JP4445903B2 - Infusion management system using biological clock - Google Patents

Description

  The present invention is characterized in that different infusion components comprising an amino acid solution, a sugar solution, a vitamin solution, and an inorganic salt solution are instilled into a patient at each dropping rate and dropping time zone set using a biological clock. The present invention relates to an infusion management system for supplying liquid and an infusion control device.

Many organisms, from bacteria to humans, exhibit various physiological and behavioral circadian rhythms that are regulated by endogenous oscillators. In mammals, the suprachiasmatic nucleus (SCN) in the hypothalamus functions as the master circadian clock (Brain Res. 311: 353-357, 1984; Science 283: 693-695, 1999; Nature 382: 810 -813, 1996). The per gene, a homologue of the Drosophila clock gene, has been isolated from mammals (Cell 96: 271-290, 1999; Proc. Natl. Acad. Sci. USA 96: 8819-8820, 1999; Brain Res. Rev. 33: 34-77, 2000)
. The per genes, i.e., per1, per2 and per3, show strong circadian expression not only in SCN but also in peripheral tissues such as eyes, heart, lung and kidney (Cell 96: 271-290, 1999; Brain Res. Rev. 33: 34-77, 2000; Neurosci. Lett. 256: 117-119, 1998; J. Biol. Chem. 273: 27039-27042, 1998). The period of free run oscillation of clock gene expression is usually about 24 hours inherently,
Their circadian expression is determined by environmental stimuli. The role of light as such a determinant is well studied. Other environmental time stimuli such as temperature, social time stimuli and food intake also determine the circadian clock at SCN, but the effects of such determinants are not well understood. Restricted dosing schedules of drugs such as glucocorticoids, interferon-α and metamphetamine, for example, alter circadian gene expression in peripheral tissues, while such stimuli do not affect circadian gene expression in SCN (Genes. Dev. 14: 2950-2961, 2000; Science 291: 490-493, 2001; Embo J. 20: 7128-7136, 2001; Nat. Med. 7: 356-360, 2001; Eur. J. Neurosci. 16: 921-929, 2002). In response to these findings, recent studies by the present inventors have shown that not only the peripheral clock but also the central clock is strongly influenced by the time of total parenteral nutrition (TPN) (Hepatology 26 : 1580-1586, 1997; Neuroreport 14: 1457-1461, 2003). In rats fed TPN at night (simulating night feeding), the expression of rPer2 and rat D-site binding protein (rDBP) in SCN was similar to that of the free-dose control with peak levels late at night showed that. However, a reversal pattern of these gene expressions was observed in rats given TPN only during the daytime (rat dormancy). Such a change occurred early in the first day after the start of infusion.

  On the other hand, the question of how to achieve infusion in consideration of the quality of life (QOL) of patients in clinical settings is the most realistic and important issue for medical care and nursing. Postoperative nutritional routes are mainly divided into central parenteral nutrition (TPN) and enteral nutrition (Enteral Nutrition). Various basic researches on enteral nutrition have been developed, and a method to avoid side effects has been established by administration during the almost active period (daytime for humans). However, for central parenteral nutrition, it is common sense to administer high-calorie infusions for 24 hours continuously via an intravenous catheter. On the other hand, inducing complications has long been a problem in medical care, but recently, our study has revealed the involvement of the biological clock mechanism (the latest medicine for nursing 73). -78 (2003) Nakayama Shoten).

R. Drucker-Colin et al., Brain Res. 311: 353-357, 1984 DJ Earnest et al., Science 283: 693-695, 1999 R Silver et al., Nature 382: 810-813,1996 JC Dunlap, Cell 96: 271-290, 1999 N. Ishida et al., Proc. Natl. Acad. Sci. USA 96: 8819-8820, 1999 KE van Esseveldt et al., Brain Res. Rev. 33: 34-77, 2000 K Oishi et al., Neurosci. Lett. 256: 117-119, 1998 K Sakamoto et al., J. Biol. Chem. 273: 27039-27042, 1998 F. Damiola et al., Genes. Dev. 14: 2950-2961, 2000 KA Stokkan et al., Science 291: 490-493, 2001 N Le Minh et al., Embo J. 20: 7128-7136, 2001 S. Ohdo et al., Nat. Med. 7: 356-360, 2001 M Iijima et al., Eur. J. Neurosci. 16: 921-929, 2002 A Ogawa et al., Hepatology 26: 1580-1586, 1997 H Miki et al., Neuroreport 14: 1457-1461, 2003 The Latest Medicine for Nursing 73-78 (2003) Nakayama Shoten

  Central parenteral nutrition methods have problems such as liver damage and complications such as cholestasis caused by continuous administration of high-calorie infusions and changes in efficacy during drug administration. In addition, this conventional infusion method may cause circadian clock diseases such as insomnia and delirium. The present inventors have aimed to develop an infusion means that suppresses such harmful effects as much as possible, and surprisingly, this time, it has been found that continuous highly nutritive infusion itself perturbs the body clock rhythm. It is thought that such a deviation in biological rhythm also affects the course of disease treatment and prognosis.

