The effect of chymotrypsin on the gastrointestinal absorption, tissue penetration, and pharmacological activity of drugs. I. Penetration of penicillin through the blood–brain and blood–retinal barriers

1968 ◽  
Vol 46 (6) ◽  
pp. 815-818 ◽  
Author(s):  
Alan Wohlman ◽  
M. Syed ◽  
M. Ronchi
Keyword(s):  
Membrane Permeability ◽  
Pharmacological Activity ◽  
Guinea Pigs ◽  
Proteolytic Enzyme ◽  
Serum Proteins ◽  
Gastrointestinal Absorption ◽  
Penicillin G ◽  
Tissue Penetration ◽  
Blood Brain ◽  
The Brain

The administration of penicillin G plus the proteolytic enzyme chymotrypsin to rabbits and guinea pigs yields significantly higher serum, eye, and brain levels of penicillin than does the administration of the antibiotic alone. It is suggested that chymotrypsin exerts an effect on both the membrane permeability of cells constituting the blood–brain and blood–retinal barriers and the binding of penicillin to serum proteins. Chymotrypsin may be of considerable value in the enhancement of penicillin penetration into reiatively inaccessible tissues, such as the brain and eye, thereby making it possible to eliminate penicillin-sensitive bacteria which have become localized in these areas.

The blood–brain barrier and its regulation by NF-κB

e-Neuroforum ◽  
2016 ◽  
Vol 22 (2) ◽  
Author(s):  
J. Wenzel ◽  
M. Schwaninger
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Serum Proteins ◽  
Hereditary Disease ◽  
Brain Barrier ◽  
Incontinentia Pigmenti ◽  
Brain Endothelial Cells ◽  
Blood Brain ◽  
Endothelial Cell Death ◽  
The Brain

AbstractThe brain is protected by a tight barrier between the blood and parenchyma. This so-called blood-brain barrier protects the brain from invading pathogens, infiltrating immune cells, and the extravasation of serum proteins. Beside pericytes and astrocytes mainly endothelial cells form this barrier.Inflammation leads to an increase in the permeability of the blood-brain barrier. NF-κB is activated during inflammation and is a key regulator of inflammatory processes. In brain endothelial cells NF-κB protects the blood-brain barrier. Loss of the NF-κB activating protein NEMO in brain endothelial cells leads to endothelial cell death, increased permeability, and epilepsy inmice as well as in humans with the hereditary disease incontinentia pigmenti. Therefore, inflammatory mediators are able to disturb but also to protect the blood-brain barrier.

Radioactively iodinated cyclo(His-Pro) crosses the blood-brain barrier and reverses ethanol-induced narcosis

1993 ◽  
Vol 264 (5) ◽  
pp. E723-E729 ◽  
Author(s):  
W. A. Banks ◽  
A. J. Kastin ◽  
V. Akerstrom ◽  
J. B. Jaspan
Keyword(s):  
Blood Brain Barrier ◽  
Serum Proteins ◽  
Intraperitoneal Administration ◽  
Brain Barrier ◽  
Lipid Solubility ◽  
Peripheral Tissues ◽  
Blood Brain ◽  
Other Substances ◽  
High Lipid Solubility ◽  
The Brain

Cyclo(His-Pro) (cHP) is a peptide widely distributed in the central nervous system (CNS) and peripheral tissues that can affect brain function after either peripheral or CNS administration. This suggests that cHP may be a neuromodulator capable of crossing the blood-brain barrier (BBB). We, therefore, studied the ability of radioactively labeled cHP (I-cHP) to cross the BBB. We found that I-cHP can cross the BBB in either the direction of blood to brain or brain to blood by nonsaturable mechanisms. The rate of entry of I-cHP into the CNS was low in comparison with other peptides, especially considering its relatively low molecular weight and high lipid solubility. However, this slow entry was offset by a long half-life in blood and extreme enzymatic resistance, allowing cHP to accumulate in the CNS. This accumulation was sufficient to allow intravenous cHP to reverse ethanol-induced narcosis, an effect mediated through the CNS. The rate of entry of I-cHP was resistant to conditions that alter the passage of some other substances across the BBB or that have been shown to affect cHP metabolism such as aging, diabetes, and pretreatment with aluminum. Entry of cHP into the brain was not retarded by binding to serum proteins. Significant amounts of I-cHP entered the serum, brain, and other tissues after intraperitoneal administration, the route used in many studies of cHP. Taken together, these results show that cHP is a highly stable peptide that, after intravenous injection, slowly enters the brain by a nonsaturable mechanism in amounts large enough to affect such aspects of the CNS as ethanol-induced narcosis.

scholarly journals Potent and lasting seizure suppression by systemic delivery of antagomirs targeting miR-134 timed with blood-brain barrier disruption

