KR20010101992A - Regulation of anaesthesia - Google Patents

Abstract

The present invention relates to a method of adjusting anesthesia and assessing the amount of anesthetic required by a patient. It is about. The method of controlling anesthesia using the DSIP of the present invention can extend the anesthesia time and reduce the amount of anesthetics for inducing anesthesia, which can be used to reduce the side effects of existing anesthetics.

Description

Regulation of Anesthesia {Regulation of anaesthesia}

The metabolic activity of the brain varies with different clinical situations. For example, the metabolic activity of the brain increases during epileptic seizures and during rapid eye movement sleep (REM sleep), while the metabolic activity of the brain decreases during hibernation or general anesthesia. do.

Anesthesia is a condition in which there is no sensation or no external stimulus is detected. Anesthesia is divided into local (loss of sensory in certain tissues) and general (generally unconscious). Under normal anesthesia, brain metabolism is known to be reduced by about 47%. Overdose of anesthetics can lead to very severe anesthesia, with extremely low metabolic activity and high risk of serious side effects. Therefore, it is very important that the clinician adjust the anesthesia appropriately to control the brain activity sensitively and reliably.

Anesthesia is different from physiologically sleeping. For example, a sleeping creature can easily wake up, and thus still be sensitive to external stimuli, while in general anesthesia is not easily awakened by an external stimulus and cannot be detected. In addition, brain activity does not necessarily decrease during sleep (eg during rapid eye movement sleep, brain activity is as high as normal), but general anesthesia is associated with decreased brain activity. . Considering the difference between sleep and anesthesia, it is easy to see that anesthetics do not necessarily act as hypnotics, and conversely, sleeping pills do not act as anesthetics.

Small, variable (unstable) molecules that cause anesthesia (alcohols, halothane, ether, etc.) have long been known and are widely used to induce anesthesia before elective surgery and to maintain anesthesia during surgery. Traditional anesthetics, however, have many disadvantages, including:

(1) the area of intensive use of anesthetics is narrow (too small to enable the organism to regain its sense of external stimuli; conversely, too much can lead to coma or death);

(2) slow recovery after anesthesia;

(3) there may be general side effects such as respiratory distress, cardiovascular instability and vomiting;

(4) Uncommon but life-threatening side effects, such as malignant hyperpyrexia, may occur.

Thus, there has been a need to provide anesthetics or compounds that can be used with anesthetics that eliminate or reduce the side effects listed above.

The present invention relates to a method of adjusting anesthesia and evaluating a patient's need for anesthetics.

In the first step of the present invention, the use of a compound that modulates Delta-Sleep Inducing Peptide (DSIP) activity to produce a drug capable of modulating anesthesia is proposed.

DSIP is a nonapeptide (which may exist in a linear or cyclic form) having the amino acid sequence represented by SEQ ID NO: 1 .

DSIP was discovered in the 1970s, and its use has been proposed to induce sleep (but with only limited success), and its use has been suggested for the treatment of drug addicts who have stopped using it. However, until now it was known that it was not related to anesthesia, and the inventors found that compounds that modulate DSIP activity can modulate anesthesia.

DSIP can lead to a decrease in brain metabolic activity associated with changes in consciousness. We have found that decreased brain metabolic activity seen during anesthesia usually leads to changes in consciousness that are different from the type of sleep. In fact, after DSIP treatment, rapid eye movement sleep decreases and delta wave activity increases. We have studied these changes in association with anesthesia to synthesize compounds that modulate DSIP activity of the invention. Furthermore, the inventors believe that DSIP is also very important for inducing hibernation and is important for inducing a decrease in brain metabolic activity during hibernation or other similar conditions.

DSIP is an endogenous anaesthetic-like substance that is believed to regulate neurotransmission and brain activity. This is the result of research using PET to measure changes in metabolic activity in various areas of the brain when anesthesia is performed with traditional anesthetic materials. The invention begins with the fact that the areas of the brain that show changes in metabolic activity in response to traditional anesthetics are the same as those identified as areas where the DSIP appears using immunohistologic techniques.

