scholarly journals Neurodevelopment Outcome of Neonates Treated With Intraventricular Colistin for Ventriculitis Caused by Multiple Drug-Resistant Pathogens—A Case Series

2021 ◽  
Vol 8 ◽  
Author(s):  
Kashif Hussain ◽  
Muhammad Sohail Salat ◽  
Gul Ambreen ◽  
Javaid Iqbal
Keyword(s):  
Blood Brain Barrier ◽  
Case Series ◽  
Brain Barrier ◽  
Multiple Drug ◽  
Klebsiella Pneumonia ◽  
Drug Resistant ◽  
Neurodevelopmental Outcomes ◽  
Average Birth Weight ◽  
Blood Brain ◽  
Multiple Drug Resistant

Background: Multiple-drug-resistant Gram-negative bacteria (MDR-GNB)-associated neonatal ventriculitis is a life-threatening complication that needs timely diagnosis and effective treatment with broad-spectrum antimicrobials in critical-care settings. Inadequate penetration of antibiotics through the blood–brain barrier also demands an intraventricular (IVT) route of administration. This study reports mortality and neurodevelopmental sequelae of neonates till 18 months of age, who received IVT-colistin for treating MDR-GNB associated ventriculitis.Methods: In a case series of seven neonates with ventriculitis due to MDR-GNB at NICU of Aga Khan University Hospital, Pakistan, between June 2015 and 2018, we reviewed IVT-colistin therapy in critically ill neonates. Treatment outcomes were assessed based on clinical sign's resolution and MDR-GNB eradication in subsequent CSF cultures. Neurodevelopmental outcomes were evaluated at 18 months after discharge.Results: The average birth weight was 1.38 kg (range: 1.02–1.5 kg), and the average gestational age was 30.7 weeks (ranged: 26–34 weeks). All neonates reported colistin-sensitive MDR-GNB in CSF, five with Acinetobacter baumannii, and polymicrobial CNS infection was found in two patients (one due to Klebsiella pneumonia and A. baumannii and one due to K. pneumonia and Escherichia coli). All neonates received IVT colistin and concomitant intravenous meropenem, and five of them also received intravenous colistin. One neonate died. At the 18-month assessment, only one neonate had cerebral palsy and hydrocephaly and 50% had seizure disorders.Conclusion: Practicing intraventricular antibiotics in the neonatal population is challenging but may be used successfully, especially to overcome the limitation of poor penetration through the blood–brain barrier.

scholarly journals Refractory Epilepsy: Mechanisms of Pharmacoresistance

2021 ◽  
pp. 99-110
Author(s):  
Ariel Le ◽  
Makenzie Thomas ◽  
Brady Stallman ◽  
Kathryn Meadows ◽  
Vidya Bhargava
Keyword(s):  
Blood Brain Barrier ◽  
Refractory Epilepsy ◽  
Treatment Options ◽  
Brain Barrier ◽  
Drug Resistant ◽  
Blood Brain ◽  
Anti Epileptic Drug ◽  
Drug Resistant Epilepsy ◽  
Protein Transporters

Refractory or drug-resistant epilepsy is a complex and debilitating disorder that impacts over one-third of people diagnosed with epilepsy. Many studies have suggested a variety of possible hypotheses for drug-resistant epilepsy, including the degeneration of neural networks, alterations of anti-epileptic drug (AED) targets, intrinsic severity/frequency of seizures, and genetic predisposition to pharmacoresistance. However, extensive research suggests that the overexpression of efflux protein transporters in brain tissue is the most viable hypothesis. Specifically, the overexpression of P-glycoproteins (P-gps) at the blood brain barrier proves the most compelling mechanism to discuss further. Studying the mechanisms of these transporters provides critical insight for new ways to combat pharmacoresistance. Thus, this review evaluates the co-administration of P-gp inhibitors with AEDs as a promising, yet relatively unexplored, treatment option for refractory epilepsy. This review specifically considers Tariquidar (TQD) the most promising P-gp inhibitor for refractory epilepsy treatment. This work aims to evaluate the role of P-gp overexpression in refractory epilepsy, consolidate current research about potential treatment options, and identify discrepancies or gaps in the literature related to P-gp inhibitory treatments for refractory epilepsy. It was concluded that, as a result of increased drug efflux processes at the blood brain barrier, overexpression of P-gp is the leading cause of pharmacoresistance. By inhibiting the activity of these proteins with the drug Tariquidar, an effective treatment for refractory epilepsy may become a reality.

