Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof

Definitions

• This invention relates to the lowering of blood sugar level in vertebrates. It relates to the compounds that can be used to increase release of insulin by the beta cells of the islets of Langerhans. This occurs in diabetes mellitus (Type II) when blood sugar values rise above normal levels, i.e., hyperglycemia.
• Type II diabetes mellitus
• the invention is directed to providing pharmaceutical preparations that will increase release of insulin.
• Diabetes is a very common disease, occurring in all age groups.
• Type II the late onset diabetes results from inadequate insulin release and becomes increasingly common the older the population becomes.
• “Monoamine oxidase is a flavoprotein oxidase of purported CENTRAL METABOLIC IMPORTANCE CONVERTING NEUROACTIVE AMINES INTO INACTIVE ALDEHYDES
• the flavin linked monoamine oxidase is localized in the OUTER MITOCHONDRIAL MEMBRANE OF ANIMAL CELLS. Walsh pp. 402, 403.
• Monoamine oxidase is a complex enzyme system widely distributed throughout the body. Drugs that inhibit monoamine oxidase in the laboratory are associated with a number of clinical effects. Thus, it is UNKNOWN WHETHER MAO INHIBITOR PER SE, OTHER PHARMACOLOGICAL ACTIONS, OR AN INTERACTION OF BOTH IS responsible for the clinical effects observed. Therefore, the physician should become familiar with all the effects produced by drugs in this class. PDR (Physicians' Desk Reference 1983) p. 1516.
• A. Occurence Monoamine oxidase (MAO) has been found in all classes of vertebrates so far examined (1970) : mammals, birds, reptiles, amphibians and teleosts (161). The enzyme occurs in many different tissues, particularly in glands, plain muscle, and the nervous system (162). CHEMICAL EFFECTS OF MONOAMINE OXIDASE
• the enzyme isolated from a number of sources exhibits low specificity. In general, primary, secondary, and tertiary amines, tryptamine derivatives and catechol- amines are oxidized (1,5). The enzyme isolated from human placenta, however, will only attack primary amines and with simple alkyl amines increase in chain length results in increased affinity (7).” Barman p. 180.
• Halogenated compounds enter the body frequently from the environment.
• the anaesthetics halothane and methoxyflurane are cases in point.
• a Ca/Mg pump explains a wide variety of data. There seemed initially to be good data for high resonant phosphate compounds activating the cation pumps of mitochondria. Such a pump is affected by changes in concentration of calcium and it is also modulated by magnesium. Mn goes in and out of mitochondria readily. It dose so by active translocation and in the company of alkaline earth metal cations. Other metals participate but to a lesser degree.
• a Ca/Mg pump operating in tandem with Na/K ATPase pumps not only fits the cell membrane, but it also would have a place in the mitochondrial scheme of things.
• tertiary structure refers to the manner in which the polypeptide chain is bent or folded to form compact, tightly folded structure of globular proteins ( Figure 3-2).
• the more general term conformation is used to refer to the combined secondary and tertiary structure of the peptide chain in proteins.
• the term quaternary structure denotes the manner in which the individual polypeptide chains of a protein having more than one chain are arranged or clustered in space.
• proteins whether fibrous or globular, contain two or more polypeptide chains, between which THERE MAY BE NO COVALENT LINKAGES (Fig. 2-2).
• polypeptide chains of proteins usually have between 100 to 300 amino acid units (mol wt 12,000 to 36,000).
• a few proteins have longer chains, such as serum albumin (about 550 residues) and myosin (about 1,800 residues).
• serum albumin about 550 residues
• myosin about 1,800 residues
• any protein having a molecular weight exceeding 50,000 can be suspected to have two or more chains.
• oligomerie proteins possessing more than one chain are known as oligomerie proteins; theircoraponent chains are called protomers.
• a well-known example of an oligomerie protein is hemoglobin, which consists of four polypeptide chains, two identical alpha-chains and two identical beta-chains. Each chain has about 140 amino acids. The four chains fit together tightly to form a globular assembly OF GREAT STABILITY, despite the fact that THERE ARE NO COVALENT LINKAGES.
• Oligomerie proteins usually contain an even number of peptide chains. There may be anywhere from two to twelve subunit chains among the smaller oligomerie roteins to dozens or even hundreds among the larger proteins. Tobacco mosaic virus particles have over 2,000 peptide chains.
• oligomerie proteins contain two or more polypeptide chains, which are usually not covalently attached to each other, it may appear poproper or at least ambiguous to refer to oligomeric proteins as "molecules" and to speak of their "molecular weight. However, in most oligomerie profceins, the separate chains are so tightly associated that the complete particle usually behaves in solution like a simple molecule. Moreover, ALL THE COMPONENT CHAINS OR SUBDNITS OF OLIG0MERIC PROTEINS ARE USUALLY NECESSARY FOR THEIR FUNCTIONS.”