  Therefore, an object of the present invention is to provide an infusion management system including an infusion control device that enables infusion that does not cause a deviation in the body clock rhythm.

  The present invention is summarized as follows.

(1) An infusion management system using a body clock, at least four storage containers for storing different infusion components consisting of an amino acid solution, a sugar solution, a vitamin solution, and an inorganic salt solution, an infusion control device, and a liquid supply conduit Here, the drip control device sets a dropping speed and a dropping time zone of the solution, and a control means for controlling the liquid supply according to the setting, for monitoring the liquid supply state of each solution Display means, stop means for automatically stopping liquid supply when an abnormality occurs, and at least four inlet means for the solution to flow in and at least one outlet means for the solution to flow out, wherein the liquid supply conduit is the container And a conduit for connecting each solution in the drip control device to the outlet means. Stem.
(2) The system according to (1), wherein a dropping speed and a dropping time zone of the infusion component are set so as not to disturb the daily rhythm of the human body clock.
(3) The system according to (2), wherein the dropping time zone is awakening of a human.
(4) The system according to (3), wherein the dropping time zone of the amino acid solution is set between 12:00 and 22:00.
(5) The system according to (3), wherein a dropping time zone of the sugar solution is set between 10:00 and 22:00.
(6) The system according to (3), wherein the dropping time zone of the inorganic salt solution is set between 11:00 and 22:00.
(7) The system according to any one of (1) to (6), wherein the liquid supply of the infusion component is performed by a gravitational action.
(8) The system according to any one of (1) to (6), wherein the liquid supply of the infusion component is performed by a mechanical action.
(9) The system according to any one of (1) to (8), wherein the drip control device further includes means for notifying completion of liquid supply, during liquid supply, or occurrence of an abnormality.
(10) The system according to any one of (1) to (9), further including a container that stores the drug solution.
(11) The system according to any one of (1) to (9), wherein the liquid supply is performed for an amino acid solution, a sugar solution, a vitamin solution, and an inorganic salt solution.
(12) The system according to any one of (1) to (10), wherein the liquid supply is performed for an amino acid solution, a sugar solution, an inorganic salt solution, a vitamin solution, and a drug solution.
(13) The system according to any one of (1) to (12), further including a monitor for monitoring a supply state of the solution at a nurse station.
(14) Patients with different infusion components consisting of amino acid solution, sugar solution, vitamin solution and inorganic salt solution, and if necessary, a drug solution at each dropping rate and dropping time zone set using a biological clock. A drip control apparatus comprising a control unit including means for supplying liquid to the liquid.
(15) The control unit according to the dropping condition set by the setting means for setting the dropping speed and the dropping time zone, the adjusting means arranged in the flow path of the solution and adjusting the dropping speed, and the setting means The drip control apparatus according to (14), further comprising control means for controlling the flow rate adjusting means.
(16) The drip control apparatus according to (14) or (15), further including display means for monitoring a supply state of the solution.
(17) The drip control apparatus according to any one of (14) to (16), further including stop means for automatically stopping the liquid supply when an abnormality occurs.
(18) The drip control apparatus according to any one of (14) to (17), further including at least four inlet means for the solution to flow in and at least one outlet means for the solution to flow out.
(19) The drip control apparatus according to any one of (14) to (18), further including means for notifying completion of the liquid supply, liquid supply, or occurrence of an abnormality.

  In the present invention, based on the knowledge that continuous hypernutrition itself perturbs the body clock rhythm, the patient's medical condition and prognosis progress are improved by instilling the patient in a state where the body clock rhythm is not disturbed. It has the effect that it is possible.

  The infusion management system of the present invention is for instilling each of infusion components, that is, an amino acid solution, a sugar solution, a vitamin solution, and an inorganic salt solution into a patient using a biological clock. The system mainly includes at least four storage containers containing different infusion components, an infusion control device, and a supply conduit.

  The present invention is based on the knowledge that individual infusion components of infusions infused into a patient with conventional central parenteral nutrition deviate from the circadian rhythm of the living body. It is characterized by instilling the component into the patient.

  Infusion components generally comprise amino acids, sugars, inorganic salts (or electrolytes), and vitamins. Any solution containing these infusion components should be formulated in an isotonic solution. The amount of each solution is usually 500 ml or less, for example 500 ml, 300 ml, etc., preferably 500 ml.

