MXPA97009573A - Method for regulating metabolism with beta hidroxil dopamine inhibitors - Google Patents

Abstract

Method for regulating or improving lipid or glucose metabolism and reducing in a vertebrate animal fat stores in the body, insulin resistance, hyperinsulinemia, hyperglycemia, hyperlipidemia, elevated blood lipoproteins (such as triglycerides and cholesterol including chylomicrons) are described. , VLDL and LDL) and / or increase in the subject the HDL in the plasma, the methods comprise the administration or administration with time measured of inhibitors of dopamine beta hydroxylase (DB

Description

METHOD OF REGULATING THE -LETRBOLISM WITH INHIBITORS OF DOPflRIINfl BETA HIDROXILflSfl FIELD OF THE INVENTION This invention relates to methods for regulating or improving the metabolism of lipid and glucose. This invention, moreover, relates to methods for reducing in a subject, a vertebrate animal (including a human), at least one of the following metabolism indices: fat stores in the body, insulin resistance, hyperinsulinemia, hyperglycernia , hyperlipidernia, elevated blood lipoproteins (such as triglycerides and cholesterol including quilornicrones, VLDL and LDL), and / or increase in the subject the plasma HDL, and, more generally, the improvement of metabolic irregularities, especially those associated with obesity, atherosclerosis and type II diabetes. The methods comprise administration or administration with time measured (ie, administration at predetermined time in a 24 hour period) of dopamine beta hydroxylase (DBH) inhibitors.

BACKGROUND OF THE INVENTION OBESITY AND IRREGULARITIES OF LIPID METABOLISM - FAT LOSS IN THE BODY In humans, obesity can be defined as a body weight that exceeds 20% of the body weight desirable for individuals of the same sex, height and constitution (Salines, LB in Endocrinology &fletabolism, 2nd Ed., McGraw-Hill, New York 1987, pp. 1203-1244; See also, RH Uillia s, Textbook of Endocrinology, 1974, pp. 904-916). In animals (including humans), obesity can be further defined by body weight patterns correlated with prolactin profiles given that members of a species that are young, thin and "healthy" (ie free of any irregularity) , not only etabolic irregularities) have daily plasma prolactin level profiles that follow a regular pattern with little or no normal deviation. The "healthy" prolactin profile for humans (male and female) is illustrated in Figure 1. Obesity, or excess fat deposits, correlates with and may cause the onset of various irregularities of lipid metabolism, for example, hypertension, Type II diabetes, atherosclerosis, etc. Even in the absence of clinical obesity (in accordance with the above definitions) the reduction of fat stores in the body (notably visceral fat storage) in humans, especially on a long-term or permanent basis, would be of significant benefit, both cosmetic as physiologically. Reducing the storage of body fat in pets (including pets) especially on a long-term or permanent basis would also obviously be of considerable economic benefit to humans, particularly since farm animals provide a larger portion of a diet. a person; and animal fat can end up as new fat deposits in humans. Although controlled diet and exercise can produce modest results in the reduction of body fat deposits, prior to the cumulative work of the present invention (including the above copending patent applications and the US Patents issued with reference below), no truly effective or practical treatment to control obesity or other irregularities of lipid metabolism that usually accompany obesity has been discovered. High plasma concentrations of one or more lipoproteins that carry cholesterol or triglyceride (such as chylous chyrogens, very low density lipoproteins (VLDL), and low density lipoproteins (LDL)) are considered abnormal when they exceed a well-established normal limit, for Generally defined as 95% of a random population - Elevated levels of these substances have been positively correlated with atherosclerosis and increased risk of cardiac infarction (ie, heart attack) which is the leading cause of death in the United States . Important clinical evidence has been presented where a reduction in the plasma concentration of these substances correlates with a reduced risk of atherosclerosis (Noma, A., and other fltherosclerosis 49: 1, 1983).; Illingworth, D. and Conner, l., In Endocrinology & fletabolisrn, McGraw-Hill, New York 1987). In this way, a significant amount of research has been devoted to the search for treatment methods that reduce the elevated levels of cholesterol and triglycerides in the plasma. Another subset of plasma lipoproteins found in vertebrates are high density lipoproteins, or HDL. HDL serve to remove free cholesterol from plasma. A high HDL concentration as a percentage of total cholesterol in the plasma has been associated with a reduced risk of atherosclerosis and heart disease. In this way, the HDL are known in the press to the public, "good" cholesterol. Therefore therapeutic strategies involve attempts both to reduce the content of LDL and VLDL in plasma (ie, reduce total cholesterol in the plasma), and to increase the HDL fraction of total cholesterol in the plasma. Several lines of research have indicated that simply increasing HDL is beneficial even in the absence of reducing the concentration of LDL or VLDL (Bell, GP et al., Fterherosclerosis 3_6: 47-54, 1980; Fears, R., Biochern, Pharrnacol. : 219-22B, 1984; Thompson, G., Br. Heart 3. 51: 585-588, 1989, Blackburn, HNEJM 309: 426-428, 1983). Current therapies for high lipid and lipoprotein values include a low-fat diet and the elimination of aggravating factors such as sedentary lifestyle. If the elevated lipid and lipoprotein levels are secondary (ie, incidents to, for example, a deficiency of lipoprotein lipase or LDL receptor, various endocrine pathologies, alcoholism, renal irregularities, liver irregularities) then control of the underlying irregularity also It is central to the treatment. The elevated levels of lipid and lipoprotein in the blood are also treated with drugs, which usually alter the levels of particular components of total cholesterol in the plasma, as well as reduce the total component of lipid in the plasma. Among the drugs most recently introduced to treat these conditions is lovastatin (MEVACORTM) q and selectively inhibits an enzyme involved in the production of cholesterol, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. This drug especially reduces total coleeterol and may cause a modest increase (5-10%) in HDL concentrations. However, the benefit of this therapy varies from subject to subject. In addition, the use of the HMG-CoA enzyme inhibitor is sometimes accompanied by side effects such as liver toxicity, renal rhinoglobinuria, renal arrest and lenticular opacities. The risk of such side effects needs close control of the patients (for example, monthly tests of liver function are required). Another drug prescribed against high cholesterol and triglycerides is clofibrate. The effectiveness of clofibrate also varies from subject to subject and its use is often accompanied by such side effects as nephrotic syndromes, rhinalgia, nausea and abdominal pain.

