scholarly journals EXTH-77. ONC201 EXHIBITS PASSIVE DIFFUSION AND BROAD DISTRIBUTION IN THE CENTRAL NERVOUS SYSTEM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii104-ii104
Author(s):  
Sara Morrow ◽  
Varun Prabhu ◽  
Rohinton S Tarapore ◽  
Gina Theerman ◽  
Leah Lake ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Clinical Trials ◽  
Nervous System ◽  
Single Agent ◽  
Passive Diffusion ◽  
The Body ◽  
Whole Body ◽  
Distribution Profile ◽  
Apparent Permeability ◽  
The Central Nervous System

Abstract Imipridone ONC201 is an investigational agent in phase II clinical trials for H3 K27M-mutant diffuse midline glioma with evidence of durable objective responses and clinical symptom improvements as a single agent. The systemic pharmacokinetics of ONC201 and its ability to achieve target concentrations in supratentorial glioblastoma have been demonstrated in clinical trials; however, its clearance and distribution in midline structures and other areas of the central nervous system (CNS) haven’t been evaluated. A quantitative whole-body autoradiography study was conducted in Long-Evans rats with a single dose of [14C]-ONC201. [14C]-ONC201-related material was rapidly distributed throughout the body, with concentrations peaking at 1h for most tissues. The endocrine, metabolic/excretory, ocular and gastrointestinal tract tissues contained the highest distribution of [14C]-ONC201-derived radioactivity. Importantly, [14C]-ONC201 material was distributed evenly across brain substructures, including the meninges and midline structures of the brain; all tissues had a half-life of 1.4–7.9h, with the exception of the meninges (2397.3h). Given the uniform distribution throughout the CNS, we evaluated the permeability and efflux potential of ONC201 in bidirectional transport assays using human Caco-2 cell monolayers. ONC201 displayed high permeability in the apical to basolateral direction with apparent permeability values of 23–31×10–6 cm/s at 7–700μM. In the basolateral to apical direction, apparent permeability values were 11–24 × 10–6 cm/s. The efflux ratio values were 0.46–0.79 for ONC201, suggesting that ONC201 is not a substrate of efflux transporters. However, ONC201 exerted inhibitory potential on MDR1- (90.6%) and BCRP-mediated (81.6%) transport at 200mM. In summary, ONC201 exhibits passive diffusion without being effluxed, which may enable its rapid and wide distribution throughout the CNS. This distribution profile suggests that the compound may achieve therapeutic concentrations throughout the CNS with oral administration and that investigation of additional CNS tumors will not be hindered by drug delivery to specific anatomic structures.

Use of rituximab in lymphomatoid granulomatosis with isolated central nervous system involvement

2020 ◽  
Vol 13 (9) ◽  
pp. e235412
Author(s):  
Jesse Mooneyham ◽  
Cesar Gentille ◽  
Andrea Barbieri ◽  
Shilpan Shah
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Single Agent ◽  
Central Nervous System Involvement ◽  
Brain Lesions ◽  
The Body ◽  
Lymphomatoid Granulomatosis ◽  
Vasogenic Oedema ◽  
The Central Nervous System

A 33-year-old woman presented to the emergency room with severe headaches. A CT scan of the head revealed two brain lesions with associated vasogenic oedema. Diagnostic resection of one of the lesions followed by pathological analysis revealed grade III lymphomatoid granulomatosis (LYG). Staging investigations elsewhere in the body were negative, isolating this case of LYG to the central nervous system, an atypical presentation. After the resection, she was treated with single-agent rituximab 375 mg/m2. The follow-up MRI demonstrated the resolution of brain lesions and no progression of the disease.

Characteristics of the dynamics of the central nervous system and att ention function in workers of shoe production

2020 ◽  
pp. 64-68
Author(s):  
F. L. Azizova ◽  
U. A. Boltaboev
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Women Workers ◽  
Functional State ◽  
The Body ◽  
Conflict Of Interests ◽  
Professional Groups ◽  
Universal Device ◽  
The Central Nervous System ◽  
Working Day

The features of production factors established at the main workplaces of shoe production are considered. The materials on the results of the study of the functional state of the central nervous system of women workers of shoe production in the dynamics of the working day are presented. The level of functional state of the central nervous system was determined by the speed of visual and auditory-motor reactions, installed using the universal device chronoreflexometer. It was revealed that in the body of workers of shoe production there is an early development of inhibitory processes in the central nervous system, which is expressed in an increase in the number of errors when performing tasks on proofreading tables. It was found that the most pronounced shift s in auditory-motor responses were observed in professional groups, where higher levels of noise were registered in the workplace. The correlation analysis showed a close direct relationship between the growth of mistakes made in the market and the decrease in production. An increase in the time spent on the task indicates the occurrence and growth of production fatigue.Funding. The study had no funding.Conflict of interests. The authors declare no conflict of interests.