We do not wish to be limited to any one hypothesis, but we believe that compounds that modulate DSIP activity are effective because these compounds are neuromodulatory binding of neuroreceptors that are involved in the regulation of anesthesia. sites, by regulating the binding of ligands (eg the site described by Mihic et al . (1997) Nature 389 p385-389 on GABAa receptors and glycine receptors). The inventors believe that DSIP regulates the signaling from these receptors by binding to these receptors, thereby regulating the degree of brain metabolism and anesthesia.

Our hypothesis that DSIP acts as an anesthetic has been confirmed by experiments demonstrating that administration of DSIP can induce anesthesia and prolong the anesthetic state induced by other anesthetics. For example, when anesthetizing an experimental animal by intravenous injection of 7 mg / kg of propofol, the animals treated with DSIP (1 mg / kg IP, 15 minutes before propofol) were treated with propofol. Anesthesia continued about 28% longer than animals treated alone. More experimental data illustrate the efficacy of DSIP and related compounds, which are shown in the examples below.

More specifically, the inventors have found that compounds that increase DSIP activity may be used alone to induce anesthesia or to maintain anesthesia, but are more effective when used in combination with other anesthetics. When used as part of a device for inducing anesthesia, compounds which increase these DSIP activities may be used at the time of anesthesia induction or as part of a preliminary anesthesia.

Several kinds of compounds that can increase DSIP activity can be used in accordance with the present invention. These compounds include agonists or partial agonists of DSIP neuromodulatory binding sites, which include the release of endogenous agonists of DSIP neuromodulatory binding sites. Heightening agents, agents that increase the synthesis of endogenous agonists at DSIP neuromodulatory binding sites, agents that reduce the destruction (or elimination / isolation) of endogenous DSIP agonists, agents that increase DSIP expression or activity, And agents that enhance the mechanism involved in signal transduction between ligands and effector systems that are bound to the DSIP binding site.

Preferred compounds that increase DSIP activity are the DSIP agonist per se and its derivatives and / or pharmaceutical acceptable salts.

Preferred DSIP agonists that can be used according to the first embodiment of the invention are described in British Patent No. Phosphorylated nonapeptides shown in 2 000 511 (incorporated by reference).

Biologically active fragments of DSIP, biologically active DSIP derivatives, and larger peptides that make up nona peptides (or biologically active fragments and derivatives thereof) Are preferred compounds usable according to the first embodiment of the invention. For example, one preferred DSIP derivative is the cyclic (-GLY-DSIP) mentioned by Nekraov et al. (Biochem. Mol. Biol. Int. 1996: 38 p739-745). This derivative is more lipophilic than DSIP and can more easily cross the blood brain barrier. Cyclic (-GLY-DSIP) is particularly useful for inducing rapid anesthesia.

Non-peptide compounds, naturally occurring or artificially synthesized, which are mimic peptides with the activity of DSIP agonists are also available.

Compounds that modulate DSIP activity may be used in the process of inducing anesthesia, in order to anesthetize the patient by administering to the patient an appropriate amount of a compound that enhances the DSIP activity to at least contribute to inducing an anesthesia. Can help induction

The inventors believe that DSIP (and functional equivalents thereof) can induce or maintain anesthesia according to the first embodiment of the present invention for the following reasons:

(1) This substance is a neuromodulator, but it does not necessarily have to be a neurotransmitter. The neuromodulators are provided on GABAa, glycine and other possible receptors in the same manner as modulators that act in regions such as ethanol sites and / or enflurane anaesthetic sites. It is believed to affect the transmembrane binding site.

(2) This substance is an anticonvulsant.

(3) This substance has analgesic properties. The inventors believe that DSIP acts as an analgesic in that DSIP increases the release of met-enkephalin, an analgesic substance produced in the brain.

(4) Investigating how DSIP affects sleep promotion, it has been shown that this material does not induce normal sleep stages but increases delta wave activity like many other anesthetics. It was confirmed through). During anesthesia, the EEG recorder shows a complex pattern, which includes delta wave components, but this pattern is distinct from the pattern seen in natural sleep.

(5) This substance regulates excitation and inhibition in the brain. It also acts like a normal anesthetic to regulate body temperature.