DIABETES Diabetes, one of the most insidious major diseases, can arise suddenly or be undiagnosed for years at the same time attacking the blood vessels and nerves. Diabetics, as a group, are much more afflicted with blindness, heart disease, embolism, kidney disease, hearing loss, gangrene and impotence. One third of all visits to doctors are caused by this disease and its complications. Diabetes and its complications are a leading cause of premature death in the United States and in the Western world. Diabetes adversely affects how the body uses sugars and starches that, during digestion, turn into glucose. Insulin, a hormone prod by the pancreas, makes glucose available to the body's cells for energy. In muscles, adipose tissues (fat) and connectors, insulin facilitates the entry of glucose into cells by an action on cell membranes. In the liver, ingested glucose is normally converted to CO2 and H2O (50%), to glycogen (5%); and fat (30-40%), the last one being stored as a deposit of fat. Fatty acids from adipose tissues circulate, return to the liver for re-synthesis of triacylglycerol and are metabolized to acetone bodies for use by tissues. The fatty acids are also metabolized by other organs. The net effect of insulin is to promote the storage and use of carbohydrates, proteins and fats. Insulin deficiency is a common and serious pathological condition in humans. In insulin-dependent diabetes (IDDM or Type I), where the pancreas prod little or no insulin, insulin must be injected daily. In non-insulin dependent diabetes (NIDDM or Type II), the pancreas retains the ability to prodinsulin, in fact it can prodhigher than normal amounts of insulin (hyperinsulinemia), but due to a cellular resistance to insulin, the amount of insulin is relatively insufficient. Insulin resistance can be defined as a state in which a normal amount of insulin prod a subnormal biological (metabolic) response. In diabetic patients treated with insulin, insulin resistance is considered to be present when the therapeutic dose of insulin exceeds the rate of insulin secretion in normal persons. Insulin resistance is also associated with hyperinsulinemia when normal or elevated levels of glucose in the blood are copresent. Any type of diabetes causes expanded rnetabolic abnormalities. In the majority of subjects with NIDDM, the metabolic abnormalities associated with NIDDM (1) redthe entry of glucose into several "peripheral" tissues and (2) they redthe release of glucose in the liver circulation. In this way, there is an excess of extracellular glucose and an intracellular glucose deficiency. Elevated blood lipids and lipoproteins are a common complication of diabetes. The cumulative effect of these abnormalities associated with diabetes is severe damage to blood vessels and nerves. At present, there is no effective treatment to control either hyperinsulinemia or insulin resistance, except for some work or the present invention as follows: PREVIOUS WORK OF THE PRESENT INVENTION The present invention and its co-workers have discovered that the administration of certain prolactin inhibitors (eg, doparnin agonists such as co-bromocriptine) and / or prolactin-stimulators (eg, such as rnetochlora, idars, and serotonin percustors) as 5-hydroxytryptophanes) and particularly the administration of said substances at predetermined times, redbody fat stores, obesity, plasma triglycerides and cholesterol and insulin resistance: US Patent Nos. 4,659,715; 4,749,709; 4,783,469; 5,006,526; 5,344,832 and PCT application of E.U.A. 92/11166.

RELATED REQUESTS Copending patent application Serial No. 07 / 192,332 (now abandoned in favor of its continuation of rule 62 Serial No. 07 / 919,685) describes methods for regulating irregularities of lipid metabolism by administering prolactin (or prolactin and a glucocorticosteroid) ("GC")) in the bloodstream of an animal or a human on a daily basis with time measured in an amount and for a period of time sufficient to increase the sensitivity to insulin. Prolactin (or prolactin and glucocorticosteroid - "GC") injections are measured at the time to create a peak in the daily prolactin level profile of a subject (or of prolactin and glucocoticosteroids) that coincides in time with the peak prolactin level (or with prolactin and GC levels, respectively) of a thin, insulin-sensitive human in order to increase insulin sensitivity and reduce insulin storage. fat in the body. Alternatively, injections of the same agent are measured in time to the peak prolactin level of an obese subject to achieve fat gain in a thin subject, if desired. Copending application Serial No. 07 / 463,327 (now abandoned in favor of its continuation of rule 62 08 / 249,808 which is a continuation of serial No. 07 / 719,745, now US Patent 5,344,832) discloses a method for modifying and re-adjust prolactin and GC rhythms in an obese animal by administering a dopamine agonist at a predetermined time of day, so that the prolactin peak (and / or GC) of the obese animal will be phase-shifted to match those of a thin animal. This results in the reduction of at least one of the following: storage of fat in the body, body weight, hyperinsulinemia, hyperglycemia and increased sensitivity to insulin. Copending application Serial No. 07 / 719,745 (now of US Pat. No. 5,344,832) describes and claims improved methods for modifying and re-adjusting the phase as well as the amplitude of the daily prolactin rhythms. These methods comprise (a) administering to the subject a dopamine agonist just after the time in which the normal prolactin profile rises to reduce the levels of prolactin at low "day" levels and (b) administering to the subject a stimulator of prolactin at a time before the prolactin level rises in normal subjects to achieve or maintain a peak for prolactin during the night. The objective of this treatment is to alter the profile of prolactin secretion of a subject to mimic in form and time the profile of a healthy, thin human who does not suffer from one or more of these etabolic irregularities. The Patent of E.U.A. 5,344,832 describes and also claims the administration of a thyroid hormone to subjects who are being treated with a dopamine agonist and prolactin stimulator, especially for those subjects who are chronically or temporarily hypothyroid. Copending Application Serial No. 07 / 995,292 (which is a continuation in part of the continuation of US Series No. 07 / 719,745, now US Patent 5,344,832) and Application Serial No. 08 / 264,558 (which is a Some of the applications of US Nos. Nos. 07 / 995,592, 08 / 178,569 and 08 / 171,897) describe methods for determining whether the prolactin profile of daily circulation of a subject is abnormal, and methods for normalizing prolactin profiles that they are aberrant. In relevant part, the method of treatment involves administering a prolactin inhibitor no later than the time at which, during the first hours, the prolactin level in the subject is higher. The method may also involve administration of a prolactin stimulator with measured time to cause a peak prolactin level that occurs overnight. The objective of this treatment is to alter ("create") the profile of prolactin of a subject to imitate or reach in form and time the profile of a healthy, thin human that does not suffer from any irregularity. Copending Patent Application Serial No. 08 / 263,607; Further part of copending Application Serial No. 07 / 995,292, which in itself is a continuation in part of Serial No. 07 / 719,745 (now U.S. Patent No. 5,344,832), describes methods for regulating lipid metabolism and glucose by the measured administration of pirenzepine, methyl scopolanine or another uscarinic receptor antagonist (preferably useful) alone or in combination with a prolactin inhibitor as a treatment for (i) diabetes, particularly type II diabetes, and more generally irregularities of glucose metabolism that are associated with type II diabetes; (ii) obesity and more generally irregularities of lipid metabolism. This Application further describes maintaining the therapy for a period sufficient to cause a readjustment of the prolactin's daily rhythm of the treated subject resulting in the continuation of the metabolic improvement after the sensation of the therapy.

