine with 18.4 lg epinephrine (control solution) and a 2.90-mL solution of 36.8 mg lidocaine with 18.4 lg epinephrine (1.84 mL) plus 0.5 M mannitol (1.06 mL) in 2 separate appointments spaced at least 1 week apart. The maxillary lateral incisor was blindly electric pulp-tested in 2-minute cycles for 60 minutes postinjection. No response from the subject to the maximum output (a reading of 80) of the pulp tester was used as the criterion for pulpal anesthesia. Total percent pulpal anesthesia was defined as the total of all pulpal anesthesia readings (at output of 80) over the 60-minute test period. Pain during solution deposition and postoperative pain were also measured. The results demonstrated that a 2.90-mL solution of 36.8 mg lidocaine with 18.4 lg epinephrine (1.84 mL) plus 0.5 M mannitol (1.06 mL) was not statistically significantly superior to a 1.84-mL solution of 36.8 mg lidocaine with 18.4 lg epinephrine. The pain of solution deposition was lower with the lidocaine/mannitol formulation. Postoperative pain was not statistically significantly different between the lidocaine/mannitol formulation and the lidocaine formulation without mannitol. We concluded that adding 0.5 M mannitol to a lidocaine with epinephrine formulation was not significantly more effective in achieving a greater percentage of total pulpal anesthesia (as defined in this study) than a lidocaine formulation without mannitol in the maxillary lateral incisor.

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Blood-Brain Barrier Disruption in the Treatment of Brain Tumors

Cited by 39 publications

References 138 publications

Perineurial defect and peripheral opioid analgesia in inflammation

Perineurial defect and peripheral opioid analgesia in inflammation

The blood-brain and blood-tumor barriers: A review of strategies for increasing drug delivery

Anesthetic Efficacy of a Combination of 0.5 M Mannitol Plus 36.8 mg of Lidocaine With 18.4 μg Epinephrine in Maxillary Infiltration: A Prospective, Randomized, Single-Blind Study

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