US20140206635A1 - Metal-salen complex compound, local anesthetic and antineoplastic drug - Google Patents

Metal-salen complex compound, local anesthetic and antineoplastic drug Download PDF

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US20140206635A1
US20140206635A1 US14/126,205 US201214126205A US2014206635A1 US 20140206635 A1 US20140206635 A1 US 20140206635A1 US 201214126205 A US201214126205 A US 201214126205A US 2014206635 A1 US2014206635 A1 US 2014206635A1
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general name
drug
salen complex
hydrochloride
complex compound
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Yoshihiro Ishikawa
Haruki Eguchi
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IHI Corp
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IHI Corp
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Assigned to IHI CORPORATION, ISHIKAWA, YOSHIHIRO reassignment IHI CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ISHIKAWA, YOSHIHIRO, EGUCHI, HARUKI
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Definitions

  • the present invention relates to a metal-salen complex compound and to a metal-salen complex compound, which is self-magnetic and can be applied to ointment compositions, a local anesthetic containing this metal-salen complex compound, and an antineoplastic drug containing this metal-salen complex compound.
  • a technique to guide the drug to the affected site is called drug delivery, which has been actively studied and developed recently.
  • This drug delivery has at least two advantages.
  • One advantage is that a sufficiently high drug concentration can be obtained at the affected site tissue. Pharmacological effects will not be seen unless the drug concentration at the affected site is a constant value or more. The sufficient therapeutic effects cannot be expected if the drug concentration is low.
  • the second advantage is that the drug is guided to only the affected site tissue and, therefore, adverse reactions to the normal tissue can be inhibited.
  • antitumor agents inhibit the cell growth of cancer cells which divide actively, so that the antitumor agents will also inhibit the cell growth of even the normal tissue in which cells divide actively, such as bone marrow, hair roots, or alimentary canal mucosa. Therefore, cancer patients to whom the antitumor agents are administered suffer adverse reactions such as anemia, hair loss, and vomiting. Since such adverse reactions impose heavy burdens on the patients, the dosage needs to be limited, thereby causing a problem of incapability to sufficiently obtain the pharmacological effects of the antitumor agents.
  • Alkyl antineoplastic drugs among such anti-tumor agents are a generic term for antitumor agents having the ability to combine an alkyl group (—CH2-CH2-) with, for example, a nucleic acid protein and have the effects of alkylating DNA and inhibiting DNA replication, causing cell death. These effects work regardless of cell cycles, also works on cells of the G 0 period, has a strong effect on cells which grow actively, and tends to damage, for example, bone marrow, alimentary canal mucosa, germ cells, or hair roots.
  • antimetabolite antineoplastic drugs are compounds having structures similar to those of nucleic acids or metabolites in a protein synthesis process, impairs cells by, for example, inhibiting synthesis of the nucleic acids, and specifically acts on cells of a mitotic period.
  • Antitumor antibiotics are chemical substances produced by microorganisms, have actions such as DNA synthesis inhibition and DNA strand breaking, and exhibit antitumor activity.
  • microtubule inhibitors have antitumor effects by directly acting on microtubules that serve important roles to maintain normal functions of cells, for example, by forming spindles during cell division, locating cell organelles, and transporting substances.
  • the microtubule inhibitors act on cells, which divide actively, and nerve cells.
  • platinum preparations inhibit DNA synthesis by forming DNA strands, interchain bonds, or DNA protein bonds.
  • Cisplatin is a representative drug, but it causes severe nephropathia and requires a large amount of fluid replacement.
  • parahormone antineoplastic drugs are effective against hormone-dependent tumors.
  • Female hormones or anti-androgen drugs are administered to an androgen-dependent prostatic cancer.
  • Molecular targeted drugs are used for a treatment targeted at molecules that correspond to molecular biological characters specific to respective malignant tumors.
  • topoisomerase inhibitors are enzymes for temporarily generating breaks in DNA and changing the number of tangles of DNA strands.
  • a topoisomerase inhibitor I is an enzyme that generates breaks in one strand of a circular DNA, lets the other strand pass, and then closes the breaks; and a topoisomerase inhibitor II temporarily breaks both the two strands of the circular DNA, lets other two DNA strands pass between the former two strands, and reconnects the broken strands.