Copending Patent Application Serial No. 08 / 271,881 describes a method for adjusting the phase relationship between circadian rhythms for prolactin and for one or more immune responses. The invention involves normalizing (or re-adjusting) the circadian rhythm for prolactin of a subject in need of such treatment to resemble that of a healthy, young subject. The invention further involves adjusting the circadian prolactin rhythm of odo that its phase and amplitude correlate with the immunological responses to prolactin thereby exerting an amplification effect on a predetermined aspect of the immune response.

OBJECTS OF THE INVENTION The present invention has co-objects to improve metabolic rates by improving one or more abnormal parameters such as those associated with obesity and diabetes. A specific object of the invention is to reduce the stores of fat in the body of a vertebrate animal, including a human, by administering at least one DBH inhibitor, preferably at a predetermined time. Another object of the invention is to correct abnormalities in glucose or lipid metabolism of a vertebrate animal, including humans, by administering a DBH inhibitor, preferably at a predetermined time. This administration is directed towards at least one of the following: reducing hyperinsulinernia; reduce insulin resistance; reduce hyperglyceria; reduce the elevated levels of at least one lipoprotein in the blood; reduce triglycerides in the serum; and increase the ratio of high density lipoprotein to low density lipoprotein. Another object of the invention is to treat diabetes in a vertebrate animal, including a human, by administering a DBH inhibitor, preferably at a predetermined time. This administration is directed toward at least one of the following: reduce hyperinsulinemia; reduce insulin resistance; and reduce the hyper glycemia. Yet another object of the invention is a method for treating atherosclerosis in a vertebrate animal, including humans, by administering a DBH inhibitor, preferably at a predetermined time. This administration is directed towards at least one of the following: reducing the elevated levels of one or more lipoproteins in the blood; reduce triglycerides in the serum. Furthermore, another object of the invention is to continue the administration of a DBH inhibitor during said period to readjust the central neural oscillators (for example, those expressed by the circadian rhythm of prolactin in circulation), so that its phase and amplitude (for example, example the phase and amplitude of the prolactin rhythm) reach those of a thin and healthy subject of the same species (and where the sex applies), this effect persisting even after the sensation of the administration of the DBH inhibitor.

BRIEF DESCRIPTION OF THE DRAWING: Figure 1 illustrates the normal prolactin profile for healthy young humans in terms of average prolactin values (ng / ml) against the time of day in hours. I "l = normal prolactin profile for males, F = normal prolactin profile for females Figure 2A illustrates the daily prolactin rhythm in plasma in rats treated with fusaric acid at 0700 hours Figure 2B illustrates the prolactin rhythm Plasma in rats treated with fusaric acid at 1900 hours Figure 2C illustrates the daily prolactin rhythm in plasma in untreated young rats (8 weeks) Figure 2D illustrates the daily prolactin rhythm in plasma in rats 50 weeks not treated.

BRIEF DESCRIPTION OF THE INVENTION At least one of the following objects is achieved by: (a) a method that involves administering to a vertebrate subject in need of such treatment, fusaric acid or another DBH inhibitor in an effective amount to improve one or more of the aberrant indices associated with irregularities of lipid metabolism (e.g., obesity, high cholesterol, and elevated levels of other lipids and lipoproteins in the blood). (b) another method that involves administering to a vertebrate subject in need of such treatment, fusaric acid and another DBH inhibitor in an effective amount to improve one or more of the aberrant indices associated with the irregularities of glucose metabolism ( example, glucose intolerance, insulin resistance, hyperglyceria, ineulinemia and type TI diabetes) and / or irregularities of lipid metabolism (eg, obesity, hyperlipidernia, hypercholesterolernia). Preferably, administration of the DBH inhibitor in (a) or (b) above should occur at a predetermined time ("time measured administration") over a period of 24 hours to increase its beneficial effect. The continuation of therapies with time measured with previous reference over a period of time stabilizes these improvements and often causes them to persist after the sensation of treatment. The persistence and stabilization of these improvements and readjustment of circadian rhythms is referred to as the "indirect effect" or "long-term effect" of DBH inhibitors (alone or in combination with prolactin inhibitors) and is attributed to the readjustment of a hypothalamic metabolic state expressed by means of circadian rhythms, more specifically prolactum rhythms and neural phase oscillators in the central nervous system. These effects may persist on a long-term basis after the treatment sensation. As used herein, the term "DBH inhibitor" should include compounds having this property as well as prodrugs and metabolites thereof in free form or with pharmaceutically acceptable salts. As used herein, "prodrug" means a compound which, once administered to a host, is converted to a DBH inhibitor compound described herein or to a DBH inhibitor thereof. A "metabolite" of a compound described herein is an active derivative of a compound described herein that is formed when the compound is metabolized.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES All patents, patent applications and literature references cited herein are incorporated by reference in their entirety as if their descriptions were physically present in the present specification. However, in case of conflict, the present description controls. Vertebrate animals include, without limitation, humans, other mammals (e.g., domestic animals, laboratory animals and pets) and birds.

