US3929995A - Method for treating diabetic ketoacidosis - Google Patents

Method for treating diabetic ketoacidosis Download PDF

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Publication number
US3929995A
US3929995A US509604A US50960474A US3929995A US 3929995 A US3929995 A US 3929995A US 509604 A US509604 A US 509604A US 50960474 A US50960474 A US 50960474A US 3929995 A US3929995 A US 3929995A
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octanoylcarnitine
insulin
body weight
plasma
administering
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Yuzo Kawashima
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins

Definitions

  • ABSTRACT A method for treating diabetic ketoacidosis comprising administering a therapeutically effective amount of a pharmaceutical composition comprising (+)-octanoylcarnitine and, optionally, insulin is disclosed.
  • This invention relates to a method for treating diabetic ketoacidosis. More particularly, this invention relates to a method for treating diabetic ketoacidosis using a pharmaceutical composition comprising (+)-octanoylcarnitine alone or in combination with insulin.
  • Diabetic ketoacidosis which is a lethal diabetic disorder is a common clinical emergency which is often observed. For example, at the University of Southern California, admissions of as many as 340 cases for the 3 year period from July 1, 1965 to June 30, 1968 were reported (Diabetes, 20, 490, (1972)).
  • (+)-decanoylcarnitine which is a potent inhibitor of long-chain acylcarnitine transferase in the tests using severely ketotic alloxan diabetic rats (Proc. Natl. Acad. Sci., U.S.A., 58, 790, (1967)) was found to be a substance which exhibits an extremely rapid effect in the treatment of the acidosis and that the mechanism of the action is the blockage of free fatty acids which are increased in the cytoplasm of the liver due to the insulin deficiency to transfer into the mitochondria where ketone bodies are produced.
  • (+)-octanoylcarnitine could be practically used as a therapeutic tool for diabetic ketoacidosis and, particularly, that a combination of (+)-octanoylcarnitine and insulin can markedly control or alleviate diabetic ketoacidosis.
  • (+)-octanoylcarnitine for diabetic ketoacidosis
  • (+)-octanoylcarnitine is orally or parenterally administered, optionally in combination with insulin, for the treatment of diabetic ketoacidosis
  • ketone bodies in the plasma can-remarkably be reduced and that the (+)-octanoylcarnitine is substantially non-toxic.
  • (+)-decanoylcarnitine as a control which is an analogue of (+)-octanoylcarnitine, produces hemolysis as a deleterious side effect due to its strong surface activity when it is administered intraveneously, whereas (+)-octanoylcarnitine according to the present invention does not have such an untoward effect.
  • the present inventor has found that (+)-octanoylcarnitine exhibits an unexpectedly superior anti-ketogenic effect in comparison with (+)-decanoylcarnitine and (+)-hexanoylcarnitine and thereby is a promising therapeutic agent for treating ketoacidosis. It will be obvious to those skilled in the art that (+)-octanoylcarnitine of the present invention also will exhibit this excellent antiketogenic effect when administered'orally and can be conveniently used in practical treatment.
  • FIG. 1 shows the relative hemolytic capacity in vitro of (+)-octanoylcarnitine and (+)-decanoylcarnitine.
  • the ordinate indicates the percent hemolysis and the abscissa indicates the concentration of (+)-octanoylcarnitine and (+)-decanoylcarnitine.
  • FIG. 2 shows the reversibility of the (+)-octanoylcarnitine effect in vivo.
  • the ordinate indicates the concentrations of plasma ketones (dotted line) and plasma glucose (solid line), and the abscissa indicates the time after the administration.
  • FIG. 3 shows the effects of oral administration of (+)-octanoylcarnitine on plasma ketone levels.
  • the ordinate indicates the concentration of plasma ketone bodies and the abscissa indicates the time.
  • FIG. 4 shows the relationship between the dosage of (+)-octanoylcarnitine and the decrease in plasma ketone levels.
  • the ordinate indicates the amount of the decrease in plasma ketone bodies and the abscissa indicates the dosage administered.