Amino acids consist of all of the essential amino acids necessary for protein synthesis, etc., and the required amount of amino acids in high-calorie infusion is about 1.0-1.5 g / kg / day, which is the ratio of non-nitrogen heat to grams of nitrogen Appropriate value of non-protein calorie nitrogen ratio (NPC / N ratio) is, for example, 225 for normal people, 165 for internal medicine patients without fever and trauma, 175-185 for postoperative patients, 185-250 for patients with burns or infections, 300-50 in patients with renal failure
Since it is known to be 0, the optimal amino acid amount is prescribed according to the patient's condition.

  Sugar is a component used as a calorie source, and glucose (ie, glucose) is usually used as the sugar. However, fructose, xylitol, maltose, etc., which do not depend on insulin, are used in patients with impaired glucose utilization such as diabetic patients, and sorbitol, which produces a large amount of liver glycogen, is used in patients with liver diseases. Generally, to maintain nutritional status, it is prescribed to sugar in an amount equivalent to 20-30 Kcal / kg / day, but it can be prescribed 30-60 Kcal / kg / day depending on the patient's condition. is there.

  Inorganic salts include sodium ions, potassium ions, calcium ions, magnesium ions, phosphorus, zinc, iron and the like. These inorganic salts may be included in the form of a salt with an organic acid such as acetic acid, lactic acid or glycerophosphoric acid, or may be in the form of a so-called inorganic salt. In general, it should be formulated to the concentration of inorganic salts used for infusion.

Vitamins include vitamins B1, B6, B12, C, E, thiamine hydrochloride, pyridoxine hydrochloride, folic acid,
Contains biotin. Commercially available products such as “Neolamin” (Nippon Kayaku) may be used as the infusion vitamin.

  In the present invention, each storage container containing the above four infusion components is prepared. Such a container is a container of the material and shape normally used for infusion, such as a transparent polymer bag (that is, a bag) and a glass bottle. The container preferably has a structure that can be hung upside down on a drip support, and is aseptically sealed with a rubber cap so that a conduit (tube) with a syringe needle for liquid supply can be easily connected. .

  According to an embodiment of the present invention, the system may further include a container (usually in an amount of 500 ml or less) containing a drug solution formulated in an isotonic solution. Such drugs include drugs used for patient treatment, antibiotics to prevent infection, and the like. By adjusting the administration time zone without disturbing the internal rhythm, the efficacy of the drug can be increased and the side effects can be reduced. For example, the anticancer agent is preferably administered to the patient at night and the antithrombotic agent is conversely administered to the patient in the morning, and it is preferable to select the administration time according to the type of the drug. According to the present invention, the infusion drip time zone that does not disturb the circadian rhythm of the human body clock exists in the wakefulness period (that is, the active period) that is not bedtime, and the four infusion components and the drugs each have the optimum drip time. Have. In humans, for example, the dropping time zone of the amino acid solution is from 12:00 to 22:00, the dropping time zone of the sugar solution is from 10:00 to 22:00, and the dropping time zone of the inorganic salt solution is from 11:00 to 22:00. Each exist until

  The dropping speed of the solution may be different or the same for each solution, but is preferably adjusted so that the amount of infusion to the patient becomes a constant speed. The dropping speed is generally 10 to 500 ml / hour, such as 10 to 50 ml / hour, 50 to 100 ml / hour, 100 to 200 ml / hour, 200 to 300 ml / hour, 300 to 400 ml / hour, 400 to 500 ml / hour, etc. It is adjusted to the range.

  Furthermore, in the present invention, the infusion of an infusion solution may consist of four solutions of an amino acid solution, a sugar solution, a vitamin solution, and an inorganic salt solution, depending on the purpose of treatment or prevention of the patient, It may consist of five solutions: a sugar solution, an inorganic salt solution, a vitamin solution, and a drug solution.

  The system of the present invention further includes an infusion control device. This device uses different infusion components consisting of amino acid solution, sugar solution, vitamin solution and inorganic salt solution, and if necessary, a drug solution at each dropping rate and dropping time zone set using a biological clock. It includes a control unit including means for supplying liquid to a patient.

  Such control can be performed by adjusting opening / closing of a flow rate control valve or tube clamp under microcomputer control. In order to automatically control the dropping speed and dropping time zone of the solution, a setting function for inputting an optimum numerical value, a memory function for storing this numerical value, and a dropping operation (run) as set. Includes functionality for.

  Specifically, the control unit includes a setting unit that sets the dropping speed and a dropping time zone, an adjusting unit that is arranged in the flow path of the solution and adjusts the dropping rate, and a dropping condition set by the setting unit. Control means for controlling and operating the flow rate adjusting means can be included.