Without wishing to be bound by theory, the present invention believes that fusaric acid and other DBH inhibitors have the ability to regulate and improve lipid and glucose metabolism by one mode of action (i.e., a mechanism or path) which is different from that of dopamine D2 agonists or rnuscarinic receptor antagonists til.

ADMINISTRATION WITH MEASURED TIME TO ALTER METABOLISM OF LIPID AND GLUCOSE The direct effect of fusaric acid or other DBH inhibitors to achieve one or more of the following: reduce the stores of fat in the body, reduce blood lipids, reduce lipoproteins in the blood (LDL, VLDL and chylous) and increasing the HDL / LDL ratio, can be performed by administering a vertebrate animal in need of such treatment and from about 1 to about 150 mg / kg body weight per day and preferably 5 to 100 rng / kg body weight of the body per day of fusaric acid. Non-limiting examples of DBH inhibitors which are preferred for use in the practice of the present invention are fusaric acid, disulfirane, 3-phenylpropargylamine and 5- (4'-chlorobutyl) -picolinic acid. The maximum dose of fusaric acid in humans is anticipated at approximately 2000 rng / patient / day.

If disulfirane is used, the general dose is about 50 about 9700 rng / kg body weight per day with 100-500 rng / kg being preferred. The maximum anticipated dose for humans is approximately 1200 rng / patient / day. If 3-phenylpropargylamine is used, the general dose is from about 10 to about 150 rng / kg body weight per day with 20-40 rng / kg body weight per day being preferred. The maximum anticipated dose for humans is approximately 5 g / patient / day. If 5- (4'-chlorobutyl) -picolinic acid or the DBH inhibitor is used, the general dose scale is between about 10 and 200 rng / kg body weight per day. The preferred dose scale is between about 20 and 40 mg / kg body weight / day. Other inhibitors of DBH with similar pharmacokinetic properties are anticipated to be used in comparable amounts on a molar basis. The amounts of other DBH inhibitors will have to be adjusted as is well known in the art based on their individual pharmacokinetic properties (see, for example, Benet et al., 1990, Pharmacokinetics: The Dynamics of Druq Absorption, Distribution and Eli Gil an and other Eds, the Pharmacological Basis of Therapeutics, Pergamon et al. Press, NY). In addition, it is expected that the amount of each compound will undergo optimization, but this will involve no more routine experimentation. Other DBH inhibitors that can be used in the practice of the invention include without limitation diethyldithiocarbamate, beta-chlorophenethylamine, 4-hydroxybenzyl cyanide, 2-halo-3- (p-hydroxyphenyl) -l-propene, 1-phenyl-1 -propyne, 2-phenylalanylamine, 2- (2-thienyl) allylamine and derivatives thereof such as 2-thiophene-2- (2-thienyl) allylamine, 3-phenylpropargylamine, 1-phenyl-1 (arninoethyl) ethene and derivatives thereof, such as n- (trifluoroacetyl) phenyl-KaminoetiDetene and 5-picolinic acid derivatives, such as 5- (4'-chlorobutyD-picolinic acid and other similarly alkyl- or haloalkyl-substituted 5-picolinic acids, for example, with Ci-Cß alkyl groups substituted by themselves optionally with one or more halogen atoms As used herein, the inhibition of DBH (or DBH inhibitory activity, or reducing DBH) refers to reducing the "in vivo" activity of the DBH enzyme and at least about 10%. A preferred embodiment involves administering a sufficient amount of a DBH inhibitor of the present invention to inhibit DBH in a subject in order to regulate or improve glucose or lipid metabolism. The amount effective to inhibit DBH (or the dose scale of inhibition of DBH) for the DBH inhibitors of the invention is available in the literature or can be readily ensured by administering increased levels of the DBH inhibitor to a patient until inhibition occurs. DBH (as measured by the patient's serum analysis). The effective amount (or dose) of fusaric acid to obtain 10% inhibition of DBH in humans is between about 0.7 and 1.5 mg / kg body weight per day. It is preferred that a DBH inhibitor be administered at a predetermined time for a period of 24 hours designed to reduce lipogenesis more preferably during a daily lipogenic interval when most of the fat is synthesized. The range is determined indirectly by measuring one or more plasma lipid values, preferably VLDL values at several separate times (for example 3 or 4) within all or a portion of a 24 hour period and determining the range when decreasing the circulation VLDL reaches a maximum and then begins to decline. In general, the increased lipogenesis interval precedes the increased VLDL interval in phase and occurs during the latter half of the subject's daily activity period (for humans, usually in the afternoon). However, it is preferred to do the measures described above, instead of depending on the general rule due to possible changes of this interval in subjects needing treatment. For example, the DBH inhibitor can be administered approximately 6-12 hours before the increase in VLDL values, or at the beginning of the daily activity / wake period. Since the time of administration will vary with the species to be treated (diurnal / nocturnal) and the dose and half-life of the DBH inhibitor, the 6-12 hour interval above can serve as a guide for further determinations. accurate. The effectiveness of the administration at a particular time is ensured by said indices such as triglyceride level, body fat, cholesterol level, VLDL level, etc. Alternatively, the DBH inhibitor can be administered at the beginning of the subject's daily activity period, (in humans within the range of 0700 to 1300) and the same indices can be measured only to ensure the effectiveness of the treatment (ie, it can be omit the determination of the lipogenesis interval as such). The glucose metabolism can also be altered by the administration of a DBH inhibitor, preferably by the "measured time" administration of the same, and the symptoms associated with type II diabetes can be reduced or eliminated as such. Instead of the lipid values, one or more appropriate ratios for glucose metabolism and / or type II diabetes should be measured (eg, glucose tolerance, glucose level, insulin level, insulin sensitivity, glycosylated hemoglobin) to determine an increased glucose production interval and / or to ensure the effectiveness of the treatment. The amounts and time measurement of DBH inhibitors to treat irregularities of glucose metabolism are generally the same as before.