  • FIG. 5 shows the disapperance of (+)-octanoylcarnitine -l- C from the blood of alloxan diabetic rats.
  • the ordinate indicates dpm/ml plasma X 10 and the abscissa indicates the time.
  • (+)-octanoylcarnitine [hereinafter referred to as (+)-OC]used in the present invention is 'a known compound and can be easily prepared by the acylation of (+)-carnitine chloride with octanoyl chloride, these being disclosed in Japanese Patent Publication 2247/71.
  • the (+)OC of the present invention can be administered either orally or parenterally, e.g., subcutaneously or intravenously.
  • a dose usually ranges from about 50 mg to about 100 mg, preferably 65 mg to 85 mg/kg body weight.
  • the compound can be used in a common preparation form, such as in the form of a powder, tablets, capsules, syrup, elixir and the like. It is preferable that 100 mg to 400 mg of the compound be contained per unit dose form.
  • a dose usually ranges from about 1 mg to 25 mg, preferably to mg/Kg body weight. It is usually preferable to formulate as an aqueous solution of 100 mg to 300 mg/ml.
  • local anesthetic agents such as lidocain chloride and benzyl alcohol and glucose and saline etc. to render the solution isotonic, or other active ingredients.
  • the compound is preferably given in a form of intravenous injection.
  • the proportion of insulin to (+)OC is usually about I to about 10 units, preferably 5 unit/Kg body weight.
  • EXAMPLE 1 Determination of Hemolytic Capacity Relative hemolytic capacities of (+)OC and (+)decanoylcarnitine were determined using human blood. Human erythrocytes were suspended in a solution of 5 percent bovine albumin in 0.9 percent sodium chloride (pH 7.4) containing (+)OC or (+)decanoylcarnitine at various concentrations as indicated in FIG. 1. After incubation at 37C for minutes, the cells were removed by centrifuging and the amount of hemoglobin present in the supernatant was measured spectrophotometrically. The results obtained are shown in FIG. I.
  • (+)decanoylcarnitine causes extensive hemolysis at concentrations greater than about 3mM, whereas (+)OC is less hemolytic up to the maximum concentration, i.e., 15.4 mM.
  • EXAMPLE 2 Inhibition of Ketone Body Production 3 to 8 unanesthetized alloxan diabetic rats per group (Wistar; both sexes; body weight, about 120 g) received intravenously 17 mg of (+)-OC, and as controls, (+)hexanoylcarnitine [(+)-HC] or (+)decanoylcarnitine, [(+)DC] with or without insulin (0.85 U) were used. Two hours after the administration, plasma glucose and ketone body concentrations were determined, and the results obtained are shown in Table 1 below. In Table I, the values represent the means i SEM for the number of animals in each group.
  • (+)OC either alone or in combination with insulin is found to exhibit an excellent reduction of ketone bodies in blood. Further, it can be seen that (+)OC has almost no effect on blood glucose levels despite its capacity to reverse ketosis when given to acute diabetic ketotic rats.
  • EXAMPLE 4 Effects of Orally Administered (+)OC on Plasma Ketones Alloxan diabetic rats weighing approximately I00 g received through a stomach tube 1 ml of a neutralized aqueous solution containing 25 mg and 75 mg (+)OC, respectively. The plasma ketone level was determined on samples taken at hourly intervals and the results obtained are shown in FIG. 3.
  • LD of the ad'mistration of (+)-DC in the method of this invention is about 0.2 g/Kg body weight when administered intravenously, about 0.6 g/Kg body weight for intraperitoneal administration and about 4 g/Kg for oral administration.
  • a capsule containing 200 mg of (+)-OC was prepared using the following components.
  • a method for treating diabetic ketoacidosis which comprises orally or parenterally administering to a subject afflicted with diabetic ketoacidosis to reduce keto bodies in plasma a therapeutically effective amount of (+)-octanoylcarnitine.
  • said pharmaceutical composition includes insulin in such a proportion that about 1 to 10 units of insulin are administered per Kg of body weight.
  • composition is administered in an amount to provide 5 units of insulin