• Hemoglobin contains four structural subunits or protomers, i.e., the two alpha and two beta chains, but two functional subunits, i.e., the two alphabeta half molecules.
• lactate dehydrogenase one of the first enzymes in this class to have been studied extensively, exists in five different major forms, or isozymes, in the tissues of the rat ( Figure 9-12). These have been obtained in pure form. Although all five isozymes of lactate dehydrogenase catalyze the same reaction overall, they have DISTINCTLY DIFFERENT
• K m VALUES for their substrates; the biological significance of these differences will be described in Chapter 15 and 18.
• the five isozymes all have the same particle weight, about 134,000, and all contain four polypeptide chains, each of mol wt 33,5000. Diabetes mellitus was named for its frequency of urination
• Pyruvate from the breakdown of glucose provides oxaloacetate and acetyl CoA for the citrate synthase step of the Krebs cycle. There is a pool of each of these substrates. In addition, of course, there are pools of citrate molecules, alpha-ketoglutarate molecules and of molecules of succinyl CoA, succinate, fumarate, and malate.
• each of these pools is determined in part by the preceding enzyme substrate in the cycle, BUT ONLY IN PART.
• the oxaloacetste pool is directly increased by the breakdown of asparagine and aspartic acid.
• the fumarate is increased by the degradation of the aromatic amino acids phenylalanine and tyrosine.
• the pyruvate from the breakdown of alanine, threonine, glycine, serine, and cysteine becomes available for formation of both the oxaloacetate pool and the acetyl CoA pool
• the great portion of the acetyl CoA pool is derived from the breakdown of fatty acid chains by beta oxidation in the lipolytic cycle.
• the tricarboxylate cycle has some seven other enzyme reactions.
• Citric acid is part of a three member tautomeric isomerization, which includes aconitate and isocitric acid.
• the interconversions are assisted enzymatically by aconitase.
• Isocitrate is drained off by isocitrate dehydrogenase for forming of alpha-ketoglutarate.
• the latter in turn is converted into succinyl CoA by alpha-ketoglutarate dehydrogenase.
• the succinyl CoA is acted upon by succinyl CoA synthetase. While it is producing a molecule of guanosine triphosphate (GTP), succinyl CoA synthetase releases the succinic acid from the succinyl CoA. The resonance of the CoA sulfur bond is thus transferred to GDP in forming the GTP.
• GTP guanosine triphosphate
• succinate dehydrogenzse From the succinic acid two hydrogen atoms are removed by succinate dehydrogenzse to produce a double bond.
• the compound formed is fumarate with hydrogen atoms trans to one another at the double bond.
• a water molecule is added across the double bond. This is achieved by the activity of fumarate hydratase (fumarase) and forms malate.
• malate dehydrogenase we have oxaloacetate again and have completed a full cycle around the Krebs (TCA) cycle.
• ketogenic acid If we define a ketogenic acid as one WHOSE CARBON CHAIN CAN GIVE RISE ONLY TO ACETOACETATE, there are only two ketogenic amino acids - leucine and lysine. The other four - isoleucine, tryptophan, phenylalanine, and tyrosine - can also give rise to glucose precursors and are, therefore, both ketogenic and glucogenic.
• amino acids that can serve as precursors of phosphoenolpyruvate are called GLYCOGENIC OR GLUCOGENIC. These amino acids are: alanine cysteine(ine) histidine serine arginine glutamate methionine threonine aspartate glutamine proline tryptophan asparagine glycine hydroxyproline valine" p. 245 Frisell (1982)
• acetyl CoA pool is a crossroads substrate for the TCA cycle and that it enters at the rate-limiting citrate synthase step in the cycle.
• Lysine and threonine are the two essential amino acids not transaminated. In fact, they are not broken down readily. Lysine is used for forming organic electrolytes, the polyamines, and for the synthesis of carnitine, necessary for carnitine acyl transferase activity needed to transfer branched chain fatty acids into the mitochondria.
• the methylmalonyl CoA rearranges through the action of a mutase to form succinyl CoA. This conversion requires B-12 for the enzyme to be active. The reaction on propionyl CoA itself requires biotin. 4. pyrimidine breakdown products including those from thymine also contribute to the succinyl CoA pool. The point has been made in detail before that the polymeric glutamate dehydrogenase feeds into this pool indirectly through the alpha-ketoglutarate (2-oxo-glutarate). When the polymeric form is inhibited, the monomeric forms increase breakdown of the above amino acids to produce succinyl CoA as if replacing that which was lost when the polymeric form was inhibited.
• the leucine metabolism within the beta cells therefore, is of special interest.
• the release of insulin can be demonstrated to be associated with compounds that are intimately involved in the metabolism of the tricarboxylic acic cycle.
• the present invention provides a method for lowering blood glucose in vertebrates with hyperglycemia.