In more detail, a preferred effective time for administering a DBH inhibitor is first identified. This can be achieved by routine experiment as described below, using one or more groups of animals (preferably at least 5 animals per group). In animals, lipogenic inhibition by treatment with DBH inhibitor can be assured by administering the inhibitor at a particular time of the day by determining the effect of administration (if any) by measuring one or more indices associated by lipogenesis (Meir, AH, Am. 3.

Physiol. , supra, 1977 or Cincotta, A.H. and other Horrn. lletabo1, Res., supra, 1989), and comparing the values of the subsequent treatment of these indexes with the values of the loe miemoe indicee antee of the treatment. A convenient first time to administer the DBH inhibitor is towards the beginning of the daily activity period of the host. If the chosen moment is sufficiently effective in reducing the rates of lipid etabolism, experimentation may stop. If the administration results are not satifactory, then the appropriate administration time is adjusted as follows: the DBH inhibitor can be administered to the same (or preferably another) group of animals at a different time of day and the same Indices can be inhibited, and compared with the first series of lipogenic index values and / or a series of previous treatment of lipogenic index variables.

The second test administration time is preferably 6-12 hours before (or after) the first time of test administration. Based on the difference of the index values, the second test period can be selected with the therapy time, or another (third) administration test time can be selected by interpolation (or extrapolation). For example, if a third tier is selected in Example 2 or 3 it would be around 1400 hours. At best, this time-determining experiment would need to be conducted four times. The duration of each test treatment is 2-14 days. The same procedure can be followed to determine a preferred effective rate of administration to affect glucose metabolism, i.e., a time of administration during the "window" or "interval" of glucose metabolism response. The present invention has also discovered that DBH inhibitors have more pronounced beneficial effects on aberrant glucose metabolism if they are administered at predetermined times (which may not have to be the same as the preferred times for altering lipid metabolism) during a period of 24 hours. Once it is over, a first time of administering test is selected and a test run is conducted for 2-14 days. If the result is not satisfactory (based on the comparison of the values of the glucose metabolic rates of pre-treatment and subsequent treatment) a second administration time is selected (and optionally a second group of animals is tested), and so on as described above for the treatment of aberrations of lipid metabolism. The proposal for determining a preferred effective administration time in a human is basically the same: a DBH inhibitor is administered daily to a human in need of modification of the lipid (or glucose) metabolism at a first moment of the day (for example to 0.7: 00h) for 2-14 days, preferably one week. The relevant rnetabolic indices are measured before, during, and after treatment. The measurement of these indices is done preferably at the same moment of the day (between 2:00 p.m. and 10:00 p.m.). If the selected treatment is effective, the time of the test administration is adopted as the treatment time for the human. If the selected time is not sufficiently effective (ie, does not produce significant changes, or produces an adverse change in the parameter or relevant metabolic parameters) then the administration at this moment is discontinued immediately and a different time is selected (6-12 hours before or after the first time). The test treatment and the rnetabolic index measurement are repeated afterwards. It should be noted that the time of mild start and duration of daylight as well as age, sex and physical condition and the activity / rest regime of the subject to be treated will influence the time or time at which the administration of the DBH inhibitor will be effective. In this way, it is very preferred to ensure an effective administration time for each individual, using the method described above. This is true in particular of humans who have diverse pictures of daily times. The amount of fusaric acid (or other DBH inhibitor) to be used depends in part on the duration of the interval or window of response of the increased lipid metabolism (or glucose metabolism response) and in part of the half-life of the compound used. For example, fusaric acid has a half-life of about 8-9 hours and therefore the above quantity scale is selected from about 1 to about 150 mg / kg. The half-life for 3-phenylpropargylamine and for 5- (4 * chlorobutyD-picolinic acid is approximately 6 hours) The precise time of administration and / or amount of DBH inhibitor that will produce the most effective results in terms of treatment efficacy in a given patient will depend on the activity, far acocysticity, and bioavailability of a particular compound, physiological condition of the patient (including age, sex, type and condition of disease, general physical condition, response to a given dose and type of medication), via of administration etc. However, the above guidelines can be used as the basis for the final refinement of the treatment, for example, determining the optimal time and / or amount of administration, which will require no more than the routine experimentation that consists in controlling a subject and adjust the dose and / or measurement of time.While the subject is being treated, the metabolism of lipid or glucose is controlled One or more of the relevant indexes at predetermined times during a 24-hour period. The treatment (amounts, administration times and type of medication) can be adjusted (optimized) in accordance with the results of said control. The patient (or other subject) is re-evaluated periodically to determine the degree of improvement by measuring the maximum number of parameters, the first re-evaluation that typically occurs at the end of four weeks from the start of therapy, and the re-evaluations increase in frequency. occurring every 4 to 8 weeks during therapy and after every 3 months. Therapy may continue for several months or even years, with a one-year period lasting a typical length of therapy for humans. Some patients (for example, patients in particularly poor physical condition, or those of advanced age) may require a longer or even continuous treatment with a DBH inhibitor. Adjustments to the amount of drug administered and possibly to the time of administration can be made based on this re-evaluation. For example, after 4 months of treatment one of the metabolic rates has not improved but at least one other index has improved, the dose can be increased by 1/3 without changing the time of administration. The adjustments will be further coded and fine-tuned on an individual basis and with reference to the pharmacokinetics of the agent used. In most cases, adjustment of drug time and quantity measurement is not considered necessary if the results (ie, improvement of the metabolic irregularity involved) are positive, ie, if a clinically significant improvement has been achieved. . In the treatment of non-human vertebrates, generally, the dose within the aforementioned scale of one or more DBH inhibitors, respectively, is read each, typically, over a period ranging from about 10 days to about 180 days. Longer treatment times are possible when a benefit is obtained. In the practice of this invention, a DBH inhibitor is administered daily to a subject preferably orally, or by subcutaneous, intravenous or intramuscular injection. Dermal assortment systems, for example, skin patches, as well as suppositories and other well-known systems for administering pharmaceutical agents such as by inhalation of an atomized solution may also be employed. Treatment with time measured with an inhibitor of DBH may have the additional benefit of reducing cholesterol levels, at the same time reducing HDL levels. As discussed above, such alteration is highly desired to reduce a subject's risk of developing atherosclerosis and subsequent heart disease. Suitable DBH inhibitors include substances that directly or indirectly block doparnin beta hydroxylase. Non-limiting examples include those given above, which are available commercially. The dose of said DBH inhibitors will generally be subject to optimization as outlined above. The dose optimization may be necessary independently if the administration time is exceeded by reference to the increased lipogenesis interval or not.