Neural Stem Cells to Glial Cells an Important Factor for Brain Injury

2020 ◽  
Author(s):  
Prithiv K R Kumar
Keyword(s):  
Stem Cells ◽  
Central Nervous System ◽  
Nervous System ◽  
Neural Stem Cells ◽  
Glial Cells ◽  
Brain Injuries ◽  
The Body ◽  
The Central Nervous System ◽  
Near Future

Stem cells have the capacity to differentiate into any type of cell or organ. Stems cell originate from any part of the body, including the brain. Brain cells or rather neural stem cells have the capacitive advantage of differentiating into the central nervous system leading to the formation of neurons and glial cells. Neural stem cells should have a source by editing DNA, or by mixings chemical enzymes of iPSCs. By this method, a limitless number of neuron stem cells can be obtained. Increase in supply of NSCs help in repairing glial cells which in-turn heal the central nervous system. Generally, brain injuries cause motor and sensory deficits leading to stroke. With all trials from novel therapeutic methods to enhanced rehabilitation time, the economy and quality of life is suppressed. Only PSCs have proven effective for grafting cells into NSCs. Neurons derived from stem cells is the only challenge that limits in-vitro usage in the near future.

Bone-brain crosstalk and potential associated diseases

2016 ◽  
Vol 28 (2) ◽  
Author(s):  
Audrey Rousseaud ◽  
Stephanie Moriceau ◽  
Mariana Ramos-Brossier ◽  
Franck Oury
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Development ◽  
Cognitive Functions ◽  
Intimate Relationship ◽  
Whole Body ◽  
Reciprocal Relationships ◽  
Skeletal Homeostasis ◽  
The Central Nervous System ◽  
The Brain

AbstractReciprocal relationships between organs are essential to maintain whole body homeostasis. An exciting interplay between two apparently unrelated organs, the bone and the brain, has emerged recently. Indeed, it is now well established that the brain is a powerful regulator of skeletal homeostasis via a complex network of numerous players and pathways. In turn, bone via a bone-derived molecule, osteocalcin, appears as an important factor influencing the central nervous system by regulating brain development and several cognitive functions. In this paper we will discuss this complex and intimate relationship, as well as several pathologic conditions that may reinforce their potential interdependence.

scholarly journals Convection-enhanced delivery to the central nervous system

2015 ◽  
Vol 122 (3) ◽  
pp. 697-706 ◽  
Author(s):  
Russell R. Lonser ◽  
Malisa Sarntinoranont ◽  
Paul F. Morrison ◽  
Edward H. Oldfield
Keyword(s):  
Drug Delivery ◽  
Central Nervous System ◽  
Clinical Trials ◽  
Nervous System ◽  
Convective Flow ◽  
Clinical Applications ◽  
Systemic Delivery ◽  
Convection Enhanced Delivery ◽  
The Central Nervous System ◽  
Real Time Tracking

Convection-enhanced delivery (CED) is a bulk flow–driven process. Its properties permit direct, homogeneous, targeted perfusion of CNS regions with putative therapeutics while bypassing the blood-brain barrier. Development of surrogate imaging tracers that are co-infused during drug delivery now permit accurate, noninvasive real-time tracking of convective infusate flow in nervous system tissues. The potential advantages of CED in the CNS over other currently available drug delivery techniques, including systemic delivery, intrathecal and/or intraventricular distribution, and polymer implantation, have led to its application in research studies and clinical trials. The authors review the biophysical principles of convective flow and the technology, properties, and clinical applications of convective delivery in the CNS.

scholarly journals VI. —Anaphylaxis and anaphylatoxins

1923 ◽  
Vol 211 (382-390) ◽  
pp. 273-315 ◽  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Guinea Pig ◽  
Anaphylactic Shock ◽  
The Body ◽  
Muscle Fibres ◽  
Direct Stimulation ◽  
Fundamental Conception ◽  
The Central Nervous System ◽  
Stimulation Of

