JPS58501130A - How to slow down heme metabolism - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Background of the invention: Method for reducing heme metabolic rate and composition used therefor The present invention provides methods and methods useful for reducing the metabolic rate of heme in mammals. Regarding the composition. In more detail, the present invention is based on the fact that heme is produced in the living mammalian body. Using metal protoporphyrin IX to reduce the rate of metabolism Regarding.

Iron protoporphyrin, which is called heme. More precisely, ferroproto Porphyrin IX is a specific porphyrin isomer in mammalian blood. heme is an essential component in the energy transfer reactions that occur in the respiratory system and within the mammalian body.

Heme is synthesized and degraded by known metabolic routes via known enzymatic reactions. Ru.

In the normal decomposition process, heme first undergoes a ring-opening reaction to become biriperinone, and then to biriperinone. Becomes Lilvin. Bilirubin is toxic, but this toxicity is usually not manifested. Reason This is because biliperone immediately binds to albumin and is sent to the liver. liver In the heart, proteins are released and bilirubin is converted into uridine diphosphogluculone. It reacts with d and turns into the corresponding noglucuronide. Take diglucuronide in the bath Being ostracized.

A number of homologues synthesized from iron protoporphyrin IX are known. They are It is commercially available or can be easily synthesized by known methods. For example, platinum, zinc, There is Porphyrin IX. For convenience, these compounds are generally referred to as metal It is written as rotoporphyrin. Individually, chrome-zolotoporphyrin, tin-pro Toporphyrin is a compound of chromium and tin.

One of the more difficult aspects of bilirubin toxicity is what is referred to as "neonatal yellowing". , the concentration of bilirubin in the blood of newborn mammals is undesirably high. It is due to this. Immediately after birth, the concentration of heme in pharyngeal mammals is high. Also, heme Oxygenase activity is also high. This enzyme is essential for the metabolism of heme to bilirubin. be. Due to a combination of several factors, a large amount of heme is metabolized and the newborn's body This results in an increase in the concentration of bilirubin in the fluid.

Since bilirubin is yellow, newborns appear yellow and are called "neonatal jaundice." Ru.

Free bilirubin is fat-soluble and easily obstructs blood flow to the head, so Causes extensive and severe brain damage. One manifestation of bilirubin toxicity is kerosene or It is a bilirubin brain disease. As for the external pressure, coma, rigidity and tension, and cancer are high. There may be crying, fever, convulsions, and death. In addition, survivors suffered cerebral palsy, Chorea Acetoid-like symptoms, hearing loss, intellectual retardation, and other mental disorders can be caused in newborns and young children. It is often left in childhood.

The treatment of choice for severe bilirubinism is phototherapy and blood exchange. With the former treatment The patient will be exposed to intense visible light between 420-470 nm, and this This may increase the dispersion of bilirubin or result in its transformation into a currently unknown substance. . This procedure is widely used, especially in the United States, but no one can answer questions about its safety and effectiveness. Questions remain, and this is not something we should be satisfied with.

A more surgical method of blood exchange involves the use of unconjugated hilirubin. When the carbon content was 20η/dt, all newborns were adopted. There is. For premature newborns, the concentration is as low as 9 μ/aA for blood exchange. However, it is important to keep the level of this highly toxic drug as low as 2 my/a min. is desirable.

When bilirubin appears in high concentrations in the blood of adult humans and other mammals, it causes Cytocytic anemia, Mediterranean anemia.

Acquired liver disease is also often present along with other congenital anemias. to such individuals As a matter of fact, the concentration of bilirubin can reach high concentrations as in newborns. There are few. However, toxic concentrations have been reached and should be controlled.

From the above, it is possible to suppress the metabolism of heme and reduce the rate at which it is degraded. There are methods and substances available to reduce the rate at which this accumulates in the blood. It is a desirable place to keep it.

Disclosure of invention The rate of heme metabolism in sentinel mammals is significantly affected by the administration of effective doses of the synthetic metal-protoporphyrin. It has been found that it can be reduced by giving Currently preferred are tin-protocols. porphyrins and chromium-protoporphyrins. This side compound is reasonable It can be easily synthesized and used in a purer form at a lower cost. These are water soluble; Can be formulated with a variety of pharmaceutically acceptable carriers. Tin compounds are more active It seems like.