EFFECTS fl LONG TERM Another aspect of the invention is directed to the administration of a DBH inhibitor (e.g., fusaric acid) to produce long-term, long-lasting or even permanent effects on lipid and / or glucose metabolism by the administration of daily doses with time measured to a vertebrate, animal or human, of a DBH inhibitor. Doses continue on a daily basis for a period sufficient to cause the beneficial effects on lipid and / or glucose metabolism to persist. This gives rise to the readjustment of the phase of at least one major circadian neuroendocrine rhythm (for example, the central neural oscillator expressed by the circadian rhythm of circulating prolactin) in the subject being treated, in that the phase and amplitude of the rhythm of prolactin is modified to reassemble that for a healthy, thin, young subject of the same species (and, if applicable, of the same sex), that is, it moves closer to that illustrated in figure 1. This change in Phase and amplitude can be ensured by comparing the prolactin values of pretreatment at various times of the day before and after treatment. (See, for example, applications 07 / 995,292 or 08 / 264,558). The range of increased lipogenic activity (or reduced glycogenesis) of the subject can be related to the rhythm of the daily prolactin level of the subject. Essentially, any change in secretion, or blood level, or any hormone or other phenomenon that occurs in a circadian pattern and constitutes an expression of a central neural oscillation can be used to control the alterations in the central neural oscillation it expresses. Examples include prolactin, cortisol, thyrotropin, insulin, and body temperature without limitation. The readjustment of circadian rhythms occurs if the administration of the DBH inhibitor (at a predetermined time) continues for a period, generally of at least about 10 days, preferably several months (eg, typically 6 meeee for humans). The readjustment has occurred if the beneficial effect (s) on glucose / lipid metabolism persists on a long-term basis (eg, months and even years) after discontinuing the drug (s). ). The amount, periods and previous administration times are the same as before. The doses of the inhibitor can be adjusted in accordance with the results they produce in terms of lipid values (or glucose metabolism indices), as described above. These and other features of the invention will be better understood by reference to the experiments described in the examples below. In the examples the terminology "LD" refers to the light / dark cycle, the first number after the expiry LD refers to the hours of light, and the second to the hours of darkness in the cycle. In this way, LD 14:10 refers to a cycle that has 14 hours of light and 10 hours of darkness, and the period of one day is expressed in terms of 2400 hours. "BU" denotes peeo of the body, g repreeenta grams, and mg represents milligrams. All reagents and materials are commercially available. It should be noted that the Sprague-Da? Ley rat is a good and reliable model for conditions of resistance to obesity and insulin in humans.

EXAMPLE 1; EFFECTS OF THE ADMINISTRATION OF ACID FUSARICQ AD LIBITUM IN VARIOUS METABOLIC INDEXES IN MACHO SPRAGUE-DAULEY RATS Eighteen male Sprague-Dawley rats (7.5 months old) were given feed for untreated rodent (Purina) or food treated with fusaric acid (5 rng / kg BU / day, Sigrna Chemical, St. Louis) ad libitun for 2 days. weeks Eighteen days after the last day of treatment, blood samples were taken every eight hours over a period of twenty-four hours at the power-up (0700, LD 12:12) in order to obtain overall daily mean concentrations of the measured parameters. The rats fasted for six hours before the blood sample, sacrifice and measurement of retroperitoneal fat. Triglycerides were determined in plasma, total cholesterol and glucose concentrations using diagnostic equipment obtained from Sigma. The concentration of cholesterol in the plasma was determined, after precipitation of foefogentisic acid from another lipoprotein, using equipment obtained from Sigma. The concentration of ineulin in the plasma was determined using a radioimmunoassay kit of double antibody obtained from ICN Biochemicals (Irvine, CA). The food intake was monitored at regular intervals of 3 days throughout the study.

TABLE 1 EFFECT OF THE ADMINISTRATION OF ACID FUSARICQ AD LIBITUM IN GREASE OF THE RETROPERITONEAL BODY AND VARIOUS METABOLIC INDEXES Fusaric Acid Control Fat retroper. (g) 3.75 ± 0.18i'2 2.33 ± 0.07 * Triglyceride in 199 ± 15 11B ± 8 «plasma (rng / dL) Cholesterol in 107 + 6 109 + 7 plasma (rng / dL) Glucose in 214 ± 8 140 ± 6"plasma (rng / rnL) Insulin in 189 ± 8 IOI ± IO» plasma (μU / mL) i Mean error ± nor to the mean (n = 9 / group). 2 Food consumption was not significantly different between the groups. »Differ significantly from control (P <0.05).