The analgesic effect of this compound (Example 3 above) is unique among the advantages of the compounds used in the first embodiment of the present invention. In some cases, the effect of the compound as an analgesic may precede the effect as an anesthetic. This is a great advantage in relieving the patient's pain during the postoperative recovery period. Moreover, the analgesic effects enhanced by this compound were found to be independent of respiratory depression, a common side-effect of conventional anesthetics such as morphine.

These compounds, which increase DSIP activity, are particularly useful for patients who require long-term treatment by relying on ventilators, etc., in the intensive care unit. The problems with these patients are the long-term maintenance of proper anesthesia, and it is important for them to be pain-free and able to continue the circulation of fresh air in their blood. Extensive clinical experience suggests an increasing use of anesthetics. In general, anesthesia gas is not used well because it has important defects such as polluting the local environment. Anesthesia methods for propofol intravenous injection continue to be commonly used methods. However, the continued accumulation of propofol components has several undesirable side effects. One of the main problems is that propofol's resistance to anesthesia effects increases gradually (in some cases the resistance increases very rapidly), and an increasing amount of anesthetic is needed to maintain the patient's anesthesia. When the ventilator is removed from the patient and anesthetized, respiratory distress, a problem of traditional anesthetics, is commonly used. The use of compounds that increase DSIP activity in these clinical settings is of great benefit because enhanced DSIP activity does not cause respiratory distress. Furthermore, it was observed that resistance to the effects of naturally increased hormones did not occur. In addition, the activity of DSIP has many advantages over traditional anesthetics such as:

(1) DSIP itself has analgesic effects, probably because it causes the release of met-enkephalin (pain is often the most important issue for patients relying on long-term respiratory organs);

(2) DSIP has been shown to have the advantage of appropriately coping with stress (the environment in the middle- and high-intensity room is very stressful to the patient).

We have found that compounds that increase DSIP activity are particularly useful as adjuncts to other anesthetics. Compounds that increase these DSIP activities when used in combination with other anesthetics prolong the duration of anesthesia. When the compound is used as an anesthetic additive in accordance with the first embodiment of the present invention, it can be seen that even if less anesthetic is used, a more sufficient anesthetic state can be reached than when anesthetic is used alone. This has the advantage of reducing the risk of side effects and alleviating the discomfort associated with using an increasing amount of anesthetic. For example, existing anesthetics may cause respiratory disorders that prevent patients from breathing spontaneously, but DSIP has nothing to do with these breathing disorders. Therefore, if you reduce the amount of existing anesthetics and use DSIP together instead of a small amount of anesthetics that do not cause respiratory failure can be sufficient effect.

The use of DSIP and other compounds according to the first embodiment of the present invention can minimize the risk of cardiovascular instability, in addition to the following advantages:

(Iv) The kinetics of DSIP in vivo are non-saturable. That is, metabolism is accomplished by plasma and other non-specific esterases;

(Ii) Peptide compounds such as DSIP are not toxic and need not be used in gaseous form. Thus, environmental pollution can be reduced during manufacture, use and disposal; And

(Iii) Compounds that increase DSIP activity can enable immediateaneous reversal or at least rapid reversal of general anesthesia, thereby reducing the time it takes to recover from anesthesia and increasing the safety of anesthesia (ie, adding DSIP to anesthesia). When used in combination with propofol, it can smooth the propofol-induced anesthesia and reduce intraoperative side-effects).

DSIP is degraded by a number of non-specific peptidases, including Angiotensin Converting Enzyme (ACE). Therefore, in order for the activity of DSIP to add its effect, it is more preferable to use the compounds shown in the first embodiment of the present invention together with the ACE inhibitor. This is particularly desirable when DSIP needs to be used for a relatively long time (ie when anesthesia and pain relief are needed during intensive care).

According to a second embodiment of the invention the compounds may be used for the purpose of reducing DSIP activity.

According to a second embodiment of the invention these compounds can be used to increase brain activity to induce recovery from anesthesia.

