Injections, into the central nervous system

When CGRP is injected into the central nervous system, it produces a variety of effects, including hypertension and suppression of feeding. When injected into the systemic circulation, the peptide causes hypotension and tachycardia. The hypotensive action of CGRP results from the potent vasodilator action of the peptide indeed, CGRP is the most potent vasodilator yet discovered. It dilates multiple vascular beds, but the coronary circulation is particularly sensitive. 

When injected intravenously, kinins produce a rapid fall in blood pressure that is due to their arteriolar vasodilator action. The hypotensive response to bradykinin is of very brief duration. Intravenous infusions of the peptide fail to produce a sustained decrease in blood pressure prolonged hypotension can only be produced by progressively increasing the rate of infusion. The rapid reversibility of the hypotensive response to kinins is due primarily to reflex increases in heart rate, myocardial contractility, and cardiac output. In some species, bradykinin produces a biphasic change in blood pressure—an initial hypotensive response followed by an increase above the preinjection level. The increase in blood pressure may be due to a reflex activation of the sympathetic nervous system, but under some conditions, bradykinin can directly release catecholamines from the adrenal medulla and stimulate sympathetic ganglia. Bradykinin also increases blood pressure when injected into the central nervous system, but the physiologic significance of this effect is not clear, since it is unlikely that kinins cross the blood-brain barrier. 

Studies in animals clearly indicate that prostaglandins can produce fever when injected into the central nervous system and that Cox-2 induction is responsible for the fever that occurs with bacterial endotoxin and cytokines. To address the potential for an antipyretic effect in humans, Schwartz et al. (1999) administered rofecoxib or ibuprofen to young adults who presented to an infirmary for acute, nonbacterial... 

Absorption of the quaternary carbamates from the conjunctiva, skin, and lungs is predictably poor, since their permanent charge renders them relatively insoluble in lipids. Thus, much larger doses are required for oral administration than for parenteral injection. Distribution into the central nervous system is negligible. Physostigmine, in contrast, is well absorbed from all sites and can be used topically in the eye (Table 7-4). It is distributed into the central nervous system and is more toxic than the more polar quaternary carbamates. The carbamates are relatively stable in aqueous solution but can be metabolized by nonspecific esterases in the body as well as by cholinesterase. However, the duration of their effect is determined chiefly by the stability of the inhibitor-enzyme complex (see Mechanism of Action, below), not by metabolism or excretion. 

Choline esters are poorly absorbed and poorly distributed into the central nervous system because they are hydrophilic. Although all are hydrolyzed in the gastrointestinal tract (and less active by the oral route), they differ markedly in their susceptibility to hydrolysis by cholinesterase in the body. Acetylcholine is very rapidly hydrolyzed (see Chapter 6 Introduction to Autonomic Pharmacology) large amounts must be infused intravenously to achieve concentrations high enough to produce detectable effects. A large intravenous bolus injection has a brief effect, typically... 

The delivery of macromolecules into the central nervous system (CNS) via the blood stream is seriously limited by the blood-brain barrier (BBB). Noninvasive, transient, and local image-guided blood-brain barrier disruption (BBBD) can be accomplished using focused ultrasound exposure with intravascular injection of pre-formed microbubbles. A detailed description of the method for MRI-guided focal BBBD in animals will be described in this chapter. The method may open a new era in CNS macromolecular drug delivery. 

To further evaluate the potential utility of the Ga-complex as an in vivo marker of Pgp-mediated transport activity, the complexes were injected in wild-type and mdrla/lb (-/-) knoekout mice to study the drug transport across the BBB. As previously mentioned, Pgp is expressed in the luminal surfaces of brain endothelial cells preventing the entry of amphipathic compounds into the central nervous system. Therefore, the mdrla/lb (-/-) knockout mice offer an interesting model to evaluate the applicability of radiotracers for in vivo transport activity of Pgp. At 5 min after injection, the brain uptake of Ga-complex in Pgp-knockout miee was 10-fold higher compared with that in the wild-type mice. As the cerebral blood flow did not differ significantly between the wild-type and the knockout mice, differences on initial brain uptake and retention of Ga-complex were not attributed to changes in cerebral perfusion. 

