Method of producing anorexia as a treatment for obesity
United States Patent 3867539
A method of suppressing the appetite as a treatment for obesity by internally administering histidine or a pharmaceutically acceptable non-toxic salt thereof.
US Patent References:
/3632774.html
Gerber - January 1972 - 3632774
/3697287.html
Winitz - October 1972 - 3697287
/3632774.html
Gerber - January 1972 - 3632774
/3697287.html
Winitz - October 1972 - 3697287
Application Number:
05/355296
Publication Date:
02/18/1975
Filing Date:
04/27/1973
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Export Citation:
Assignee:
The United States of America as represented by the Secretary Department (Washington, DC)
Primary Class:
Other Classes:
514/910
International Classes:
A61K31/195; A61K31/185; A61K27/00
Field of Search:
424/269,319,273
Primary Examiner:
Friedman, Stanley J.
Assistant Examiner:
Drezin, Norman A.
Claims:
1. A method for suppressing the appetite of humans which consists essentially of internally administering to an obese patient an effective anorexigenic amount of histidine or a pharmaceutically acceptable
2. The method of claim 1 wherein said histidine is administered orally in a dosage of from about 1 to about 32 grams, calculated as free base, daily.
2. The method of claim 1 wherein said histidine is administered orally in a dosage of from about 1 to about 32 grams, calculated as free base, daily.
Description:
This invention relates to anorexigenic agents and to a method for suppressing appetite by the internal administration thereof.
Various therapeutic agents have previously been employed in the treatment of obese individuals in order to decrease their appetite so as to assist them in enduring a weight-reducing program. The most widely used agent for this purpose has been d-amphetamine. This compound, however, being a central nervous system stimulant, produces some undersirable and unpleasant side effects, including, for example, nervous tension, insomnia, headache, palpitations and elevation of blood pressure. Hence, this compound has been found to be unsuitable for use with many patients.
In accordance with the present invention, it has been found that the internal administration to human patients of the amino acid histidine has an anorexigenic or appetite-suppressing effect without producing the undersirable side effects associated with the previously employed anorexigenic agents, and hence is highly effective in the treatment of obesity.
The histidine, which is preferably L-histidine but may also be D-histidine, DL-histidine or mixtures thereof, may be employed either as the free base or in the form of various pharmaceutically acceptable, non-toxic, water-soluble salts thereof. Examples of such salts are the mono- or di-hydrochlorides, sulphates and phosphates, and such non-toxic alkaline metal salts as the potassium and sodium salts.
Anorexigenic pharmaceutical preparations may conveniently and easily be produced by compounding the histidine or a pharmaceutically acceptable salt thereof with conventional inert pharmaceutical carriers into dosage forms which are suitable for oral or parenteral administration, in accordance with conventional manufacturing processes common in the art. Such dosage forms include tablets, capsules, suspensions, solutions, and the like. Among the various pharmaceutical carriers that may be employed for this purpose are lactose, starch, gelatin, talc, magnesium stearate, stearic acid, gums, water, saline solution, glucose solution, and the like.
The daily dosage of histidine which are effective in producing anorexia may be varied within a relatively wide range and, to some extent, are dependent upon the needs and requirements of the individual patient. It has been found, however, that as a general rule, the daily administration of from about 1 to about 32 grams of histidine, calculated as free base, will prove to be effective. Preferably the histidine is orally administered to the patient in suitable dosage forms containing from about 0.5 to about 16 grams of histidine per dosage unit, one to three times a day as conditions demand, desirably before meals. Under ordinary circumstances, a suitable oral dosage form containing about 8.1 grams of histidine, administered twice a day before meals for a total daily dose of about 16.2 grams, will prove to be effective for producing anorexia without any undesirable side effects. Moreover, at this dosage level, normal appetite will generally return within 24 to 48 hours following discontinuation of the treatment.
Although the precise mechanism by which the administration of histidine produces anorexia is not fully understood, it is believed to be at least in part related to the ability of histidine to complex loosely bound zinc in the plasma, thereby upsetting normal zinc transport and storage processes in the body. Such reaction is evidenced by increased urinary zinc excretion observed in patients treated with histidine in accordance with the invention.
As illustrative embodiments of the invention, the following examples are presented to illustrate the anorexigenic effect produced in patients treated with histidine in accordance with this invention.