Some types of compounds that can reduce DSIP activity, which can be used in the second embodiment of the present invention, include antagonists or partial agonists of DSIP neuromodulatory binding sites. These include agents that inhibit the secretion of endogenous agonists at the DSIP neuromodulatory binding site, agents that inhibit the synthesis of endogenous agonists at the DSIP neuromodulatory binding site, and destroy (removal or isolate) the endogenous DSIP agonist. Agents to help reduce the expression or activity of DSIP, and agents that inhibit signal transduction mechanisms between the ligand-associated DSIP binding site and effector systems.

Preferred among the compounds that reduce DSIP activity are DSIP antagonists and include melatonin, dalargin and neokitotorphin.

Compounds that reduce DSIP activity are preferably used to promote recovery from anesthesia. Therefore, immediately before surgery, the compounds shown in the first embodiment of the present invention are used to anesthetize the patient (alone or in combination with other anesthetics) and after the surgical procedure is completed the compounds shown in the second embodiment of the present invention from anesthesia It is desirable to use to promote recovery.

Compounds that modulate DSIP activity according to the first and second embodiments of the present invention can modulate brain activity either alone or in combination with other agents. In other words, the compounds shown in the first embodiment of the present invention can cause anesthesia alone or in combination with other existing anesthetics (ie, reducing MAC when anesthesia with propofol or gas, for example). The DSIP agonist can be used together as a common anesthetic, MAC, which stands for Minimum Alveolar Concentration of anaesthesia, which is necessary to eliminate the movement of harmful stimuli in 50% of patients).

When these compounds are used with other anesthetics, the amount of anesthetic should be used less than usual. This can reduce and lessen the incidence of side effects known to be caused by general anesthetics. The amount of anesthetic used is usually reduced by 20% -50% depending on the combination method used.

The compounds used in the first embodiment of the present invention can take many different forms depending on the method of their construction. For example, in the form of composites, powders, tablets, capsules, liquids, ointments, creams, gels, hydrogels, It may be used in the form of an aerosol, spray, micelle, liposome, or the like, or may be prepared in other suitable forms for administration to other humans or animals. The transport medium of the composite of the present invention should be easy for the patient receiving it to be able to tolerate and deliver the composite well to the target tissue.

Sterilized isotonic solutions are preferred for injection and micronised powder with excipients is preferred for inhalation by mouth.

The compounds can be used in a variety of ways. For example, the inclusion of the compound in a compound administered into the bloodstream by injection affects the whole body. Injection methods are both intravenous or subcutaneous. The compound may also be orally administered. The compound may be taken by mouth in the form of tablets or capsules or in liquid form.

Compounds that modulate DSIP activity are transported and acted into the intracerebral and intracerebroventricular or intrathecal regions of the cerebrum.

The required amount of the compound is determined by the biological activity and the bioavailability of the drug, which in turn depends on the method of administration, the physicochemical capabilities of the compound used, and whether the compound is administered alone or in combination with other anesthetics. Different. Frequency and / or rate of administration are also affected by the factors mentioned above, in particular by the half-life of the composition already administered to the patient. In addition, anesthetists should monitor the patient's anesthesia (depth) during anesthesia to control the dose of the compound.

Existing procedures traditionally used in the pharmaceutical industry (ie biopsies, clinical trials, etc.) can be used to make certain types of composites and to determine the correct therapeutic range.

In general, the dosage of a compound that modulates DSIP activity, which is used to modulate brain activity, is appropriate between 0.01 μg-1.0 g per kilogram of body weight, which is also why certain compounds are used and why do they regulate brain activity? It depends on your cognition. For example, for DSIP antagonists a suitable dosage is 1.0 μg / kg-1.0 mg / kg (20-400 μg / kg is preferred). A simple example of the use of DSIP with propofol (7 mg / kg IVbolus) at anesthesia is between 0.01 mg / kg-100 mg / kg and more preferably 0.02 mg / kg-100 mg / kg. .

Administration should be often or continuously as required by the anesthesiologist. The amount of DSIP required to maintain anesthesia is about 1 μg / kg / hr −1 g / kg / hr, particularly up to 10 μg / kg / hr-100 mg / kg / hr.