2019 ◽  
Author(s):  
C. R. Reschke ◽  
L. F. A. Silva ◽  
V. R. Vangoor ◽  
M. Rosso ◽  
B. David ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Blood Brain Barrier ◽  
Serum Proteins ◽  
Neurological Diseases ◽  
Brain Barrier ◽  
Systemic Delivery ◽  
Systemic Injection ◽  
Blood Brain ◽  
Disease Modifying ◽  
The Brain

AbstractRNA therapies such as oligonucleotides (OGNs) offer precision treatments for a variety of neurological diseases, including epilepsy but their deployment is hampered by the blood brain barrier (BBB). Here we used brain imaging and assays of serum proteins and tracer extravasation, to determine that BBB disruption occurring after status epilepticus in mice was sufficient to permit passage of systemically-injected antisense OGNs targeting microRNA-134 (Ant-134) into the brain parenchyma. A single intraperitoneal injection of Ant-134 two hours after status epilepticus in mice resulted in potent suppression of spontaneous recurrent seizures, reaching a 99.5% reduction during recordings at three months. The duration of spontaneous seizures, when they occurred, was also reduced in Ant-134-treated mice. These studies indicate that systemic delivery of Ant-134 reaches the brain and produces disease-modifying effects after systemic injection in mice when timed with BBB disruption and may be a clinically-viable approach for this and other disease-modifying microRNA therapies.

Ligand and Structure-based Modeling of Passive Diffusion through the Blood-Brain Barrier

2018 ◽  
Vol 25 (9) ◽  
pp. 1073-1089 ◽  
Author(s):  
Santiago Vilar ◽  
Eduardo Sobarzo-Sanchez ◽  
Lourdes Santana ◽  
Eugenio Uriarte
Keyword(s):  
Blood Brain Barrier ◽  
In Silico ◽  
Passive Diffusion ◽  
Brain Barrier ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Different Types ◽  
The Brain

Background: Blood-brain barrier transport is an important process to be considered in drug candidates. The blood-brain barrier protects the brain from toxicological agents and, therefore, also establishes a restrictive mechanism for the delivery of drugs into the brain. Although there are different and complex mechanisms implicated in drug transport, in this review we focused on the prediction of passive diffusion through the blood-brain barrier. Methods: We elaborated on ligand-based and structure-based models that have been described to predict the blood-brain barrier permeability. Results: Multiple 2D and 3D QSPR/QSAR models and integrative approaches have been published to establish quantitative and qualitative relationships with the blood-brain barrier permeability. We explained different types of descriptors that correlate with passive diffusion along with data analysis methods. Moreover, we discussed the applicability of other types of molecular structure-based simulations, such as molecular dynamics, and their implications in the prediction of passive diffusion. Challenges and limitations of experimental measurements of permeability and in silico predictive methods were also described. Conclusion: Improvements in the prediction of blood-brain barrier permeability from different types of in silico models are crucial to optimize the process of Central Nervous System drug discovery and development.

Liposomes: Novel Drug Delivery Approach for Targeting Parkinson’s Disease

2020 ◽  
Vol 26 (37) ◽  
pp. 4721-4737 ◽  
Author(s):  
Bhumika Kumar ◽  
Mukesh Pandey ◽  
Faheem H. Pottoo ◽  
Faizana Fayaz ◽  
Anjali Sharma ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Drug Delivery ◽  
Parkinson's Disease ◽  
Side Effects ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Targeting ◽  
Neural Cells ◽  
Blood Brain ◽  
The Brain

Parkinson’s disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson’s disease.

Brain Drug Delivery: Overcoming the Blood-brain Barrier to Treat Tauopathies

2020 ◽  
Vol 26 (13) ◽  
pp. 1448-1465 ◽  
Author(s):  
Jozef Hanes ◽  
Eva Dobakova ◽  
Petra Majerova
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Neurodegenerative Disorders ◽  
Brain Barrier ◽  
Neuronal Function ◽  
Brain Drug Delivery ◽  
Naturally Occurring ◽  
Blood Brain ◽  
Traditional Approaches ◽  
The Brain

Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The application of potentially effective therapeutics for their successful treatment is hampered by the presence of a naturally occurring brain protection layer called the blood-brain barrier (BBB). BBB represents one of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders, where sufficient BBB penetration is inevitable. BBB is a heavily restricting barrier regulating the movement of molecules, ions, and cells between the blood and the CNS to secure proper neuronal function and protect the CNS from dangerous substances and processes. Yet, these natural functions possessed by BBB represent a great hurdle for brain drug delivery. This review is concentrated on summarizing the available methods and approaches for effective therapeutics’ delivery through the BBB to treat neurodegenerative disorders with a focus on tauopathies. It describes the traditional approaches but also new nanotechnology strategies emerging with advanced medical techniques. Their limitations and benefits are discussed.

scholarly journals Miniaturization and Automation of a Human In Vitro Blood–Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 892
Author(s):  
Elisa L. J. Moya ◽  
Elodie Vandenhaute ◽  
Eleonora Rizzi ◽  
Marie-Christine Boucau ◽  
Johan Hachani ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Blood Brain Barrier ◽  
Early Stage ◽  
Molecular Transport ◽  
Brain Barrier ◽  
Blood Brain ◽  
Cns Drugs ◽  
The Impact ◽  
The Brain

