Efflux of radiolabeled polyethylene glycols and albumin from rat brain

Cserr, Helen F.; Cooper, Douglas N.W.; Suri, Parmjeet K.; Patlak, Clifford S.

doi:10.1152/ajprenal.1981.240.4.f319

Cited by 220 publications

(236 citation statements)

References 0 publications

Supporting

Mentioning

219

Contrasting

Unclassified

Order By: Relevance

“…This is partly the result of the very slow turnover of brain extracellular¯uid, which drains into the CSF (Cserr et al, 1981;Szentesvanyi et al, 1984), but is also related to the rate of bulk¯ow of the CSF out of the ventricles (Collins & Dedrick, 1983). Thus the CSF acts as a sink to the brain rather than the brain acting as a sink to the CSF (Davson et al, 1961).…”

Section: Discussionmentioning

confidence: 99%

“…The CSF bathes the exterior surfaces of the brain and ®lls the ventricles. Although exchange between brain and CSF is relatively unrestricted, the sink action of the CSF to the brain tissue prevents the CSF and brain interstitial uid from being in dynamic equilibrium (Davson et al, 1961;Cserr et al, 1981;Szentesvanyi et al, 1984). Overall, it would justi®ably appear that the blood-CSF barrier has the same functional goals as the BBB, with regard to protection and homeostasis, however the actual behaviour and ultrastructure of the choroid plexuses are quite di erent from that of the cerebral capillaries.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The transport of the anti‐HIV drug, 2′,3′‐didehydro‐3′‐deoxythymidine (D4T), across the blood‐brain and blood‐cerebrospinal fluid barriers

Thomas

Segal

1998

British J Pharmacology

View full text Add to dashboard Cite

1 The brain is a site of infection, viral replication and sanctuary for HIV-1. The treatment of HIV-1 infection therefore requires that an e ective agent be delivered to the brain. 2',3'-Didehydro-3'-deoxythymidine (D4T) is a nucleoside analogue which has been shown to have bene®cial clinical e ects in the treatment of HIV infection. However, although D4T has been detected in human CSF, the ability of this drug to cross both the blood-brain and blood-cerebrospinal¯uid (CSF) barriers and gain entrance into the brain tissue is not known. 2 This study examined the CNS entry of D4T by means of the bilateral vascular brain perfusion technique in the anaesthetized guinea-pig. 3 The results indicated that [ 3 H]-D4T had a limited ability to cross the blood-brain barrier (BBB), which was not signi®cantly greater than D-[ 14 C]-mannitol (a slowly penetrating marker molecule). Although D4T was found to cross the blood-CSF barrier, the presence of D4T in the CSF did not re¯ect levels of the drug in the brain tissue. 4 These results can be related to the measured low lipophilicity of D4T, the higher paracellular permeability characteristics of the choroid plexus (blood-CSF barrier) compared to the BBB, and the sink action nature of the CSF to the brain tissue. 5 In conclusion, these animal studies suggest that D4T may only penetrate the brain tissue to a limited extent and consideration should be given to these ®ndings in the clinical situation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The transport of the anti‐HIV drug, 2′,3′‐didehydro‐3′‐deoxythymidine (D4T), across the blood‐brain and blood‐cerebrospinal fluid barriers

Thomas

Segal

1998

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…For camptothecin, the elimination rate was determined in rat brains by measuring the total amount of CPT released from a biodegradable polymer implant and remaining in the brain at various time points after implantation. Elimination of PEG4000 and PEG900 has been previously studied in the rat brain (13). We have estimated the conjugate elimination rate in a human brain based on these rat data.…”

Section: Methodsmentioning

confidence: 99%

Conjugation to Increase Treatment Volume during Local Therapy: A Case Study with PEGylated Camptothecin