In a second embodiment of the invention, the invention provides a method of modulating anesthesia comprising administering to a patient a compound that modulates the activity of Delta-Sleep Inducing Peptide (DSIP) for the treatment of the patient.

The above-mentioned compounds for modulating the activity of DSIP described in the first embodiment of the present invention can be used according to the method of the second embodiment of the present invention.

In a third embodiment of the present invention, the present invention provides a method for evaluating anaesthetic needs for anesthesia in a patient, including sampling from the patient and analyzing the presence of Delta-Sleep Inducing Peptide (DSIP). To provide.

As used herein, the term “anaesthetic needs” refers to the standard amount of anesthetic that is required to induce or maintain an appropriate level of anesthesia.

We found that the amount of anesthetic required is directly related to the endogenous level of DSIP. Therefore, the patient's DSIP level can be assessed before surgery (measured by simple urinalysis or blood test) to determine the dose of anesthetic needed for anesthesia. Sample testing suggests that the higher the endogenous level of DSIP, the lower the mean anesthetic dose required by the patient. Conversely, the lower the endogenous level of DSIP at the test result, the greater the patient's need for anesthetic than the average.

The normal range of endogenous DSIP will depend on the assay used and the population targeted. The assay described by Seifritz et al. (Peptides 1995; 16 (8); p1475-1481) can be used to determine the level of DSIP by way of example only. Is approximately 0.1-11 ng / ml. Therefore, patients with DSIP levels above about 5.0 ng / ml should use less than average anesthetics, whereas patients with DSIP levels below 5.0 ng / ml require more than average anesthetics.

A suitable way to measure the DSIP level of a sample is quantitative immunoassay, which examines the increased amount of antibodies against DSIP. For example, the enzyme immunoassay described by Kato, Neuroendocrinology 1984; 39: p39-44, et al. Can be used as a preoperative test to calculate the required amount of anesthetic. Another alternative that can be used according to the third embodiment of the present invention is radioimmunoassay (Seifritz et al . Supra). An evaluation method that considers color change that can be analyzed visually or by using a spectrophotometer is preferable.

The most suitable for specimen testing is a blood sample or urine sample.

This method is available as a method of preoperative testing to determine the amount of anesthetic needed before the patient undergoes surgery.

As shown in the third embodiment of the present invention, an anesthesiologist, nurse or technician may take a blood or urine sample from a patient immediately before anesthesia (approximately within 30 minutes before anesthesia) and test to determine the amount of anesthetic suitable for the patient. Can be. At this time, the test method is to insert a long paper rod into the obtained sample and observe the color change (this bar is designed to change color depending on the level of DSIP in the sample). The anesthesiologist then analyzes the measured levels and determines the dose of the anesthetic accordingly.

Hereinafter, the present invention will be described in detail by way of examples.

However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

We conducted the following experiments using rodents to analyze the effect of DSIP on anesthesia induced by propofol.

Way

Nine Sprague-Dawley rats, weighing 230-287 g, were given free water and rat Purina chow. All animals were maintained and handled in accordance with the IACUC Animal Use Policy. The animals were divided into two groups and examined the correlation between DSIP and intravenous anesthetic, propofol (n = 5) or inhalation anisoflurane (n = 4). For propofol experiments, rats were randomly selected and administered with either 3 ml of sterile water (1 mg / kg of Peninsula Lab, CA) or 3 ml of sterile water (placebo). After 15 minutes, 7 mg / kg of Propofol (Diprivan or Rapinoivet) was intravenously injected over about 10 seconds into the tail vein of the rats and the loss of righting reflex was examined. The loss of lighting reflexes allowed the animals to lie on their side lying in the center of a large ball with a flat bottom. They recorded their sleep time and the time to recover lighting enough to stand back on all fours. The following week, animals receiving DSIP received placebo and animals receiving placebo this time received DSIP. An amount of propofol equal to the amount of propofol administered in the previous week was administered to each rat and the sleep times of each of these rats were recorded again.