  • nonspecific immunopotentiators inhibit an increase of cancer cells by activating the immune system.
  • Topical anesthetics also have the advantage of drug delivery.
  • the topical anesthetics are used to treat topical itches and pains of, for example, mucosa or skin caused by hemorrhoidal disease, stomatitis, gum disease, cavities, tooth extraction, or operations.
  • Lidocaine product name: xylocaine
  • xylocaine is known as a representative topical anesthetic; however, this lidocaine is faster-acting, but has an antiarrhythmic effect.
  • lidocaine which is an anesthetic is injected into the spinal fluid when giving spinal anesthesia
  • lidocaine will spread through the spinal fluid; and in a worst-case scenario, there is fear that lidocaine might reach a cervical part of the spinal cord and thereby cause a respiratory function to stop and bring about critical adverse effects.
  • An example of a specific method for the drug delivery is the use of a carrier. This is to load the carrier, which tends to concentrate on the affected site, with the drug and have the carrier carry the drug to the affected site.
  • a promising candidate of the carrier is a magnetic substance and there is a suggested method of attaching the carrier, which is the magnetic substance, to the drug and allowing the carrier to be accumulated at the affected site by a magnetic field (see, for example, Patent Literature 1).
  • a topical anesthetic is introduced in which side chains for giving positive or negative spin charge density are bonded to a basic skeleton of an organic compound, and which has suitability as a whole insofar as the topical anesthetic is guided, by means of magnetism by an external magnetic field; and if the topical anesthetic is applied to a human body or an animal, it is retained in an area where a magnetic field is applied topically by the magnetic field outside the body and the medicinal effects that the topical anesthetic originally has are exerted on the area.
  • the above-mentioned technique uses the iron-salen complex as an example of such a drug (see Patent Literature 2).
  • the present invention was devised in light of such circumstances and it is an object of the invention to provide a metal-salen complex compound, which exhibits excellent noninvasiveness and can be efficiently transferred to an affected site, a local anesthetic containing this metal-salen complex compound, and an antineoplastic drug containing this metal-salen complex compound.
  • the present invention provides a metal-salen complex compound in which a metal atom part in each of multiple molecules of a metal-salen complex or a derivative of the metal-salen complex is multimerized via water, and which is mixed with a base to produce an ointment.
  • the multiple molecules should more preferably be two molecules and the metal atom part of each of the two molecules should more preferably be dimerized via water.
  • this metal-salen complex compound can be mixed with the base to produce the ointment, it can be administered as the ointment to the affected site. Therefore, the metal-salen complex compound exhibits excellent noninvasiveness and can be transferred efficiently to the affected site.
  • the “ointment” according to the present invention includes, in addition to, for example, ointments using oleaginous bases, creams using emulsion bases as specified by Japanese Pharmacopoeia.
  • the “base” used to produce the ointment serves to adhere to the skin and make active ingredients stay on the skin for a long time and the base which can be easily applied, has no irritating effect on the skin, and does not affect stability of the active ingredients is required.
  • the metal-salen complex compound according to the present invention can be applied to, for example, a tongue, gums, and the inside of cheeks by being mixed with a base which can be used in the oral cavity.
  • Examples of such a base can include hydrophobic bases (oleaginous bases), hydrophilic bases (emulsion bases, water-soluble bases, lyophobic bases), special formulations (such as liniments, pastes (pastas), plasters, lotions, and sprays), oral ointments, and ophthalmic ointments. More specifically, for example, ointment bases such as Vaseline (yellow Vaseline, hydrophilic Vaseline, and white Vaseline), Kenalog, liquid paraffin, castor oil polyethoxylated hydrogenated, macrogol, and gelled hydrocarbon.
  • ointment bases such as Vaseline (yellow Vaseline, hydrophilic Vaseline, and white Vaseline), Kenalog, liquid paraffin, castor oil polyethoxylated hydrogenated, macrogol, and gelled hydrocarbon.
  • a preferred embodiment of the present invention is a self-magnetic metal-salen complex represented by the following chemical formulas (I), (II), (III) and its derivatives.