In the study of the phenomena of anaphylaxis there are certain points on which some measure of agreement seems to have been attained. In the case of anaphylaxis to soluble proteins, with which alone we are directly concerned in this paper, the majority of investigators probably accept the view that the condition is due to the formation of an antibody of the precipitin type. Concerning the method, however, by which the presence of this antibody causes the specific sensitiveness, the means by which its interaction with the antibody produces the anaphylactic shock, there is a wide divergence of conception. Two main currents of speculation can be discerned. One view, historically rather the earlier, and first put forward by Besredka (1) attributes the anaphylactic condition to the location of the antibody in the body cells. There is not complete unanimity among adherents of this view as to the nature of the antibody concerned, or as to the class of cells containing it which are primarily affected in the anaphylactic shock. Besredka (2) himself has apparently not accepted the identification of the anaphylactic antibody with a precipitin, but regards it as belonging to a special class (sensibilisine). He also regards the cells of the central nervous system as those primarily involved in the anaphylactic shock in the guinea-pig. Others, including one of us (3), have found no adequate reason for rejecting the strong evidence in favour of the precipitin nature of the anaphylactic antibody, produced by Doerr and Russ (4), Weil (5), and others, and have accepted and confirmed the description of the rapid anaphylactic death in the guinea-pig as due to a direct stimulation of the plain-muscle fibres surrounding the bronchioles, causing valve-like obstruction of the lumen, and leading to asphyxia, with the characteristic fixed distension of the lungs, as first described by Auer and Lewis (6), and almost simultaneously by Biedl and Kraus (7). But the fundamental conception of anaphylaxis as due to cellular location of an antibody, and of the reaction as due to the union of antigen and antibody taking place in the protoplasm, is common to a number of workers who thus differ on details.

The Co-Ordination of Insect Movements

1957 ◽  
Vol 34 (3) ◽  
pp. 306-333
Author(s):  
G. M. HUGHES
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
The Body ◽  
The Other ◽  
Limb Amputation ◽  
Normal Movement ◽  
Thoracic Ganglia ◽  
Blatta Orientalis ◽  
The Central Nervous System ◽  
Leg Movements

I. The effects of limb amputation and the cutting of commissures on the movements of the cockroach Blatta orientalis have been investigated with the aid of cinematography. Detailed analyses of changes in posture and rhythm of leg movements are given. 2. It is shown that quite marked changes occur following the amputation of a single leg or the cutting of a single commissure between the thoracic ganglia. 3. Changes following the amputation of a single leg are immediate and are such that the support normally provided by the missing leg is taken over by the two remaining legs on that side. Compensatory movements are also found in the contralateral legs. 4. When two legs of opposite sides are amputated it has been confirmed that the diagonal sequence tends to be adopted, but this is not invariably true. Besides alterations in the rhythm which this may involve, there are again adaptive modifications in the movements of the limbs with respect to the body. 5. When both comrnissures between the meso- and metathoracic ganglia are cut, the hind pair of legs fall out of rhythm with the other four legs. The observations on the effects of cutting commissures stress the importance of intersegmental pathways in co-ordination. 6. It is shown that all modifications following the amputation of legs may be related to the altered mechanical conditions. Some of the important factors involved in normal co-ordination are discussed, and it is suggested that the altered movements would be produced by the operation of these factors under the new conditions. It is concluded that the sensory inflow to the central nervous system is of major importance in the co-ordination of normal movement.

Intrasellar Paraganglioma with Suprasellar Extension: Case Report

1998 ◽  
Vol 84 (3) ◽  
pp. 408-411 ◽  
Author(s):  
Maria Laura Del Basso De Caro ◽  
Antonella Siciliano ◽  
Paolo Cappabianca ◽  
Alessandra Alfieri ◽  
Enrico de Divitiis
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Case Report ◽  
Pelvic Floor ◽  
The Body ◽  
Benign Tumors ◽  
Sellar Region ◽  
The Central Nervous System ◽  
Base Of The Skull ◽  
Suprasellar Extension

Paragangliomas are usually benign tumors which can be found in many sites of the body, from the base of the skull down to the pelvic floor. In the central nervous system the sellar region is very rarely involved; only three well studied cases have been reported to date. We present the cytological, histological, histochemical, immunocytochemical and ultrastructural features of an intrasellar and suprasellar paraganglioma in an 84-year-old man.