To determine the case of inhalation, place the rat on a rotating rod in the middle of the anesthesia chamber and inhale 0.05% every 10-15 minutes until the rats can no longer walk forward on the rotating rod. The amount of anesthetic was slowly raised. In the first week of the experiment, rats were randomly selected to administer either DSIP 0.1 mg / kg or placebo 15 minutes prior to testing. In the second week, the mice were reversed (ie, placebo-injected with DSIP for mice receiving placebo and placebo for mice receiving DSIP).

All results were statistically analyzed by paired two-tailed t-test.

result

None of the rats injected with 1 mg / kg of DSIP in the peritoneum lost consciousness. However, some movement was seen in rats immediately after DSIP injection into the peritoneum. Rats have been shown to be affected by the pharmacological effects of DSIP pretreatment. If they are left undisturbed, they will simply “pomp”, which is probably the most appropriate expression of their condition. However, the rats moved moderately when someone approached, but soon returned to squat if left alone.

Table 1 shows the results of measuring sleep time after intravenous injection of 7 mg / kg propofol in each rat.

Table 1

Laboratory animals Sleep time (seconds) DSIP 1 mg / kg Placebo (sleep) One 406 242 2 527 446 3 748 577 4 637 581 5 737 689

Each rat was found to have longer sleep time when pretreated with DSIP, and the average sleep time when propofol only was administered to rats was 477 +/- 158 seconds, and the average when propofol was administered after pretreatment with DSIP. Sleep time was 611 +/- 145 seconds. This difference is significant at a level of p <0.01 and represents an average increase in sleep time of 28%.

The amount of anesthetic isoflurane (chamber ISO%) required for each rat to be unable to walk forward on the rotating rod is shown in Table 2.

TABLE 2

Laboratory animals Isoflurane (Chamber iso%) DSIP 1 mg / kg ip Isoflurane (Chamber iso%) placebo One 406 242 2 527 446 3 748 577 4 637 581

The average concentration of isoflurane (+/- SD) required for placebo-injected rats to be unable to walk on the rotating rod was 0.26 +/- 0.06%, which was 0.20 when pretreated with DSIP. A 23% decrease was found to be +/- 0.06%. This figure shows a statistically significant decrease in the p = 0.01 level.

Taken together, the results show that DSIP is particularly effective when used together as additives for propofol and isoflurane. As shown in Table 1, it was confirmed that DSIP prolongs anesthesia time, and as shown in Table 2, it was confirmed that DSIP can lower the amount of anesthetic (concentration) required to induce anesthesia.

As described above, the method of controlling anesthesia using the DSIP of the present invention can extend the anesthesia time and reduce the amount of anesthetics for inducing anesthesia, which can be used to reduce side effects of existing anesthetics.

Claims (13)

Use of a compound that modulates Delta-Sleep Inducing Peptide (DSIP) activity in the manufacture of a medicament that modulates anesthesia. The method of claim 1, wherein the compound enhances or mimics DSIP activity, and the medicament induces anesthesia or enhances its effect. 3. Use according to claim 2, characterized in that the compound is used in combination with other anesthetics. Use of a compound that enhances DSIP activity to prepare a medicament that induces or augments sedation. 5. The use according to claim 2, wherein the compound is a DSIP or a derivative thereof having biological activity. Use according to claim 5, characterized in that the compound is a nonapeptide having an amino acid sequence represented by SEQ ID NO: Amino acid sequence represented by SEQ ID NO: 1 Or derivatives thereof having biological activity. 7. Use according to claim 6, wherein the nonapeptide is at least one amino acid or derivative thereof phosphorylated. 2. Use according to claim 1, characterized in that the compound inhibits DSIP activity, and the medicament induces recovery from anesthesia or enhances its effect. A method of modulating anesthesia, comprising administering a compound that modulates DSIP activity. A method of determining an appropriate amount of anesthetic for anesthesia by examining the presence of DSIP in a patient's sample. The method of claim 10, wherein the sample is blood or urine. 12. The method according to claim 10 or 11, wherein less than the average amount of anesthetic is used if the endogenous level of DSIP in the patient's sample test is higher than the average. 12. The method of claim 10 or 11, wherein a greater than average amount of anesthetic is used if the endogenous level of the DSIP is below the mean in the patient's sample test.