An example of such adjustment / control means is shown in FIG. In the figure, the stepping motor (1) is rotated, and the actuator (3) is driven forward and backward through the gear (2), thereby adjusting the throttle amount (or throttle force or pressing force) of the conduit (tube) diameter. . The pressure sensor (4) detects the throttle amount, converts the throttle amount into a flow rate, and detects the dropping speed (or dropping amount).

  In the present invention, the adjustment / control means is preferably provided for each solution so that the dropping state can be controlled for each solution.

  In the present invention, the dropping speed can be controlled by changing the amount of the solution passing through the flow rate adjusting means according to the dropping speed. Further, the dropping time zone can be set by the control means by opening the flow path at the start of infusion and closing the flow path at the completion of infusion.

  The infusion control device of the present invention can further include a display means for monitoring the liquid supply state of each solution. The display unit can display, for example, a dropping speed, a remaining time for dropping, a dropping liquid amount, a liquid temperature, a battery remaining amount, an END display notifying completion of infusion, and the like.

Furthermore, the drip control device of the present invention can further include a stopping means for automatically stopping the liquid supply when an abnormality occurs. The stop means automatically stops the drip control device when an abnormality such as an abnormal flow rate or air mixing occurs in conjunction with a sensor such as a flow rate or pressure sensor or a bubble sensor. Alternatively, the drip control device may be manually stopped by pressing an emergency stop button. The infusion control device may also include means for notifying such a situation, for example an alarm lamp and / or an alarm. Such lamps and / or alarms can also be activated when notifying the completion of the supply of each solution and the supply liquid. The lamp can be, for example, LED blinking (red) or lighting (red or blue). It can also include means for releasing the lamp or alarm sound.

  The infusion control device of the present invention further comprises at least four, preferably five inlet means through which the solution flows in, and at least one, preferably one outlet means through which the solution flows out. The inlet means is for taking each solution from each container into the inside of the apparatus, and is composed of a member that can be simply plugged into a conduit port from the container and fixed so as not to leak. The outlet means is for connecting to a drip tube (the dripping state is known) via a conduit. It is desirable to have a structure in which four or five conduits for supplying the solution are preferably led to one conduit, but in this case, the inner diameter of the outlet side conduit is made larger than that of the inlet side conduit. Therefore, the flow rate can be easily controlled. The conduit is preferably a flexible tube made of the same material as the drip tube.

  The infusion component can be supplied by gravity or mechanical action. Preferably, it is a gravity action, that is, a natural fall method. This is because there is little or no risk of air entering the patient's veins.

  The mechanical system is a so-called pump. For example, an infusion tube is sandwiched and pressure is supplied continuously or intermittently to the tube, or the syringe is pushed by pushing the pusher continuously or intermittently. It consists of a liquid structure. When using the pump, it must be equipped with safety measures such as a bubble sensor, a stop in case of an abnormality, and an alarm. The pump may be present inside the infusion control device. A pump may be provided upstream of each drip control device for each solution, or may be arranged downstream of the solution junction.

  The infusion control device may further include an AC power source (AC) or a DC power source (DC) including a power source, but a DC power source is preferable so that it can be carried. Preferred power sources are a plurality of dry batteries, rechargeable rechargeable batteries, and the like. It is also possible to energize via a dedicated AC adapter. Furthermore, the remaining battery level should be displayed on the display unit so that the remaining battery level can be recognized. Further, a start button for starting the liquid supply after turning on the power and inputting the condition setting necessary for the liquid supply can also be provided.

  As shown in FIG. 4, the infusion management system of the present invention includes at least four storage containers that contain different infusion components consisting of an amino acid solution, a sugar solution, a vitamin solution, and an inorganic salt solution, an infusion control device, and a supply conduit. Here, the drip control device sets a dropping speed and a dropping time zone of the solution, and a control means for controlling the liquid supply according to the setting, for monitoring the liquid supply state of each solution Display means, stop means for automatically stopping liquid supply when an abnormality occurs, and at least four inlet means for the solution to flow in and at least one outlet means for the solution to flow out, wherein the liquid supply conduit is the container And a conduit for connecting each solution in the drip control device to the outlet means.

  In the outlet means, preferably, the solutions are merged inside the drip control device and collected in one outlet. The tube fitted in the outlet means is aseptically attached to the patient via the drip tube. The drip state can be visually recognized by the drip tube.

  It is preferable that the storage container and the drip control device are fixed to the drip stand and the patient can move with the stand.