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Zoology (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
US509604A 1973-09-26 1974-09-26 Method for treating diabetic ketoacidosis Expired - Lifetime US3929995A (en)

Applications Claiming Priority (1)

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JP48107613A JPS5058213A (enrdf_load_stackoverflow) 1973-09-26 1973-09-26

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US3929995A true US3929995A (en) 1975-12-30

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US (1) US3929995A (enrdf_load_stackoverflow)
JP (1) JPS5058213A (enrdf_load_stackoverflow)
DE (1) DE2445801C2 (enrdf_load_stackoverflow)
FR (1) FR2244487B1 (enrdf_load_stackoverflow)
GB (1) GB1474424A (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10799564B1 (en) * 2019-05-06 2020-10-13 Baxter International Inc. Insulin premix formulation and product, methods of preparing same, and methods of using same

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1143611B (it) * 1977-11-03 1986-10-22 Sigma Tau Ind Farmaceuti Applicazione della acetil-carnitina nella terapia delle affezioni cardiache di/tipo anossico,ischemico,cardiotossico e nelle sindromi aritmiche
IT1156741B (it) * 1978-05-15 1987-02-04 Sigma Tau Ind Farmaceuti Applicazione terapeutica della carnitina e di alcuni derivati acilati della carnitina nell'emodialisi
IT1206954B (it) * 1979-02-12 1989-05-17 Sigma Tau Ind Farmaceuti Agenti terapeutici a base di un acil derivato della carnitina per la cura di vasculopatie periferiche
IT1116037B (it) * 1979-04-23 1986-02-10 Sigma Tau Ind Farmaceuti Esteri e ammidi di acil carnitine loro procedimenti di preparazione e loro uso terapeutico
IT1133010B (it) * 1980-05-15 1986-07-09 Sigma Tau Ind Farmaceuti Metodo terapuetico per il trattamento del diabete mellito a insorgenza giovanile e composizione farmaceutica per tale metodo
US4537772A (en) * 1984-05-02 1985-08-27 Merck & Co., Inc. Enhancing absorption of drugs from gastrointestinal tract using acylcarnitines
US4731360A (en) * 1985-08-16 1988-03-15 Merck & Co., Inc. Acylcarnitines as absorption-enhancing agents for drug delivery through mucous membranes of the nasal, buccal, sublingual and vaginal compartments
IT1231944B (it) * 1989-05-05 1992-01-16 Sigma Tau Ind Farmaceuti Composizione farmaceutica per il trattamento di protozoosi, particolarmente della tripasonomiasi comprendente d-carnitina o un alcanoilderivato della d-carnitina

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS462247A (enrdf_load_stackoverflow) * 1970-03-02 1971-10-12

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS462247A (enrdf_load_stackoverflow) * 1970-03-02 1971-10-12

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Canadian Journal of Biochemistry, Vol. 49, 599-605; 941-948, (1971) *
The Journal of Clinical Investigation, Vol. 52, Apr. 1973, 877-884 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10799564B1 (en) * 2019-05-06 2020-10-13 Baxter International Inc. Insulin premix formulation and product, methods of preparing same, and methods of using same
US11033608B2 (en) 2019-05-06 2021-06-15 Baxter International, Inc. Insulin premix formulation and product, methods of preparing same, and methods of using same
US11707509B2 (en) 2019-05-06 2023-07-25 Baxter International, Inc. Insulin premix formulation and product, methods of preparing same, and methods of using same

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DE2445801C2 (de) 1985-05-09
FR2244487B1 (enrdf_load_stackoverflow) 1978-06-30
JPS5058213A (enrdf_load_stackoverflow) 1975-05-21
DE2445801A1 (de) 1975-04-03
AU7226574A (en) 1975-05-01
FR2244487A1 (enrdf_load_stackoverflow) 1975-04-18
GB1474424A (en) 1977-05-25

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