Treatment of fusaric acid resulted in significant reductions in retroperitoneal fat (38%), as well as in plasma concentrations of triglycerides (41%), glucose (35%), and insulin (47%) (TABLE 1). These reductions represent significant improvements in glucose and lipid metabolism (ie, reduction in insulin resistance) that persist most after discontinuing treatment.

EXAMPLE 2: EFFECTS OF FUSEPLIC ACID ADMINISTRATION WITH TIME MEASURED IN VARIOUS METABOLIC INDICES IN RATAS MACHO SPRflGUE- DAULEY Thirty-four male Sprague-Dawley rats (9 months old) were divided into 3 groups of 11-12 rats each. Two groups were provided with an oral dose of fusaric acid (5 mg / Kg B.W in 1 rnL of peanut butter) when the light came out or went in (LD 12:12, lights in 0700). A dosie of 1 ml of peanut butter was only given at the alternative time of day. A control group received 1 ml of peanut butter at both times (exit and entry of light). Rat food (Purina) was available for all the groups ad libitum. Lae rats were treated for 2 weeks. Nineteen days after the last day of treatment, 7-8 animals from each group were randomly selected for blood meal and fat measurements (retroperitoneal and epididymal). As described in Example 1, 2-3 animals of each group were sacrificed every 8 hours at the beginning of the light output. All the animals fasted for 6 hours before the blood sample and sacrifice. The concentrations of triglyceride, total cholesterol, glucose and insulin in the plasma were measured as described in example 1.

TABLE 2 EFFECT OF THE FUSARY ACID ADMINISTRATION WITH MEASURED TIME IN GREASE STORAGE AND VARIOUS METABOLIC INDICES IN THE MACHO SPRRGUE-DflULEY RATS Fusaric Acid Control Fusaric Acid (1900) (0700) Retro fat- 4.63 ± 0.271.2 3.19 ± 0.50 * 3.18 ± 0.50 * per. (g) Fat epidi 7.47 ± 0.44 5.16 + 0.57 »5.67 + 0.50 * mal (g) Triglyceride 149 ± 22 104 ± 23 113 ± 9» in plasma (rng / dL) Cholesterol 172 ± 10 175 ± 12 132 ± 23 ». * > in plasma (mg / dL) Glucose 159 ± 6 160 ± 12 108 ± 14 «.b in plasma (mg / dL) Insulin 178 ± 11 157 ± 9 113 ± 5« .b in plasma (μU / rnL) i Mean ± normal error of the medium (n = 7-8 / group). 2 Food consumption was not significantly different between the groups. • Differ significantly from control (P <0.05). b It differs significantly from the time of administration of 0700.

The experiment reported in this example was designed to test the differences in the effectiveness of fusaric acid based on the time of administration. Times were selected to identify the fusaric acid treatment towards (1900) or far (0700) of the peak range of lipogenic and glycogenic activity in the healthy Sprague-Dawley rat. Both fusaric acid treatment times were equally effective in producing significant reductions in retroperitoneal and epididymal fat stores (both were reduced by approximately 30%) (TABLE 2). However, only the administration time of 1900 hours significantly reduced the concentrations of cholesterol, glucose and insulin in the plasma compared to the control and administration of 0700 hours. These results underscore the additional benefit of the appropriate time measurement in the administration of barium acid. Only the time of 1900 simultaneously reduced the storage of fat in the body together with reductions in the indices associated with diabetes mellitus dependent on ineulin.

EXAMPLE 3: INDIRECT (LONG-TERM) INDIRECT EFFECT OF THE ADMINISTRATION WITH MEASURED TIME OF FUSICAL ACID IN METHODOLOGICAL INDICES 3 MONTHS AFTER THE CESSATION OF TREATMENT Three months after the cephalotherapy treatment was performed, blood samples were taken from the remaining 4 animals in control and treatment groups described in Example 2. Blood samples were taken over a period of twenty-four hours in order to obtain Mean global daily concentrations of triglyceride, cholesterol, glucose and insulin in the plasma. All measurements were made in accordance with the methodologies described in Example 1.

TABLE 3 EFFECTS OF FUSARY ACID ADMINISTRATION ON METABOLIC INDICES 3 MONTHS AFTER THE CESSATION OF TREATMENT Fueric Acid Fusaric Acid Control (0700) (1900) Triglyceride 164 + 41 180 ± 7 117 ± 10 ». < > in plasma (mg / dL) Cholesterol 162 ± 4 186 ± 5 »139 ± 6 * > < > in plasma (mg / dL) Insulin 165 ± 10 143 ± 6 107 ± 6 *. < > in the plasma (μU / nL) i Mean ± normal error of the medium (n = 4 / group). * Differ eignificativamente of the control (P <0.05). * > It differs eignificantly from the group of 0700 (P < 0.05) Tree months after cessation of treatment, plasma triglyceride, cholesterol and insulin concentrations were significantly reduced in the 1900 fusaric acid treatment group compared to the control or 0700 group (p <0.05). In fact, the values in the plasma for these parameters (group of 1900) were not significantly different from those obtained only 2.5 weeks after treatment. However, the treatment of fusaric acid of 0700 hours did not reduce triglyceride, cholesterol or insulin levels compared to controls. 3.5 months after cessation of treatment, blood samples from individual rats (n = 3) and rats treated with fusaric acid (0700, n = 4; 1900, n = 4) were again used to determine concentrations of blood. of prolactin in the plasma. Samples were taken by puncture in the orbital cavity starting at the beginning of the light (0700) and continuing every 4 hours after a period of 24 hours. Prolactin was measured in the plasma using an antibody and a rat prolactin standard provided by the National Pituitary program. 3.5 months after treatment, overall mean prolactin levels in the treated group of 1900 (8.3 ng / nL, Figure 2b) were significantly reduced compared to the controls (22 ng / mL, Figure 2d) and similar to the controls of prolactin from young, healthy rats of 8 eemanae that are thin and sensitive to ineulin (9.2 ng / rnL, Figure 2c). The level of prolactin in the treated group of 0700 (19.8 ng / mL, Figure 2a) were similar to those of the 50 week insulin resistant controls (22 ng / mL). In addition, the prolactin profile of the treated group of 1900 reached the profile of young, thin, insulin-resistant rats although at the time of the prolactin test the members of the 1900-treated group had 50 weeks. This experiment provides proof that fusaric acid administered at the appropriate time adjusts the profile of prolactin to a profile that reaches that of a healthy, young individual and readjusts the prolactin rhythm, as long as the modified profile favorably persists for a period of time. considerable after cessation of treatment with time measured with fusaric acid. These effects of fusaric acid treatment with time appropriately measured demonstrate long-term improvements in metabolic conditions associated with non-ineulin-dependent diabetes mellitus that persist longer after the treatment is ceased. The invention was described above with reference to the preferred embodiments. However, in view of this description, it will be apparent to those skilled in the art that many omissions, additions and modifications are possible within the scope of the following claims.