  The system of the present invention may further include a monitor for monitoring a supply state of the solution at a nurse station. On the monitor screen, information from the drip control device, such as drip rate, remaining time for drip, amount of drip liquid, liquid temperature, remaining battery power, etc., is displayed throughout the drip. Information from the infusion control device is preferably sent wirelessly (ie, non-wired) to the nurse station so that the patient can move with the infusion stand. Wireless transmission of information is possible by installing a transmitter in the drip control device, while installing a receiver in the nurse station monitor. Such a transmission means can be achieved using known techniques.

  The system of the present invention is a device for performing infusion to a patient in an optimal instillation time zone of each infusion component that does not cause a deviation in the biological clock rhythm. Therefore, the dropping is performed at the same or different time period depending on the infusion component. In order to administer an infusion solution to a patient at a predetermined flow rate (for example, 10 to 500 ml / hour), the infusion rate of each infusion component is, for example, one-fourth of the predetermined flow rate at the outlet of the device when four components are instilled simultaneously. The flow rate is set to one third of the predetermined flow rate for three components, one half of the predetermined flow rate for two components, and the same as the predetermined flow rate for one component. sell.

The invention is further illustrated by the following illustrative examples, which are not intended to limit the invention. The example below demonstrates that rats (nocturnal) use continuous hypernutrition in itself to disrupt the circadian rhythm.

1. Method
Animals :
Six-week-old male Wister rats (Charles River, Japan) were individually housed and maintained in a 12-hour light-dark cycle (lighted from 7 o'clock to 19 o'clock and from 19:00 to 7 am the next morning). At 8 weeks of age, according to the disclosed method, a tip was inserted with a silastic catheter (inner diameter 0.5 mm; Dow Corning, USA) from the right carotid artery to the right cavity (Arch. Surg. 104: 330-332, 1972). For anesthesia, pentobarbituric sodium was injected intraperitoneally at a dose of 35 mg / kg body weight. These rats were divided into 4 groups. Sham-operated rats were starved and received saline at the lowest rate (36 ml / kg / 12 hours) just sufficient to maintain the infusion route from 8 to 20 o'clock. Glucose group from 20 o'clock to 20
Until, glucose solution at a rate of 240 ml / kg / 12 h (20% w / v glucose, 261kcal / kg / day, Na ⁺ 50 meq / L and Cl ^- 50meq / L) received the. The amino acid group consists of amino acid solution (Amiparen (trade name), Otsuka Pharmaceutical, Japan; 4.3% w / v 1.78 gN / kg / day, Na ⁺ 50meq / L and Cl ⁻ 50 meq / L). The saline group received saline at a rate of 240 ml / kg / 12 hours from 8:00 to 20:00. These rats were not allowed any oral intake during the experiment. The control group allowed free intake of crude rat diet (Oriental yeast, Japan) and water.

On the first day of infusion, rats were killed at the indicated times (9 o'clock = Zeitgeber time (ZT) 02; 13:00 = ZT06; 17:00 = ZT10; 21 o'clock = ZT14; 1 o'clock = ZT18; 5 o'clock = ZT22) Brain and liver samples were removed from each animal (n = 3 at each time point in each group). Anesthesia and sampling from ZT14 to ZT22 were performed under dim red light. A committee on the use of laboratory animals at Osaka University School of Medicine approved all procedures.

In situ hybridization of rat brain frozen sections :
Rat brain and liver were fixed with 4% paraformaldehyde PBS by transcardiac perfusion from the left ventricle. After fixation, the brain and liver were immersed in 0.1 M PBS containing sucrose, and then these organs were embedded in Tissue-Tek OTC compound (Sakura Fine Technical, Japan) and slowly frozen on dry ice. Parietal brain serial sections and liver serial sections (both 8 μm thick) were prepared using a cryostat (HM 505E MICROM, Germany) to examine the entire SCN area and liver and kept at −80 ° C. until use. A digoxigenin-labeled RNA probe was prepared using the DIG RNA labeling kit (Boehringer Mannheim, Germany) and the rPer2 cDNA fragment (base: 1-5453; GenBank
It was prepared from registration number AB016532). In situ hybridization and detection of the probe was performed by the disclosed method (Neurosci. Prot. 1: 1-9, 1996; Neurosci. Prot. 2: 1-13, 1996)
. Densitometer analysis of hybridization intensity was performed using Mc Scope Ver. 2.5 (Mitani Corporation, Japan). Since SCN is an oval nucleus and mRNA signals such as rPer2 in SCN are easy to distinguish from other adjacent regions, the DIG signal of each SCN was analyzed by microscopic analysis.