To determine the effect of tin-protoporphyrin on rate control of heme metabolism, Tin-protoporphyte at 12°24.48.72 hours after birth for newborn rats. Phosphorus 0,1 rnl solution was injected subcutaneously. The material is used to make a parenteral injection solution. Dissolve it in a small amount of 0.2N caustic soda and adjust the pH to 7.4 with IN hydrochloric acid. The salt content was adjusted to 09%. The composition made and used in this way is , approximately 100 μmol/# body weight of tin-protoporphyrin in 0.1 ml injection volume. It contained. Control newborn rats received the same volume of saline at each time point. I shot it. Newborn rats were placed in glue f (groups of 6-30 rats) for a predetermined period of time. Dissected at intervals.

Heme oxygenase activity and bilirubin in treated and control subjects. The concentration was analyzed. Heme oxygenase is essential for heme catabolism. , an increase in heme oxygenase activity implies an increased rate of heme catabolism. . Heme oxygenase was determined by Noe Biol Chem (J, Biol, Chem, ) Maines, 253, 2321-2326 (1978) and Kappas. in serum Total bilirubin is determined by Roth Clin Heme Acta (C1in Che It was evaluated by the method of M, Acta, ) 17, 487-492 (1967).

In a six-week experiment, the controls were levels increase rapidly, reaching levels four times higher than those found in the adult liver. The level of HA in adults gradually decreased from 7 t to Return to Bell. Regarding newborns treated with tin-protoporphyrin, Does administration of active drugs completely normalize heme oxygenase activity in the liver after birth? This suppressed a significant increase in the number of cases. In these newborns, heme oxygenase activity immediately (1 day), the level decreased to less than half of the control level, and the control level remained for about 3 weeks. remained at a fairly low level and finally reached the normal control level on day 422. .

Administration of tin-protoporphyrin rapidly and clearly increases serum bilirubin in treated animals. reduce the level. This low level of bilirubin concentration persists until about the fourth day. , then remained at nearly the same level as controls for the remainder of the 42-day study period.

In a similar study, newborn rats immediately after birth showed that chromium protochloride per kilogram of Subcutaneous treatment with porphyrin 2 and lO mmol was performed. About various organs, Muxoxygenase activity and bilirubin concentration were analyzed. The result is 0.1 subcutaneously. Heme oxygen in the liver, kidneys, and paralyses compared to each of the saline-treated controls. The results of the enzyme activity are shown.

As can be seen from Table 1, the efficacy of administering chromium-protoporphyrin is The goal is to rapidly lower xycanase. Similar results are shown in Table 2. For serum bilirubin, the concentration is expressed in milligrams per deciliter. Admitted.

Table 2 Comparison 039 0.48 042 0.31 0,33 0,46 0.38 2μmol/reduction -0,390,330,280,320,330,4010μmol le/ni 9-043 033 0.24 0.30 033 0.28 hemeoxy Strontium to determine the effect on genease activity and bilirubin production A study was conducted using adult rats treated with norotoporphyrin.

Three rats, each weighing approximately 230 g, were given suzuzo in saline in pit 8. Roto I Lufilin 50 μmol/9 was injected subcutaneously. Three control animals were given physiological saline. Similar treatment was performed. Rats were sacrificed 16 hours after treatment. liver part Granular protein (M’icrosoma) in both kidneys and three kidneys combined. l Protein) and □ heme oxygenase activity by It was measured by the Lamise method. This method is used to quantify the amount of bilirubin produced. This method measures heme oxygenase activity. It is a knot.

Table 3 Control 1 2.19 Control 2 3.29 1.24 Control 3 239 Experiment 1 095 Experiment 2 0.95 0.055 Experiment 3 1.53 From the above, it is clear that suprotoporphyrin plays a role in bilirubin production and regulation in adult mammals. It can easily be seen that it is extremely effective in reducing muxoxygenase activity.

With respect to newborn salivary mammals, the therapeutic compositions of the invention may be administered to the animal's body immediately after birth. 10-25 μmol per # of weight.

The bilirubin concentration is maintained at the desired low level until the newborn reaches an age when heme metabolism is at equilibrium. It's good enough to keep the bell. However, monitoring serum bilirubin concentrations It is preferable to use an efficacy enhancer if necessary. Appropriate administration by a physician or veterinarian Choose quantity. Dosages are usually within the ranges listed above, but to treat specific symptoms Please change it.

In adults with sickle cell anemia or other conditions that increase bilirubin levels. For all but the most acute conditions, the dosage unit is usually smaller. This is because the bilirubin concentration is not as high as in newborns. For adults The standard dosage for is usually about 0.05 to 1 .mu.mol/kg body weight.

To enable the availability of suitable dosage units, the compositions of the present invention are typically prepared at a pH of 7 to 7. Prepare a large amount of buffered physiological aqueous solution 1 of No. 8 at a concentration of 100 to 2,500 μmol each, and approximately Subdivide into dosage units containing ~25 μmol OI/ml of solution.