• the use of amino acids having hypoglycemic actions in various ratios each wi.ch the other and each with manganese in effective ratios increases insulin release in NIDDM (Type II) diabetes mellitus.
• NIDDM Type II diabetes mellitus.
• the present invention differs in its relation to effective amounts given in that these amounts are constantly changing so that there is a pattern of changing administration in terms of frequency, amount and individual requirements.
• NIDDM Type II diabetes mellitus
• a hypoglycemic agent such as sulfonylurea medication.
• the above program and medication can be continued as this method of treatment is initiated.
• hypoglycemic agents named in the invention should be introduced stepwise.
• the introductory period permits evaluation of the fasting blood sugar.
• a fasting blood sugar is taken.
• the desired amount of the agent is then given with food and a subsequent fasting blood sugar determined ⁇ h a day or two to observe for any change in blood glucose.
• tryptophan in the amount of 100 mg may be given initially. If there is no change, this should be increased stepwise until a drop in the blood glucose can be orrelated with the amount given.
• an initial amount of 250 or 500 mg may be used and increased up to 1000 or 1500 with a similar correlation of drop in blood glucose with the amount given.
• valine no such correlation is anticipated.
• its relation to leucine would warrant an effort to correlate a combination of leucine and valine in equal amounts with drop in blood glucose.
• the indirect actions of arginine and ornithine are best explored after a treatment schedule has been undertaken. The effects of these are sometimes dramatic,but the blood glucose level may quickly return to its former level.
• a small dose of one or two mg (manganese content) manganese gluconate can be given separately. Both the subjective response and the glucose level are monitored. If initial amounts tolerated are large, the increments of one or two mg can be increased to increments of five to ten mg. Usually more than 25 mg are not required at any one time, and these levels are likely to decrease quickly. There is no need to activate special methods of disposing of manganese by giving large amounts. The amount reached for positive correlation with glucose level dropping is likely to fall progressively over a few weeks or days. Increments of five to ten mg used initially may just as well become decrements of five to ten mg quickly and the spacing of the manganese becomes greater and greater. It is best to be prepared to promptly drop to lower amounts at the earliest indication that the amount required is decreasing.
• Combinations of the hypoglycemic agents appear to have synergistic effects. This reflects the different modes of action of each. As amounts are adjusted downwards, increase the interval between treatments as well as decreasing the amounts given. This is the cumulative effect, as if filling a hole. The clinician must be aware of the implications of the above. It is best that the medication be administered personally during the initial period of adjustment which varies from patient to patient. It is unwise to initially provide the patient with a standard daily dosage on the assumption that the effects will be predictable.
• the combined use of manganese with one or more of the other hypoglycemic agents named here is likely to more frequently be accompanied by a drop in the blood glucose than with the other hypoglycemic agents alone.
• the manganese may be used to modulate the downward drift in the blood glucose level. No effort should be made to force the level below the normal range, which may be estimated at 110 to 140 milligrams/100 milliliters. During injury, infection or forms of stress for various reasons , there will be variations in the amounts to be iven of each of these. No manganese sh uld be given during fever.
• Ratios should be calculated in mg as between leucine/Mn, tryptophan/Mn, and leucine to tryptophan, leucine/tryptophan.
• Seldom will as much as 500 mg of tryptophan be required, and that sh uld decrease quickly. Amounts of leucine may be as much as 1500 mg or more. Leucine may be thought of as a fuel.
• Tryptophan may be thought of as primitive hormone precursor.
• Manganese may be thought of as modulator of the level of metabolism. Valine may be thought of as a precursor of leucine if needed.
• Treatment Periods daily to one to three week intervals.
• Blood glucose varied from (90-100) to (170-180) mg/100 ml, usually from 100 to 150.
• Blood pressure varied from 130/82 to 184/80 mm. of mercury.
• Systolic pressure varied from 130 to 184.
• Diastolic pressure varied from 70 to 90.
• Pulse varied from 68 to 92.
• Medication ratios As between hypoglycemic agents varied from 2.5/1 to 30/1 All dosages in milligrams. Dosages of hypoglycemic agents varied from 50 to 1500.
• hypoglycemic agent with the lowest ratio to manganese ranged from 17/1 to 100/1 when given concurrently.
• hypoglycemic agent with the highest ratio to manganese ranged from 167/1 to 750/1.
• Treatment intervals for Mn varied from daily to 2 weeks or more.
• Treatment Periods daily to every 4 to 5 days.
• Blood sugar varied from 175 mg to 120 mg over six week interval.
• Objective of treatment to restore blood sugar to normal range with 110 to 140 mg acceptable.

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• 1985
  • 1985-03-01 WO PCT/US1985/000328 patent/WO1985003872A1/en not_active Application Discontinuation
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  • 1985-03-01 JP JP50128385A patent/JPS61501569A/ja active Pending
  • 1985-03-01 AU AU40665/85A patent/AU598721B2/en not_active Ceased

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