Northern blot analysis :
Rats were killed and their liver tissue was minced, immediately frozen and stored in liquid nitrogen until analysis. Total RNA was isolated from liver tissue using Isogen (guanidine hydrochloride / phenol method; Nippon Gene, Japan) and separated on 1% agarose / 0.7M formaldehyde gel. RNA was transferred onto nylon membrane (Gene Screen Plus (trade name); DuPont, USA) by passive capillary transfer. 20 μg of total RNA from liver tissue was placed in each lane. To evaluate each loading in each lane, agarose gel was stained with ethidium bromide and visualized under UV light. ³² P-labeled random-primed probe, random primer DNA labeling kit Ver.
2 (Takara Bio, Japan) was prepared from rPer2 cDNA fragment (base: 1144-1797; GenBank accession number AB016532), hybridized with tissue RNA, and detected by the disclosed method (Neurosci. Lett. 245: 113 -116, 1998). Results were normalized by GAPDH as an internal standard.

Statistical analysis :
Statistical analysis was performed by one-way and two-way factorial ANOVA using the Bonferroni / Dunn post-hoc test and periodic analysis. Data were expressed as mean ± SEM. P values less than 0.05 were considered significant.

2. Results FIG. 1 shows rPer2 gene expression in SCN and liver of freely fed control rats and sham-operated rats. The peak of rPer2 expression in the free intake control group was observed for both SCN and liver at ZT18, whereas the expression in the sham-operated group appeared 4 hours earlier (at ZT14) in both tissues. The rPer2 mRNA expression in all groups showed significant diurnal changes (P <0.01, ANOVA and periodic analysis, respectively). In the following experiments, sham-operated rats were used as controls.

Next, the present inventors also examined rPer2 expression in SCN in rats fed with glucose, amino acids or saline at a rate of 240 ml / kg / 12 hours (FIG. 2). Compared to the sham-operated group, the glucose group signal began to increase slowly after the start of infusion and showed peak accumulation at ZT14. The peak of the glucose group was the same as that of the sham-operated rat, but the pattern was different. In the glucose group, rPer2 induction was clearly observed early in ZT06. Rats fed the amino acid solution also showed a clear induction of rPer2 mRNA in SCN, with a peak in ZT6 8 hours earlier than the sham-operated group. Interestingly, the saline group induced rPer2 mRNA expression in the SCN with a peak at ZT06. RPer2 mRNA expression in all groups showed significant diurnal changes (P <0.01, ANOVA and periodic analysis, respectively). RPer2 expression in the glucose group compared to our previous experiment (Neuroreport 14: 1457-1461, 2003) which examined the effect of daytime TPN (central venous nutrition; a mixture of glucose, amino acids and electrolytes) The pattern was most similar to that of TPN group.

We also examined the effects of glucose solution, amino acid solution and saline on rPer2 mRNA expression in the liver (FIG. 3). In contrast to the results obtained with SCN, the glucose solution delayed the rPer2 peak time by 4 hours, whereas the amino acid solution induced rPer2 expression shortly after the start of infusion and peaked at ZT14. lead. Rats given saline showed diurnal expression similar to that in the sham-operated group, and peak accumulation in ZT14. Compared to our previous findings with daytime TPN, the expression pattern of rPer2 in the liver of amino acid groups was most similar to that of daytime TPN (Neuroreport 14: 1457-1461, 2003). RPer2 mRNA expression in all groups showed significant diurnal changes (P <0.01, ANOVA, respectively). Periodic analysis also showed a significant daily change and a significant difference between the peak times of all groups in all groups except the saline group (P <0.01).

3. Discussion Previous studies with experimental animals have shown that restricted feeding alters the clock gene oscillation phase in the liver but does not change the clock in SCN (Genes. Dev. 14: 2950-2961, 2000; Science 291: 490-493, 2001). However, recent studies by the present inventors have shown that TPN shifts the expression phase of clock genes not only in the liver but also in SCN. The purpose of this study is
The purpose of this study was to clarify the mechanism that determines the cycle of the biological clock by parenteral nutrition. The contradiction between our findings and previous reports is that parenteral and oral nutrition (Genes. Dev. 14: 2950-2961, 2000; Science 291: 490-493, 2001; Neuroreport 14: 1457-1461 , 2003), ie, the presence or absence of nutrients to chew, swallow, digest and absorb via afferent sensory nerves from the gastrointestinal tract.