  • M represents Fe (iron), Cr (chromium), Mn (manganese), Co (cobalt), Ni (nickel), Mo (molybdenum), Ru (rubidium), Rh (rhodium), Pd (palladium), W (tungsten), Re (rhenium), Os (osmium), Ir (iridium), Pt (platinum), Nd (niobium), Sm (samarium), Eu (europium) or Gd (gadolinium) and each of a to f and Y is hydrogen (where M is Fe, excluding a case where all of a to f and Y are hydrogens) or any one of the following (1) to (7):
  • charge transfer of R 3 should preferably be less than 0.5 electrons (e).
  • R 3 can be any one of compounds represented by the following formulas (1) to (27).
  • Taxol (paclitaxel)
  • the present invention provides a local anesthetic having a self-magnetic metal-salen complex compound wherein R 3 is a substituent represented by any of the following formulas (28) to (38) obtained as a result of desorption of hydrogen from a compound which has a methyl group and whose charge transfer is less than 0.5 electors (e).
  • the present invention provides an antineoplastic drug having a self-magnetic metal-salen complex compound wherein R 3 is any one of compounds represented by the following formulas (39) to (103), which combines with a main skeleton of the compound of the above formula I via a linking group part obtained as a result of desorption of hydrogen (however, with the compound (83), a cyano group (—CN) is the linking group).
  • the present invention provides an antineoplastic drug having a self-magnetic metal-salen complex compound wherein R 3 is composed of any one of compounds represented by the following formulas (104) to (109).
  • a metal-salen complex compound which exhibits excellent noninvasiveness and can be efficiently transferred to an affected site, a local anesthetic containing this metal-salen complex compound, and an antineoplastic drug containing this metal-salen complex compound.
  • FIG. 1 is a graph showing changes in weight (TG) and the results of differential thermal analysis (DTA) with respect to metal-salen complex compounds according to the present invention.
  • FIG. 2 is a diagram showing an integral curve of the metal-salen complex compounds according to the present invention.
  • FIG. 3 is a diagram showing a magnetic field-magnetization curve of a Mn salen complex compound.
  • FIG. 4 is a diagram showing a magnetic field-magnetization curve of a Cr salen complex compound.
  • FIG. 5 is a diagram showing a magnetic field-magnetization curve of a Co salen complex compound at 37° C. (310 K).
  • FIG. 6 shows a magnetic field-magnetization curve of a Fe salen complex compound.
  • FIG. 7 is a diagrammatic illustration of a state where a bar magnet is made to be in contact with a rectangular flask.
  • FIG. 8 is a characteristic diagram showing the relationship between the distance from the magnet and the number of cells (pieces) per unit area.
  • FIG. 9 is a perspective view of a guidance system.
  • FIG. 10 is a characteristic diagram showing SNR measurement results of cells after being placed on the guidance system by using MRI.
  • FIG. 11 is photographs showing the effects of the Fe salen complex compound on melanoma growth in mice.
  • FIG. 12 is a characteristic diagram showing the effects of the Fe salen complex compound on melanomas.
  • FIG. 13 is a diagram showing the results of a histological examination of the Fe salen complex compound.
  • FIG. 14 is a graph showing the relationship between magnetic field intensity of the Fe salen complex and a temperature rise.
  • FIG. 15 is a graph showing the relationship between time and a temperature rise when an AC magnetic field is applied to an ointment in which Vaseline is used as a base and mixed with the Fe salen complex compound.
  • FIG. 16 is a graph showing the relationship between time and a temperature rise when the AC magnetic field is applied to an ointment in which Kenalog is used as a base and mixed with the Fe salen complex compound.
  • FIG. 17 is a graph showing the relationship between time and a temperature rise when an AC magnetic field is applied to only Vaseline and only Kenalog.
  • FIG. 18 is a graph showing the relationship between time and a temperature rise when a sample of a diatomic Fe salen complex compound dissolved in agarose is exposed to near infrared radiation.
  • a metal-salen complex compound according to the present invention was produced in the following manner.