ANTICHOLINERGIC POISONING: TREATMENT WITH PHYSOSTIGMINE

PEDIATRICS ◽  
1973 ◽  
Vol 52 (3) ◽  
pp. 449-451
Author(s):  
Barry H. Rumack
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Acetic Acid ◽  
Specific Treatment ◽  
Signs And Symptoms ◽  
The Body ◽  
Sweat Glands ◽  
Exocrine Glands ◽  
Anticholinergic Syndrome ◽  
The Central Nervous System

The increased incidence of poisoning by overdoses of commonly used drugs with anticholinergic properties (Table I) and the general lack of knowledge concerning a specific treatment for these poisons warrants a summary of the problem at this time. Some plants containing anticholinergic alkaloids are also included in this group as they may also be taken intentionally or accidentally. Drugs with anticholinergic properties primanly antagonize acetylcholine competitively at the neuroreceptor site. Cardiac muscle, exocrine glands, and smooth muscle are most markedly affected.1 Action of the inhibitors is overcome by increasing the level of acetylcholine naturally generated in the body through inhibiting the enzyme (choline esterase) which normally prevents accumulation of excess acetylcholine. It does this by hydrolyzing that compound to inactive acetic acid and choline. Agents which inhibit this enzyme, so that acetylcholine accumulates at the neuroreceptor sites, are called anticholine esterases. Physostigmine, one of the anticholine esterases which is a tertiary amine, crosses into the central nervous system and can reverse both central and peripheral anticholinergic actions2. Neostigmine and pyridostigmine are also anticholine esterases but they are quaternary amines and are capable of acting only outside the central nervous system because of solubility and ionization characteristics. The anticholinergic syndrome has both central and peripheral signs and symptoms. Central toxic effects include anxiety, delirium, disorientation, hallucinations, hyperactivity, and seizures.2 Severe poisoning may produce coma, medullary paralysis, and death. Peripheral taxicity is characterized by tachycardia, hyperpyrexia, mydriasis, vasodilatation, urinary retention, diminution of gastrointestinal motility, decrease of secretion in salivary and sweat glands, and loss of secretions in the pharynx, bronchi, and nasal passages.

The Giant Nerve-Fibres in the Central Nervous System of Myxicola (Polychaeta, Sabellidae)

1948 ◽  
Vol s3-89 (5) ◽  
pp. 1-45
Author(s):  
J.A. C. NICOL
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Nerve Cord ◽  
Size Structure ◽  
Nerve Cells ◽  
The Body ◽  
Usual Sense ◽  
Fibrous Sheath ◽  
Giant Fibre ◽  
The Central Nervous System

1. A description is given of the main features of the central nervous system of Myxicola infundibulum Rénier. 2. The nerve-cord is double in the first four thoracic segments and single posteriorly. It shows segmental swellings but is not ganglionated in the usual sense in that nerve-cell accumulations are not related directly to such swellings of the cord. 3. A very large axon lies within the dorsal portion of the nerve-cord and extends from the supra-oesophageal ganglia to the posterior end of the animal. It is small in the head ganglia where it passes transversely across the mid-line, increases in diameter in the oesophageal connectives, and expands to very large size, up to 1 mm., in the posterior thorax and anterior abdomen, and gradually tapers off to about 100µ in the posterior body. It shows segmental swellings corresponding to those of the nerve-cord in each segment. It occupies about 27 per cent, of the volume of the central nervous system and 0.3 per cent, of the volume of the animal. The diameter of the fibre increases during contraction of the worm. 4. The giant fibre is a continuous structure throughout its length, without internal dividing membranes or septa. Usually a branch of the giant fibre lies in each half of the nerve-cord in the anterior thoracic segments and these several branches are continuous with one another longitudinally and transversely. 5. The giant fibre is connected with nerve-cells along its entire course; it arises from a pair of cells in the supra-oesophageal ganglia, and receives the processes of many nerve-cells in each segment. There is no difference between the nerve-cells of the giant fibre and the other nerve-cells of the cord. 6. A distinct fibrous sheath invests the giant fibre. A slight concentration of lipoid can be revealed in this sheath by the use of Sudan black. 7. About eight peripheral branches arise from the giant fibre in each segment. They have a complex course in the nerve-cord where they anastomose with one another and receive the processes of nerve-cells. Peripherally, they are distributed to the longitudinal musculature. 8. Specimens surviving 16 days following section of the nerve-cord in the thorax have shown that the giant fibre does not degenerate in front of or behind a cut, thus confirming that it is a multicellular structure connected to nerve-cells in the thorax and abdomen. 9. It is concluded that the giant fibre of M. infundibulum is a large syncytial structure, extending throughout the entire central nervous system and the body-wall of the animal. 10. The giant fibre system of M. aesthetica resembles that of M. infundibulum. 11. Some implications of the possession of such a giant axon are discussed. It is suggested that its size, structure, and simplicity lead to rapid conduction and thus effect a considerable saving of reaction time, of considerable value to the species when considered in the light of the quick contraction which it mediates. The adoption of a sedentary mode of existence has permitted this portion of the central nervous system to become developed at the expense of other elements concerned with errant habits.

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