In order to elucidate the mechanism of the shift of the expression phase by central parenteral nutrition (TPN), the present inventors examined the influence of each nutritional component contained in the TPN solution on the expression of clock genes in SCN and liver this time. . As a result, it was found that there was a clear difference in the responsiveness of the SCN clock and the peripheral clock to each nutrient component. Expression of the clock gene rPer2 in SCN was induced by any infusion of nutrient components (ie glucose, amino acids and saline). However, the peaks were different among the three solutions, and the peak was observed in ZT14 in the glucose group, ZT06 in the amino acid group, and ZT06 in the physiological saline group. In SCN, the glucose group showed an oscillation pattern similar to that of the sham-operated group, but rPer2 induction was observed earlier (ZT06). The pattern was similar to that of rats given the daytime TPN solution (mixture of glucose, amino acids and electrolytes) by the inventors (Neuroreport 14: 1457-1461, 2003). These results indicate that glucose may be the factor that determines the cycle of the most powerful circadian rhythm of the SCN clock. Hirota et al. Recently reported that glucose transiently down-regulated mouse per1 and per2 expression in cultured cells (J. Biol. Chem. 277: 44244-44251, 2002). Thus, in the case of TPN, glucose may inhibit rPer2 induction that occurs more rapidly when only amino acids or electrolytes are administered to rats.

There is a question as to whether these effects observed in each highly nutritive group are in fact nutrient-specific effects. Total energy administration is different in each high nutrition group (ie, 44.5 kcal / kg / day for the amino acid group versus 261 kcal / kg / day for the glucose group), so the effects of malnutrition or low energy cannot be excluded. However, from our previous studies, starvation for 1-3 days may not significantly alter the expression of D-site binding protein (DBP), one of the circadian clock related genes, in rat liver. Shown (Hepatology 26: 1580-1586, 1997). In addition, rats fed a protein-free diet for 10 days did not show significant changes in DBP expression in the liver. These results indicate that, at least in the liver, protein-calorie malnutrition or low energy may not affect clock gene expression (J. Nutr. 127: 1328-1332, 1997; Nutrition 15: 213- 216, 1999). Furthermore, in this study, per2 gene expression in a sham-operated group fed a very low dose of saline without calories showed a pattern very similar to that in free-feeding control rats. The effects of fasting are therefore negligible, if any. Finally, if this experiment was designed with isocaloric conditions, each high nutrient dose would have exceeded the animal's physiological nutrient requirements. At this point, overdose effects such as high osmotic pressure or toxicity cannot be separated from hypertrophic specific effects.

  The rapid response of rPer2 in SCN to saline can affect the central clock not only by trophic factors but also by rapid changes in water volume in the blood vessels. The expression pattern in the saline group was similar to the pattern in the amino acid group. Therefore, rapid induction of rPer2 expression in the SCN of the amino acid group is not specific for amino acids but may be due to the physical effects of infusion.

I don't know why saline infusion affects the central clock, but it has been proposed that the hypothalamus is an important center of osmotic pressure and water homeostasis, and that SCN is a regulatory center of the autonomic nervous system ( J. Nutr. 131: 2509S-2514S, 2523S-2504S, 2001), the hypothalamus must respond quickly to these changes to regulate water balance and osmotic pressure. Therefore, it seems reasonable to say that the clock in SCN is involved in the mechanism of water balance through the regulation of autonomic nerves.

On the other hand, in the liver, rPer2 gene expression was not affected by saline infusion. In contrast to SCN, the peak time of rPer2 expression in the liver was shifted in the opposite direction by glucose. The glucose solution delayed this onset phase by 8 hours, while the amino acid solution accelerated it by 4 hours. From the finding that rats fed an amino acid solution showed a similar pattern to rats fed a TPN solution, amino acids appear to be inducers of clock genes in the liver (Neuroreport 14: 1457-1461, 2003). The mechanism by which amino acids affect the peripheral clock is still under investigation. Haussinger et al. Have shown that increased hepatocyte swelling by administration of amino acids such as glutamine, glycine and alanine may activate the osmotic signaling pathway by MAPK (Genes Dev. 14: 645- 649, 2000).

In conclusion, the central and peripheral clocks respond differentially to trophic factors. Our findings indicate that the SCN clock may be determined by changes in the volume of blood vessels and by amino acids and glucose. Of those, glucose appears to be the most important factor. On the other hand, in the liver, amino acids were shown to be involved in the induction of clock gene expression.

  The present invention provides an infusion management system using a human biological clock. It has now been found that the central and peripheral clocks respond differently between the nutritional components of high-nutrition fluids, and the patient's medical condition and prognostic course are improved by instilling the patient in order to avoid upsetting the clock rhythm. Improve. Such improvement is also observed during drug administration, and there is an optimal administration time zone depending on the type of drug. The system of the present invention makes it possible to administer a highly nutritive infusion solution and a drug at an optimal time zone, thereby improving the patient's medical condition and prognosis.