  • Compound 7 (8.2 g, 16 mmol) and triethylamine (22 ml, 160 mmol) were introduced into normal methanol (methanol made by Showa Chemical, purity 99.5% or more) (50 ml); and a solution of FeCl 3 .4H 2 O (iron (III) chloride tetrahydrate) (2.7 g, 16 mmol) in a case of a Fe salen complex compound, MnCl 3 .4H 2 O (manganese (III) chloride tetrahydrate) (2.7 g, 16 mmol) in a case of a Mn salen complex compound, or CrCl 3 .4H 2 O (chromium (III) chloride tetrahydrate) (2.7 g, 16 mmol) in a case of a Cr salen complex compound added to 10 ml of methanol was mixed in a nitrogen atmosphere.
  • FeCl 3 .4H 2 O iron (III) chloride tetrahydrate)
  • CoCl 2 cobalt (II) chloride produced by Alfa Aesar
  • NiCl 2 nickel (II) chloride produced by Alfa Aesar
  • MoCl 3 mobdenum (III) chloride produced by Alfa Aesar
  • RuCl 3 ruthenium (III) chloride produced by Alfa Aesar
  • RhCl 3 rhodium (III) chloride produced by Alfa Aesar
  • PdCl 2 palladium (II) chloride produced by Alfa Aesar
  • WCl 6 tungsten(VI) chloride produced by Alfa Aesar
  • the ingredients were mixed for one hour in a nitrogen atmosphere at the room temperature, thereby obtaining a brown compound. Subsequently, this compound was then dried in a vacuum or its water was dried sufficiently by, for example, using magnesium, or was adsorbed and removed by magnesium.
  • the resulting compound was diluted with 400 ml of dichloromethane, washed twice with a basic solution, dried in Na 2 SO 4 , and dried in a vacuum, thereby obtaining a metal-salen complex compound of a dimer containing water molecules.
  • the resulting compound was recrystallized in a solution of diethyl ether and paraffin, and assay by high-speed liquid chromatography revealed a dimeric metal-salen complex compound containing water molecules of purity of 95% or higher.
  • the bond between the metal and oxygen can be considered as a fusion of a covalent bond and a metallic bond.
  • Elemental analysis of the obtained dimer with water molecules revealed that it contained 57.73% C, 4.42% H, 17.2% Fe, 8.49% N, and 12.16% 0 ; and all differences between calculated values and experimental values were within an absolute error range of ⁇ 0.4%.
  • each Fe in the above chemical formulas becomes Mn or Cr.
  • TG-Mass analysis was performed in order to clarify the existence of the included water molecules. As a result, it was found that water molecules were detected within the range from room temperature to 260 degrees Celsius. This is because the water molecules are incorporated into crystals. The results of the TG-Mass analysis are shown in FIG. 1 and FIG. 2 .
  • Heating condition from room temperature to 500 degrees Celsius (temperature rise speed: 5 degrees Celsius/min)
  • a magnetic field-magnetization curve of the Mn salen complex compound obtained by the above-described method at 37 degrees Celsius (310 K) was measured by using MPMS7 by Quantum Design, Inc. and the measurement revealed that the Mn salen complex compound was paramagnetic.
  • FIG. 3 shows the results.
  • a magnetic field-magnetization curve of the Cr salen complex compound obtained by the above-described method at 37 degrees Celsius (310 K) was measured by using MPMS7 by Quantum Design, Inc. and the measurement revealed that the Cr salen complex compound was paramagnetic.
  • FIG. 4 shows the results.
  • a magnetic field-magnetization curve of the Co salen complex compound obtained by the above-described method at 37 degrees Celsius (310 K) was measured by using MPMS7 by Quantum Design, Inc. and the measurement revealed that the Co salen complex compound was paramagnetic.
  • FIG. 6 shows the results.
  • FIG. 6 shows a magnetic field-magnetization curve of the Fe salen complex compound at 37 degrees Celsius (310 K).
  • FIG. 3 , FIG. 5 , and FIG. 6 show that as compared with the Fe salen complex compound, the Co salen complex compound has larger magnetization when the magnetic field is 10000 Oe (oersted; (1 T (tesla))) or more.
  • the Mn salen complex compound has larger magnetization when the magnetic field is 30000 Oe (3 T) or more. Therefore, the Fe salen complex compound has the largest magnetization when the magnetic field is less than 10000 Oe (1 T); and is suited for use in magnetic induction drug delivery systems which use, for example, neodymium permanent magnets.