Other more specific routes are employed for the administration of the active substance directly to the therapeutic site. For administration into the central nervous system the intrathecal, epidural or infracistemal injection route is used. Intrathecal injection is an injection into the spinal canal, more specifically into the sub-arachnoid space so that it reaches the cerebrospinal fluid and is useful in spinal anaesthesia, chemotherapy, or pain management applications. This route is also used for antibiotic treatment of infections, particularly post-neurosurgical. Medicines given intrathe-cally must not contain any preservative. 

Control of food intake is certainly one of the functions of leptin — reduced food intake can be observed in response to direct injection of the peptide into the central nervous system, and in response to leptin there is increased secretion of a number of peptide neurotransmitters that are known to be involved in regulation of feeding behaviour. However, the weight loss seen in response to leptin is greater than can be accounted for by the reduced food intake alone. Furthermore, in response to leptin there is a specific loss of adipose tissue, whereas, as discussed in section 8.2, in response to reduced food intake there is a loss of both adipose tissue and lean tissue. 

Both Cushny and Dale found the amorphous gelsemium alkaloids represented by such fractions as gelseminine much more active than gelsemine. Cushny stated that gelseminine resembled coniine in action and showed a greater depressant effect on the central nervous system, but unlike coniine it exerted no pressor effect. It was also a powerful mydriatic. Dale found that 0-001 gm. of the hydrochlorides of the amorphous alkaloids injected into rabbits caused death from respiratory failure in 25 minutes, preceded by convulsions. These results are explained by the subsequent isolation from such amorphous fractions, of the potent alkaloids sempervirine and gelsemicine. 

Such hydrogels have been suggested to be suitable for biotechnological applications (DNA delivery vehicles, cell encapsulation) [28]. Recently, amphiphilic dibock copolypeptide hydrogels of KigoL2o were used in an in vivo study where the hydrogels were injected into the mouse forebrain. Evaluation of samples displayed substantial tissue integration with little or no detectable toxicity in the central nervous system [148]. 

The presence of particles in the brains of experimental rats and humans exposed to asbestos has been reported (Pontefiart and Cunningham, 1973 Auerbach et al., 1980). In experimental studies, particles of Teflon, a reflux paste, enter the brain via intravascular transport when injected into the bladder (Aaronson et al., 1993). Encephalitic reactions to accumulated calcium oxalate crystals in the brain as a result of infusions of glucose surrogate polyol solutions have been described (PciflPcr etal., 1984). Such studies indicate the capacity of particulates to enter the brain and thus pose a potential pathological threat to the functioning of the central nervous system (CNS). 

In rats exposed to 700 ppm, effects included excitement followed by eye irritation and drowsiness. The rat LCso for 4 hours was 233 ppm. Repeated daily exposure of rats to an average of 19 ppm caused moderate respiratory irritation. Intravenous injection into rabbits and cats caused depression of the central nervous system death occurred at doses of 800-1400 mg/]. ... 

Cocaine is a local anesthetic with a peripheral sympathomimetic action that results from inhibition of transmitter reuptake at noradrenergic synapses (see Chapter 6 Introduction to Autonomic Pharmacology). It readily enters the central nervous system and produces an amphetamine-like effect that is shorter lasting and more intense. The major action of cocaine in the central nervous system is to inhibit dopamine reuptake into neurons in the "pleasure centers" of the brain. These properties and the fact that it can be smoked, "snorted" into the nose, or injected for rapid onset of... 

Neurosteroids are steroids that are synthesized de novo in the central nervous system (androsterone, dihydrotestosterone, testosterone, allopregnanolone, isopregnanolone, and pregananole). After extraction of plasma and cerebrospinal fluids, using solid-phase extraction (SPE), and derivatization with carboxymethoxime, pentafluoro-benzyl, and trimethylsilyl, the derivatized samples were injected into a GC-MS system for quantitative evaluation with a selected ion monitoring (SIM) method. Details of the method have been described in Ref. [25]. 

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