Intrathecal Drug Administration

Kroin, Jeffrey S.

doi:10.2165/00003088-199222050-00001

Cited by 60 publications

(6 citation statements)

References 50 publications

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“…Different technologies to bypass the BBB include disrupting this barrier, transnasal drug delivery, and intrathecal drug delivery to the cerebrospinal fluid (CSF) ( 1 ). Intrathecal drug delivery to the CNS has a long tradition for treatment of pain and spasticity ( 2 , 3 ) and is increasingly being investigated for treatment of different neurodegenerative diseases targeted both on the brain and on the spinal cord — for example, Huntington′s disease, spinal muscular atrophy (SMA), and amyotrophic lateral sclerosis ( 4 – 7 ).…”

Section: Introductionmentioning

confidence: 99%

In vivo distribution of cerebrospinal fluid tracer in human upper spinal cord and brain stem

Melin,

Pripp,

Eide

et al. 2023

JCI Insight

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BACKGROUND Intrathecal injection is an attractive route through which drugs can be administered and directed to the spinal cord, restricted by the blood-spinal cord barrier. However, in vivo data on the distribution of cerebrospinal fluid (CSF) substances in the human spinal cord are lacking. We conducted this study to assess the enrichment of a CSF tracer in the upper cervical spinal cord and the brain stem. METHODS After lumbar intrathecal injection of a magnetic resonance imaging (MRI) contrast agent, gadobutrol, repeated blood samples and MRI of the upper cervical spinal cord, brain stem, and adjacent subarachnoid spaces (SAS) were obtained through 48 hours. The MRI scans were then analyzed for tracer distribution in the different regions and correlated to age, disease, and amounts of tracer in the blood to determine CSF-to-blood clearance. RESULTS The study included 26 reference individuals and 35 patients with the dementia subtype idiopathic normal pressure hydrocephalus (iNPH). The tracer enriched all analyzed regions. Moreover, tracer enrichment in parenchyma was associated with tracer enrichment in the adjacent SAS and with CSF-to-blood clearance. Clearance from the CSF was delayed in patients with iNPH compared with younger reference patients. CONCLUSION A CSF tracer substance administered to the lumbar thecal sac can access the parenchyma of the upper cervical spinal cord and brain stem. Since CSF-to-blood clearance is highly individual and is associated with tracer level in CSF, clearance assessment may be used to tailor intrathecal treatment regimes. FUNDING South-Eastern Norway Regional Health and Østfold Hospital Trust supported the research and publication of this work.

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Section: Introductionmentioning

confidence: 99%

In vivo distribution of cerebrospinal fluid tracer in human upper spinal cord and brain stem

Melin,

Pripp,

Eide

et al. 2023

JCI Insight

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“…It is used as a racemic mixture, but studies reveal that both the enantiomers show significant differences in their pharmacological effects. Only the (R)-enantiomer is stereoselectively active on GABA B -receptors, whereas the (S)-enantiomer is almost inactive, sometimes toxic, and even antagonizes the effects of (R)-enantiomer [5,6]. Also, the (R)-enantiomer is known to decrease the heart rate and arterial pressure, whereas the (S)-enantiomer has no effect on heart rate, on the contrary, it increases the arterial pressure [7].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of three strong UV-absorbing Naproxen-based chiral derivatizing agents and their application for enantioseparation of Baclofen by RP-HPLC

Batra¹,

Bhushan²

2015

Acta Chromatographica

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Summary.A sensitive and stereoselective high-performance liquid chromatography (HPLC) method based on diastereomer formation was developed and fully validated for the simultaneous determination of the two enantiomers of Baclofen. (S)-Naproxen was used to prepare three chiral derivatizing reagents (CDRs) which were used for synthesizing diastereomers of Baclofen. The diastereomers so synthesized were separated on C 18 column under reversed phase conditions using a binary mixture of acetonitrile and triethylammonium phosphate, with UV detection at 220 nm. The results obtained for enantioseparation of Baclofen using the three CDRs have been compiled and compared. The conditions for derivatization and chromatographic separation have been optimized. The method was validated for linearity, repeatability, limits of detection, and limit of quantification.

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“…The major obstacle for drug delivery to the brain is the blood brain barrier (BBB), which prevents nearly all large molecules and 98% of small molecular drugs from entering the central nervous system (CNS) . Although nanoparticle-based delivery systems, intrathecal administration strategy, nasal administration strategy, and BBB reversible open strategy were reported to challenge BBB and achieve successful brain accumulation, their targeting efficiency has remained relatively low and safety issues were observed when they were administered systemically. − Prodrug approaches, however, with relatively high brain targeting efficiency and low systemic toxicity have appeared as a promising strategy.…”

Section: Introductionmentioning

confidence: 99%

Scopine as a Novel Brain-Targeting Moiety Enhances the Brain Uptake of Chlorambucil

Wang

et al. 2014

Bioconjugate Chem.

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The blood brain barrier (BBB) represents the biggest challenge for therapeutic drugs to enter the brain. In our study, we selected chlorambucil (CHL), an alkylating agent, as the model therapeutic agent, and used scopine as a novel brain-targeting moiety. Here, we synthesized Chlorambucil-Scopine (CHLS) prodrug and evaluated its brain-targeting efficacy. The tissue distribution study after i.v. injection revealed that the AUC0-t and Cmax of CHLS in the brain were 14.25- and 12.20-fold of CHL, respectively. Specifically, CHLS accumulated in bEnd.3 and C6 cells in an energy-dependent manner. In C6 cells, superior anti-glioma activity with a significantly decreased IC50 of 65.42 nM/mL was observed for CHLS compared to CHL (IC50 > 400 nM/mL). The safety evaluation, including acute toxicity, pathology, and hematology study, showed minimal toxicity toward nontargeting tissues, and also reached a lower systemic toxicity at 5 mg/kg (i.v.). Our results suggested that scopine is a potential brain-targeting moiety for enhancing the brain uptake efficiency of CHL.

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Intrathecal Drug Administration

Cited by 60 publications

References 50 publications

In vivo distribution of cerebrospinal fluid tracer in human upper spinal cord and brain stem

In vivo distribution of cerebrospinal fluid tracer in human upper spinal cord and brain stem

Synthesis of three strong UV-absorbing Naproxen-based chiral derivatizing agents and their application for enantioseparation of Baclofen by RP-HPLC

Scopine as a Novel Brain-Targeting Moiety Enhances the Brain Uptake of Chlorambucil

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