2007

View full text Add to dashboard Cite

Controlled release of chemotherapy drugs from polymer implants placed directly at the tumor site is a proven method for treatment of cancers of the brain. Although this method provides high doses of drug at the tumor site, the drug does not penetrate far enough into the brain for optimum treatment in most cases. Rapid drug elimination leads to more than a 10-fold drop in concentration within 2 mm of the implant. Conjugation to water-soluble polymers, such as poly(ethylene glycol) (PEG) or dextran, has the potential to increase drug distribution in the brain. We have recently PEGylated the chemotherapy drug camptothecin and found a large increase in the extent of distribution of camptothecin in the rat brain, but most of the drug in tissue was in the less-active conjugated form. Stability of the conjugation bond, activity of the drug-polymer conjugate, solubility of the conjugate relative to the drug, and molecular weight of the polymer must all be considered in the design of a conjugate to maximize drug distribution. Therefore, to optimize the PEGylated system, we have developed a pharmacokinetic model to determine the relative importance of parameters involved in the distribution of drug-polymer conjugates after release from a polymer implant. Our modeling shows that PEGylation has the potential to increase treatment distances to more than a centimeter, which may be sufficient to prevent the recurrence of human brain tumors.

show abstract

“…It remains unclear as to whether this response arose de novo within the CSF or whether it crossed from the blood compartment. Brightman (1969) and Cserr et al (1981) have reported that clearance of macromolecules from the CSF to the blood occurs through bulk flow. Both researchers found that a range of molecules of differing sizes cleared from the CSF at similar rates.…”

Section: Discussionmentioning

confidence: 99%

Dose escalation with repeated intrathecal injections of 131I-labelled MAbs for the treatment of central nervous system malignancies

Kemshead

Hopkins²,

Pizer³

et al. 1998

Br J Cancer

View full text Add to dashboard Cite

Summary We have previously demonstrated a 33% response rate in patients with primitive neurectodermal tumours after the direct injection of 1311-monoclonal antibodies (MAbs) into the cerebrospinal fluid (CSF). Dose-limiting toxicity is myelosuppression due to the passage of the radioimmunoconjugate from the CSF to the blood compartment. This occurs at doses of 2220 MBq of 131 I-MAb and above, although this is not seen in all patients studied and appears to be related to the degree of prior therapy received. Rather than attempting to improve the efficacy of this approach to the treatment of disseminated disease within the CSF compartment by dose escalation and haemopoietic rescue, we have explored the possibility of repeatedly administering the radioimmunoconjugate. Eight patients were recruited to the study, two of whom received two and six of whom received three injections of 1311-MAb. After repeated administration of '311-MAb pharmacokinetic data revealed that, with one exception, the radioimmunoconjugate cleared from the CSF compartment with similar kinetics, while its residence time in the blood decreased with each injection. This was due to the development of an anti-mouse Ig response in the blood. Clearance of 131I-MAb from the ventricular CSF appears to be independent of the presence of an anti-mouse Ig response in this compartment. The differential clearance of the radioimmunoconjugate from the ventricular CSF and from the blood results in a marked increase in the therapeutic index that can be achieved. Up to 5920 MBq of '311-MAb was administered as the third injection of radioimmunoconjugate and combined doses of up to 12 500 MBq were given without either haematological or neurological toxicity. These data illustrate that dose escalation and thus an increase in the dose rate delivered to tumour cells within the CSF is possible if ways are found to reduce the residence time of the radioimmunoconjugate in the blood compartment. Suggestions as to how this can best be achieved are reviewed in detail.

show abstract

Efflux of radiolabeled polyethylene glycols and albumin from rat brain

Cited by 220 publications

References 0 publications

The transport of the anti‐HIV drug, 2′,3′‐didehydro‐3′‐deoxythymidine (D4T), across the blood‐brain and blood‐cerebrospinal fluid barriers

The transport of the anti‐HIV drug, 2′,3′‐didehydro‐3′‐deoxythymidine (D4T), across the blood‐brain and blood‐cerebrospinal fluid barriers

Conjugation to Increase Treatment Volume during Local Therapy: A Case Study with PEGylated Camptothecin

Dose escalation with repeated intrathecal injections of 131I-labelled MAbs for the treatment of central nervous system malignancies

Contact Info

Product

Resources

About