The circadian profile of rPer2 mRNA in SCN and liver in the control group and sham-operated group is shown. (a): Shows experimental protocol. The white bar indicates the lighting period, and the black bar indicates the extinguishing period. The hatched bar indicates the time of TPN administration. Representative results for SCN (b) using in situ hybridization and liver (c) by Northern blot analysis are presented. Representative results for SCN (d) and liver (e) are also shown. A white circle indicates a free intake control group, and a black circle indicates a simulated operation group. Peak concentration was defined as 100%. Data were expressed as mean ± S.E.M. (Standard deviation). The circadian profile of rPer2 mRNA in SCN. (a): Shows representative data of rPer2 expression in SCN. (b) shows the quantitative results from the calculation of the signal concentration of rPer2 expression in SCN. The white bar indicates the lighting period, and the black bar indicates the extinguishing period. The hatched bar indicates the time of TPN administration. Peak concentration was defined as 100%. Data were expressed as mean ± S.E.M. The circadian profile of rPer2 mRNA in the liver. (a): Representative data of rPer2 expression in the liver. (b) shows the quantitative results from the calculation of the signal concentration of rPer2 expression in the liver. The white bar indicates the lighting period, and the black bar indicates the extinguishing period. The hatched bar indicates the time of TPN administration. Peak concentration was defined as 100%. Data were expressed as mean ± S.E.M. The schematic of the infusion management system of the present invention is shown. A part of structure of the adjustment / control means of the drip control apparatus of the present invention is shown.

Explanation of symbols

1: Stepping motor 2: Gear 3: Actuator 4: Pressure sensor

Claims (19)

An infusion management system using a biological clock, comprising at least four storage containers containing different infusion components consisting of an amino acid solution, a sugar solution, a vitamin solution and an inorganic salt solution, an infusion control device, and a liquid supply conduit, Here, the drip control device sets the dropping speed and dropping time zone of the solution so as not to disturb the circadian rhythm of the human body clock, and the control means for controlling the liquid supply according to this setting, each solution Display means for monitoring the liquid supply state, stop means for automatically stopping liquid supply when an abnormality occurs, and at least four inlet means through which the solution flows and at least one outlet means through which the solution flows out The liquid supply conduit connects each of the containers to the inlet means of each solution of the drip control device, and guides each solution in the drip control device to the outlet means. System characterized in that it includes a conduit for. The system according to claim 1 , wherein the dropping time period is awakening of a human. The system according to claim 2 , wherein the dropping time zone of the amino acid solution is set between 12:00 and 22:00. The system according to claim 2 , wherein the dropping time zone of the sugar solution is set between 10:00 and 22:00. The system according to claim 2 , wherein a dripping time zone of the inorganic salt solution is set between 11:00 and 22:00. A system according to any one of claims 1 to 5, the liquid supply of the infusion components is carried out by gravity. A system according to any one of claims 1 to 5, the liquid supply of the infusion components is effected by mechanical action. The infusion control device system according to any one of claims 1 to 7, further comprising means for notifying the completion of the supply fluid, in the liquid supply, or an abnormality occurs. The system according to any one of claims 1 to 8 , further comprising a container for storing a drug solution. The system according to any one of claims 1 to 8 , wherein the liquid supply is performed for an amino acid solution, a sugar solution, a vitamin solution, and an inorganic salt solution. The system according to any one of claims 1 to 9 , wherein the liquid supply is performed on an amino acid solution, a sugar solution, an inorganic salt solution, a vitamin solution, and a drug solution. A system according to any one of claims 1 to 11, further comprising a monitor for monitoring the liquid supply condition of the solution at the nurse station. To deliver different infusion components consisting of amino acid solution, sugar solution, vitamin solution, and inorganic salt solution to the patient at each drop rate and drop time zone set so as not to disturb the circadian rhythm of the human body clock A drip control apparatus comprising a control unit including the means described above. The control unit is configured to set the dropping speed and dropping time zone, the adjusting means arranged in the flow path of the solution to adjust the dropping speed, and the flow rate according to the dropping condition set by the setting means. 14. The infusion control device according to claim 13 , further comprising control means for controlling the adjustment means. The infusion control device according to claim 13 or 14 , further comprising display means for monitoring a solution supply state of the solution. The infusion control device according to any one of claims 13 to 15 , further comprising a stopping means for automatically stopping the liquid supply when an abnormality occurs. The infusion control device according to any one of claims 13 to 16 , further comprising at least four inlet means through which the solution flows in and at least one outlet means through which the solution flows out. The infusion control device according to any one of claims 13 to 17 , further comprising means for notifying completion of the liquid supply, during liquid supply, or occurrence of an abnormality. The said control part further contains a means for supplying a chemical | medical solution to a patient with the dripping speed and dripping time slot | zone which were set using the biological clock. Infusion control device.

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