  • the Co salen complex compound or the Mn salen complex compound has large magnetization and is most suited for magnetic induction drug delivery systems which use superconducting magnets.
  • FIG. 7 shows a bar magnet in contact with a rectangular flask containing rat L6 cell culture medium.
  • a “position proximal to the magnet” means within a projection area of the magnet end surface at the bottom of the rectangular flask
  • a “position distal to the magnet” means a region on the side opposite the magnet end surface at the bottom of the rectangular flask.
  • FIG. 8 shows that, near the magnet, the Mn salen complex was attracted, resulting in a greater Fe-salen complex concentration, so that the DNA-growth inhibition action of the Fe-salen complex resulted in a dramatically lower number of cells than the position distal to the magnet.
  • the results of a dramatically lower number of cells were obtained at the position proximal to the magnet than the position distal to the magnet.
  • a pair of magnets 230 and 232 facing each other in the direction of gravity are supported by a stand 234 and clamp 235 , and a metal plate 236 is located between the magnets 230 and 232.
  • the metal plate 236 especially an iron plate, is placed between the pair of magnets 230 and 232 so that a magnetic field of locally uniform and strong strength can be created.
  • An electrical magnet can be used instead of a magnet to modify the magnetic force generated in this guidance system.
  • the magnetism-generating means can be moved to a target position of the individual on a table to allow the pair of magnetism-generating means to move in the X, Y, and Z directions.
  • the tissue of an individual can be placed in the region of the magnetic field to concentrate the drug in the tissue.
  • the aforementioned Fe salen complex compound drug concentration: 5 mg/mL (15 mM)
  • drug concentration: 5 mg/mL (15 mM) was injected intravenously into a mouse weighing about 30 g, a laparotomy was performed, and the mouse was placed on the iron plate 236 to locate its right kidney between the pair of magnets 230 and 232.
  • the magnets used were Product No. N50 (neodymium permanent magnets) by Shin-Etsu Chemical Co., Ltd. with a residual flux density of 1.39 to 1.44 T.
  • the magnetic field applied to the right kidney was about 0.3 (T), and the magnetic field applied to its left kidney was about 1/10 of the above-mentioned magnetic field.
  • FIG. 11 shows the effect of the Fe salen complex compound on melanoma growth in mice.
  • Melanoma was established in mouse tails in vivo by local grafting of cultured melanoma cells (Clone M3 melanoma cells).
  • FIG. 11 ( 1 ) is a photograph showing the effects of a saline group (saline) into which the saline water was injected instead of the Fe salen complex compound
  • FIG. 11 ( 2 ) is a photograph showing the effects of a group (SC) into which the Fe salen complex compound was injected without applying the magnetic field
  • the Fe salen complex compound (50 mg/kg) was administered intravenously via tail vein, followed by local application of a magnetic field by the use of a commercially available bar magnet (630 mT, a cylindrical neodymium magnet, 150 mm long and 20 mm in diameter). Application of a bar magnet was performed with 3 hour gentle contact with the site of melanoma immediately after injection of the Fe salen complex compound for 10-14 days.
  • a commercially available bar magnet 630 mT, a cylindrical neodymium magnet, 150 mm long and 20 mm in diameter.
  • the melanoma extension was greatest in the saline group (100 ⁇ 17.2%), in which saline, instead of the Fe salen complex compound, was injected.
  • the melanoma extension modestly decreased (63.68 ⁇ 16.3%) in the SC group, into which the Fe salen complex compound was injected without the application of a magnetic force field.
  • most melanoma disappeared (9.05 ⁇ 3.42%) in the SC+Mag group, into which the Fe salen complex compound was injected and a magnet force field was applied as described above (n 7-10).
  • a histological examination was performed as shown in FIG. 13 by means of Hematoxylin-Eosin staining and immuno-histochemical staining with an anti-Ki-67 antibody and an anti-Cyclyn D1 antibody which are both tumor proliferation markers in tissue sections.
  • the histological examination revealed that tumor expansion of melanoma diminished when the Fe salen complex compound was injected (SC); and the tumor expansion of melanoma mostly disappeared when the magnetic force field application was combined with the Fe salen complex compound.