scholarly journals Penetration of Dexamethasone into Brain Glucocorticoid Targets Is Enhanced in mdr1A P-Glycoprotein Knockout Mice*

Endocrinology ◽  
1998 ◽  
Vol 139 (4) ◽  
pp. 1789-1793 ◽  
Author(s):  
O. C. Meijer ◽  
E. C. M. de Lange ◽  
D. D. Breimer ◽  
A. G. de Boer ◽  
J. O. Workel ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Messenger Rna ◽  
Multiple Drug Resistance ◽  
Receptor Expression ◽  
Brain Barrier ◽  
Multiple Drug ◽  
Nuclear Uptake ◽  
P Glycoprotein ◽  
Blood Brain ◽  
The Brain

Abstract Mice with a genetic disruption of the multiple drug resistance (mdr1a) gene were used to examine the effect of the absence of its drug-transporting P-glycoprotein product from the blood-brain barrier on the distribution and cell nuclear uptake of[ 3H]-dexamethasone in the brain.[ 3H]-dexamethasone (4 μg/kg mouse) was administered sc to adrenalectomized mdr1a (−/−) and mdr1a (+/+) mice. One hour later, the mice were decapitated, and the radioactivity was measured in homogenates of cerebellum, blood, and liver following extraction of the radioactive steroid. The frontal brain was cut in sections for autoradiography. In the cerebellum of the mdr1a mutants, the amount of[ 3H]-dexamethasone relative to blood was about 5-fold higher than observed in the controls, whereas the ratio in blood vs. liver was not different. Using autoradiography, it was found that brain areas expressing the glucocorticoid receptor (GR) in high abundance, such as the hippocampal cell fields and the paraventricular nucleus (PVN), showed a 10-fold increase in cell nuclear uptake of radiolabeled steroid. The amount of retained steroid increased toward levels observed in the pituitary, which contains a similar density of GRs. The [3H]-dexamethasone concentration in pituitary was not affected by mdr1a gene disruption. The GR messenger RNA expression pattern in hippocampus was not different between the wild types and mdr1a mutants, which rules out altered receptor expression as a cause of the enhanced dexamethasone uptake. In conclusion, the present study demonstrates that the brain is resistant to penetration by dexamethasone because of mdr1a activity at the level of the blood-brain barrier. The data support the concept of a pituitary site of action of dexamethasone in blockade of stress-induced ACTH release. Dexamethasone poorly substitutes for depletion of the endogenous glucocorticoid from the brain and therefore, in this tissue, may cause a condition resembling that of adrenalectomy.

scholarly journals The blood-brain barrier hypothesis in drug resistant epilepsy

Brain ◽  
2012 ◽  
Vol 135 (4) ◽  
pp. e211-e211 ◽  
Author(s):  
N. Marchi ◽  
T. Granata ◽  
A. Alexopoulos ◽  
D. Janigro
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Drug Resistant ◽  
Blood Brain ◽  
Drug Resistant Epilepsy

scholarly journals ABCB subfamily (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Mary Vore
Keyword(s):  
Drug Resistance ◽  
Tumor Cells ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Multi Drug Resistance ◽  
Drug Resistant ◽  
Blood Brain

The ABCB subfamily is composed of four full transporters and two half transporters. This is the only human subfamily to have both half and full types of transporters. ABCB1 was discovered as a protein overexpressed in certain drug resistant tumor cells. It is expressed primarily in the blood brain barrier and liver and is thought to be involved in protecting cells from toxins. Cells that overexpress this protein exhibit multi-drug resistance [4].

Conformationally Constrained Peptide Drugs Targeted at the Blood-Brain Barrier

1995 ◽  
Author(s):  
Thomas P. Davis ◽  
Thomas J. Abbruscato ◽  
Elizabeth Brownson ◽  
Victor J. Hruby
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Peptide Drugs ◽  
Conformationally Constrained ◽  
Blood Brain
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