Central nervous system (CNS) diseases are one of the top causes of death worldwide. As there is a difficulty of drug penetration into the brain due to the blood–brain barrier (BBB), many CNS drugs treatments fail in clinical trials. Hence, there is a need to develop effective CNS drugs following strategies for delivery to the brain by better selecting them as early as possible during the drug discovery process. The use of in vitro BBB models has proved useful to evaluate the impact of drugs/compounds toxicity, BBB permeation rates and molecular transport mechanisms within the brain cells in academic research and early-stage drug discovery. However, these studies that require biological material (animal brain or human cells) are time-consuming and involve costly amounts of materials and plastic wastes due to the format of the models. Hence, to adapt to the high yields needed in early-stage drug discoveries for compound screenings, a patented well-established human in vitro BBB model was miniaturized and automated into a 96-well format. This replicate met all the BBB model reliability criteria to get predictive results, allowing a significant reduction in biological materials, waste and a higher screening capacity for being extensively used during early-stage drug discovery studies.

scholarly journals Probable Causes of Alzheimer’s Disease

Sci ◽  
2021 ◽  
Vol 3 (1) ◽  
pp. 16
Author(s):  
James David Adams
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lactic Acid ◽  
Blood Brain Barrier ◽  
Transient Receptor Potential ◽  
Brain Barrier ◽  
Folate Intake ◽  
Blood Brain ◽  
Age Related ◽  
The Brain

A three-part mechanism is proposed for the induction of Alzheimer’s disease: (1) decreased blood lactic acid; (2) increased blood ceramide and adipokines; (3) decreased blood folic acid. The age-related nature of these mechanisms comes from age-associated decreased muscle mass, increased visceral fat and changes in diet. This mechanism also explains why many people do not develop Alzheimer’s disease. Simple changes in lifestyle and diet can prevent Alzheimer’s disease. Alzheimer’s disease is caused by a cascade of events that culminates in damage to the blood–brain barrier and damage to neurons. The blood–brain barrier keeps toxic molecules out of the brain and retains essential molecules in the brain. Lactic acid is a nutrient to the brain and is produced by exercise. Damage to endothelial cells and pericytes by inadequate lactic acid leads to blood–brain barrier damage and brain damage. Inadequate folate intake and oxidative stress induced by activation of transient receptor potential cation channels and endothelial nitric oxide synthase damage the blood–brain barrier. NAD depletion due to inadequate intake of nicotinamide and alterations in the kynurenine pathway damages neurons. Changes in microRNA levels may be the terminal events that cause neuronal death leading to Alzheimer’s disease. A new mechanism of Alzheimer’s disease induction is presented involving lactic acid, ceramide, IL-1β, tumor necrosis factor α, folate, nicotinamide, kynurenine metabolites and microRNA.

scholarly journals The Peptide Vaccine Combined with Prior Immunization of a Conventional Diphtheria-Tetanus Toxoid Vaccine Induced AmyloidβBinding Antibodies on Cynomolgus Monkeys and Guinea Pigs

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Akira Yano ◽  
Kaori Ito ◽  
Yoshikatsu Miwa ◽  
Yoshito Kanazawa ◽  
Akiko Chiba ◽  
...  
Keyword(s):  
Immune Responses ◽  
Tetanus Toxoid ◽  
Guinea Pigs ◽  
Peptide Vaccine ◽  
Cell Epitope ◽  
T Cell Epitope ◽  
Peptide Vaccination ◽  
Binding Profile ◽  
Cynomolgus Monkeys ◽  
The Brain

The reduction of brain amyloid beta (Aβ) peptides by anti-Aβantibodies is one of the possible therapies for Alzheimer’s disease. We previously reported that the Aβpeptide vaccine including the T-cell epitope of diphtheria-tetanus combined toxoid (DT) induced anti-Aβantibodies, and the prior immunization with conventional DT vaccine enhanced the immunogenicity of the peptide. Cynomolgus monkeys were given the peptide vaccine subcutaneously in combination with the prior DT vaccination. Vaccination with a similar regimen was also performed on guinea pigs. The peptide vaccine induced anti-Aβantibodies in cynomolgus monkeys and guinea pigs without chemical adjuvants, and excessive immune responses were not observed. Those antibodies could preferentially recognize Aβ40, and Aβ42compared to Aβfibrils. The levels of serum anti-Aβantibodies and plasma Aβpeptides increased in both animals and decreased the brain Aβ40level of guinea pigs. The peptide vaccine could induce a similar binding profile of anti-Aβantibodies in cynomolgus monkeys and guinea pigs. The peptide vaccination could be expected to reduce the brain Aβpeptides and their toxic effects via clearance of Aβpeptides by generated antibodies.

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