Typical pharmaceutical carriers include buffered saline or glucose having a pH of about 7 to 81, usually 74. It is a course solution.

Alternatively, the therapeutic composition can be given in lyophilized powder form and reconstituted with water to the clinical dosage. can. For example, a selected metal protonorphyline may be mixed with sufficient common salt or other solutes. 01 molar phosphate or other pharmaceutically acceptable buffer. It can be made into a liquid and freeze-dried into a powder. Add distilled water or salt solution to the powder. In addition, 01-25 μmol/mt per milliliter of solution! Kinkaede Protopo A solution containing luphyrin is prepared.

Procedural amendment (formality) %formula% 1.Display of the incident PCT/US82100955 2. Title of the invention: Method for reducing the metabolic rate of heme 3. Person making the correction Relationship to the incident: Patent applicant 5. Date of amendment order: April 7, 1977 6. Inventions increased by amendment Number 07, subject to correction Document pursuant to the provisions of Article 184-5, Paragraph 1 of the Patent Law, (1) Article 184-5 of the Patent Law The title of the invention in the document pursuant to the provisions of paragraph 1 shall be revised to the name as of the international filing date as shown in the attached document. Correct.

(2) Correct the title of the invention in the application translation to the one as of the international filing date as shown in the attached sheet. Ru〇 (8) Change the title of the invention on page 1 of the translation of the specification to the title as of the international filing date (as of the attached document) correct.

(4) Supplement the power of attorney and translation as shown in the attached sheet.

(2) Background of the invention The present invention provides methods and methods useful for reducing the metabolic rate of heme in mammals. and compositions. More specifically, the present invention aims to improve the production of heme in the living mammalian body. The use of metal protoporphyrin Regarding.

Iron protoporphyrin, which is called heme. More precisely, Fuerobrotopo Luphyrinae XU is a specific porphyrin isomer in mammalian blood. Heme is It is an essential component in the energy transfer reactions that occur within the respiratory system and the suckling body.

Heme is synthesized and degraded by known metabolic routes via known enzymatic reactions. It will be done.

In the normal decomposition process, heme first undergoes a ring-opening reaction to become biliveridin and then to biliveridin. Becomes Lilvin. Bilirubin is toxic, but the current conduction ratio does not change. Reason This is because biliverdin immediately binds to albumin and is sent to the liver. liver In hg, protein is placed on M, and bilirubin is placed on uridine diphosphoglucuro. It reacts with nedo to form the corresponding diglucuronide. Diglucuronide dissolves It is excreted.

Many homologs synthesized from iron protoporphyrinae X are known. They are They are commercially available or can easily be synthesized by known methods. For example, platinum, i@, ni Kkel, Kobal), il, silver, mankan, chrome, susunopro.

international search report

Claims (1)

[Claims] 1. An effective amount of tin-protopol to reduce the rate of heme metabolism in mammals. Requires treatment by administering filin or chromium-protoporphyrin A method for reducing the rate of heme metabolism in mammals. 24. The method according to claim 1, wherein tin-protoporphyrin is administered. 3. The method according to claim 1, which comprises administering chrome-zolotophorphyllin. 4. The method according to claim 2, wherein the mammal is a human. 5. The method according to claim 3, wherein the mammal is a human. 6. An effective amount to reduce the rate of bilirubin accumulation in newborns immediately after birth. Newborn infants receiving tin-protoporphyrin or chromium-protoporphyrin Methods for reducing the rate of bilirubin accumulation in mammals. 7. The method according to claim 6, wherein tin-protoporphyrin is administered. 8. The method according to claim 6, which comprises administering chrome-protoporphyrin. 9. The method according to claim 7, wherein the newborn baby is a human. 10. The method according to claim 8, wherein the newborn baby is a human. 11, p) 100 to 2500 μmol of tin per 1 buffered physiological aqueous solution of 17 to 8 A pharmaceutical composition containing protoporphyrin or chromium-protoporphyrin. 12. The composition according to claim 11, containing tin-protoporphyrin. 13. The composition according to claim 11, containing chromium-protoporphyrin. . 14, 01-2.5 μmol per milliliter of buffered physiological aqueous solution with pH 7-8. Dosage unit form containing zoonorotoborphyrin or chrome-protoporphyrin pharmaceutical composition. 15. The composition according to claim 14, which contains tin-protoporphyrin. 1016 The set according to claim 14 containing chromium-protoporphyrin A product.