Claims (21)

NOVELTY OF THE INVENTION CLAIMS

1. Use of a compound that has the property of inhibiting DBH for the preparation of a medicament for the modification of glucose metabolism in a vertebrate animal or human subject, the medicament being administered to said vertebrate animal or human subject at a predetermined time.

2. The use according to claim 1, further characterized in that said administration is effective to achieve at least one of the following: i) reduce hyperglycemia, ii) reduce glucose intolerance; iii) reduce insulin resistance; and iv) reduce hyperinsulinernia.

3. The use according to claim 1, further characterized in that said compound is selected from the group consisting of fusaric acid, disulfirane, diethyldithiocarbamate, beta-chlorophenethylamine, 4-hydroxybenzyl cyanide, 2-halo-3- ( p-hydroxyphenyl) -l-propene, 1-phenyl-1-propynyl, 2-phenylallylamine, 2- (2-thienyl) allylamine, 2-thiophene-2- (2-thienyl) allylamine, 3-phenylpropargylamine, 1-phenyl -Ka inoetiDetene, N- (trifluoroacetyl) phenyl (aminoethyl) ethene and 5-picolinic acid substitued with an alkyl or haloalkyl group containing up to 6 carbon atoms, prodrugs and metabolites thereof, and pharmaceutically acceptable salts thereof.

4. - The use according to claim 1, further characterized in that said DBH inhibitor is fusaric acid and the subject is a human subject.

5. The use according to claim 4, further characterized in that said predetermined time is within the range of about 07:00 hours to about 13:00 hours.

6. The use according to claim 5, further characterized in that it comprises administering said composition in an amount that provides said inhibitor of DBH in an amount between about 1 to about 150 ng per kg body weight per day.

7. The use according to claim 5, further characterized in that it comprises administering multiple multiples within said time interval.

8. The procedure according to claim 4, further characterized in that said predetermined time precedes the interval of increased lipogenesis in the subject by 6-12 hours.

9. Ueo of a coetate which has the property of inhibiting the enzyme dopamine beta hydroxylase for the preparation of a medicament for the improvement of glucose or lipid irregularity in a vertebrate animal or a human subject, the medicament being administered to said subject at a predetermined time.

10. The use according to claim 9, further characterized in that said administration is effective to achieve at least one of the following: reduction of hyperglycemia; reduction of glucose intolerance; reduction of insulin resistance and reduction of hyperinsulinemia.

11. The use according to claim 10, further characterized in that said irregularity of glucose metabolism is diabetes? obesity.

12. The use according to claim 11, further characterized in that said DBH inhibitor is fusaric acid and the subject is a human subject.

13. The use according to claim 12, characterized in that said predetermined time is within the range of about 07:00 am to about 13:00 am.

14. The use according to claim 13, further characterized in that it comprises administering said composition in an amount that provides said DBH inhibitor in an amount between about 1 to approximately 150 g per kg body weight per day.

15. The use according to claim 13, further characterized in that it comprises injecting multiple multiples within said time interval. 16.- Ueo of a member selected from the group consisting of fusaric acid, disulfirane, diethyldithiocarbamate, beta-chlorophenethylamine, 4-hydroxybenzyl cyanide, 2-halo-3- (p-hydroxyphenyl) -l-propene, 1-phenyl-l-propynyl, 2-femlal? Larn? Na, 2- (2-t? In? L) al? Larnin, 2-thiophene-2- (2-t? In? L) al? Larnma , 3-fen lproparg? Lam? Na, 1-fen? L-KammoetiDeteno, N- (tpfluoroacet? L) feniKammoetiDeteno and 5-p? Col? N? Co acid substituted with an alkyl or halo-alkyl group that with + iene up to 6 carbon atoms, prodrugs and metabolites thereof, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the modification of the lipid metabolism in a vertebrate animal or its human e + or, the composition being administered to said animal or subject at a predetermined time in an effective amount to inhibit the activity of DBH in said animal or human. 17. The use according to claim 9, further characterized in that it comprises administering said composition containing the DBH inhibitor to reduce the storage of fat in the body. 18. The use according to claim 9, further characterized in that it comprises injecting said composition containing the DBH inhibitor to increase the HDL in the plasma. 19. The use according to claim 9, further characterized in that it comprises administering said composition containing the DBH inhibitor to reduce hyperlipidernia. 20. The use according to claim 9, further characterized in that it comprises administering said composition containing the DBH inhibitor to reduce elevated lipoproteins in the blood. 21. The use according to claim 9, further characterized in that said predetermined time is the beginning of the daily activity period of the subject.