  • FIG. 14 shows changes in temperatures with time when the AC magnetic field was applied to the drug;
  • FIG. 14 ( 2 ) shows the maximum temperature when only the magnetic field was changed while using a fixed frequency;
  • FIG. 14 ( 3 ) shows the maximum temperature when only the frequency was changed while using a fixed magnetic field.
  • the electron transfer of a compound which binds with the metal-salen complexes can be determined by first principles calculation.
  • a system for realizing this computer simulation is equipped with well-known hardware resources as a computer, that is, memory, a computing device equipped with computing circuitry such as a CPU, and display means for outputting the computed results.
  • the memory includes data specifying existing organic compounds or three-dimensional structures, and software programs for performing computer simulation.
  • the software program is capable of adding, modifying, and deleting side chains of each compound, cross linking certain side chains, calculating areas of high spin charge density, and determining the spin charge density for structures as a whole.
  • a commercially available program (Dmol3 by Accelrys) can be used as this program.
  • the user inputs the position where the side chains are to be added to a compound or selects one in which the side chains are modified or deleted, and uses a memory assisting program to designate on the computing device the location where cross linking should be formed.
  • the computer receives the input values to calculate the spin charge density, and outputs the results on a display screen.
  • the user can also add structural data on existing compounds to the computer system to obtain the spin charge density of existing compounds.
  • the charge transfer of a compound obtained by binding another compound to the metal salen complex can be determined by integrating the previously determined upward and downward spin charge density in three-dimensional space.
  • the calculated results for charge transfer to e, b, k, h, or e, h of the aforementioned chemical formulas (I) and (II) are given in each of the following tables. With each table, a minus sign ( ⁇ ) indicates an increase of electrons and a plus sign (+) indicates a decrease of electrons.
  • the aforementioned Fe salen complex compound was mixed with Vaseline, which is an adjuster for ointments, as a base at concentrations of 100 mmol and 200 mmol, respectively, to produce ointments. Then, the relationship between time and a temperature rise was measured by applying an AC magnetic field to these ointments under conditions of 258 A, 400 kHz, and 51.74 mT. The results are shown in FIG. 15 .
  • FIG. 15 shows that the temperature of the ointments at the concentrations of 100 mmol and 200 mmol immediately after the measurement (0 second) was 35 degrees Celsius and a temperature rise of approximately 5 degrees Celsius was observed for the ointment at the concentration of 200 mmol 300 seconds later.
  • FIG. 17 shows that the temperature of both Vaseline and Kenalog immediately after the measurement (0 second) was 30 degrees Celsius and a temperature rise even after application of the AC magnetic field for 300 seconds was less than 2 degrees Celsius.
  • the temperature of the ointment, in which the metal-salen complex compound was mixed, immediately after the measurement is 5 degrees Celsius higher than only Vaseline and only Kenalog and is suited as an anti-tumor agent.
  • the ointment containing the metal-salen complex compound at the concentration of 200 mmol shows a significant temperature rise after the application of the AC magnetic field and is thereby more suited as an anti-tumor agent.
  • a diatomic Fe salen complex compound (CAS#14167-12-5; produced by Tokyo Chemical Industry Co., Ltd.) was dissolved in agarose to produce a 100 mmol solution, which was put in a test tube, thereby preparing a sample.
  • a sample of pure water put in a test tube was also prepared as a comparison.
  • these samples were respectively exposed to medical near infrared radiation (wavelengths: 600 nm to 1600 nm) by TOKYO IKEN CO., LTD. by using Super Lizer PX Type I (output: 10 W).
  • the relationship between time and a temperature rise is shown in FIG. 18 .
  • FIG. 18 shows that the temperature of the sample containing the diatomic Fe salen complex compound immediately after the measurement (0 second) was 26 degrees Celsius and the temperature increased to approximately 53 degrees Celsius 300 seconds later. On the other hand, it is shown that the temperature of the sample containing the pure water immediately after the measurement (0 second) was approximately 19 degrees Celsius and its temperature 300 seconds later was approximately 23 degrees Celsius and did not increase so much.

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