Example 1
A patient was placed on a constant 9 mEq Na + diet with 100 mEq of Na + added in a salt shaker and a fixed amount of distilled water, the daily amount set by the patient. The patient was then studied for two control days during which two daily blood samples and total excretion of urine for all 24 hour periods were collected and zinc and copper measured. Mean control values for serum zinc and copper concentrations were 85 and 130 μg/ 100 ml, respectively; mean control values for urinary zinc and copper excretion were 950 and 35 μg/24 hours, respectively. On the third and fourth days of the study 8.1 gm L-histidine was administered orally, once daily, in pears, without any resultant change in either serum zinc or copper concentrations but with a significant increase in urinary zinc excretion to 1123 μg/24 hours. No change in any clinical parameters occurred at the end of these two days. On the fifth and sixth days of the study, 8.1 gm L-histidine was administered orally, twice daily, in pears, for a total daily dose of 16.2 gm, without any significant change in either serum zinc or copper concentrations but with a further increase in urinary zinc excretion to 1,490 μg/24 hours. On the morning of the sixth day of the study, at breakfast, the patient became aware of a marked loss of appetite resulting in his wish to avoid food. This symptom was very unusual for him. Following discontinuation of the L-histidine, urinary zinc excretion and appetite returned to normal within 24-48 hours. No other side effects were noted.
Example 2
A patient was placed on a constant 9 mEq NA + diet with 100 mEq of Na + added in a salt shaker and a fixed amount of distilled water, the daily amount set by the patient. The patient was then studied for two control days during which two daily blood samples and total excretion of urine for all 24 hour periods were collected and zinc and copper measured. Mean control values for serum zinc and copper concentrations were 77 and 90 μg/100 ml, respectively; mean control values for urinary zinc and copper excretion were 550 and 34 μg/24 hours, respectively. On the third and fourth days of the study, 8.1 gm L-histidine was administered orally, once daily, in pears, without any resultant change in either serum zinc or copper concentrations but with a significant increase in urinary zinc excretion to 765 μg/24 hours. On the fourth day of the study, while on 8.1 gm L-histidine daily, the patient at lunchtime noted the onset of anorexia which caused him to omit eating his potatoes, something he had never done before, while well, in his life. On the fifth and sixth days of the study, 8.1 gm L-histidine was administered orally, twice daily, in pears, for a total daily dose of 16.2 gm, without any significant change in either serum zinc or copper concentrations but with a further increase in urinary zinc excretion to 1,100 μg/24 hours. The patient's anorexia persisted during these two days of the study but did not increase in severity. Following discontinuation of the L-histidine urinary zinc excretion and appetite returned to normal within 24-48 hours. No other side effects were noted.
Example 3
A patient was placed on a constant 9 mEq Na + diet with 100 mEq of Na + added in a salt shaker and a fixed amount of distilled water, the daily amount set by the patient. The patient was then studied for two control days during which two daily blood samples and total excretion of urine for all 24 hour periods were collected and zinc and copper measured. Mean control values for serum zinc and copper concentrations were 100 and 102 μg/100 ml, respectively; mean control values for urinary zinc and copper excretion were 315 and 41 μg/24 hours, respectively. On the third and fourth days of the study, 8.1 gm L-histidine was administered orally, once daily, in pears, with a decrease in serum zinc concentration to 89 μg/100 ml and an increase in urinary zinc excretion to 630 μg/24 hours. No change in any clinical parameters occured at the end of these two days. On the fifth and sixth days of the study, 8.1 gm L-histidine was administered orally, twice daily, in pears, for a total daily dose of 16.2 gm, without any significant change in serum zinc concentration to 87 μg/100 ml and a further increase in urinary zinc excretion to 950 μg/24 hours. On the evening of the sixth day of the study, at dinner, the patient became aware of a marked loss of appetite resulting in his wish to avoid food. This symptom was very unusual for him. Following discontinuation of the L-histidine urinary zinc excretion and appetite returned to normal within 24-48 hours. No other side effects were noted.
In addition to the mechanism previously stated with respect to the manner by whic histidine functions in the product of anorexia histidine also accumulates in hypothalamic regions of the brain in and near area which exercise some control over appetite and food intake. In this sense histidine may suppress appetite and food intake either by a direct inhibitor effect on these brain centers or through an indirect effect on zinc levels in these areas of the brain.
Various therapeutic agents have previously been employed in the treatment of obese individuals in order to decrease their appetite so as to assist them in enduring a weight-reducing program. The most widely used agent for this purpose has been d-amphetamine. This compound, however, being a central nervous system stimulant, produces some undersirable and unpleasant side effects, including, for example, nervous tension, insomnia, headache, palpitations and elevation of blood pressure. Hence, this compound has been found to be unsuitable for use with many patients.
In accordance with the present invention, it has been found that the internal administration to human patients of the amino acid histidine has an anorexigenic or appetite-suppressing effect without producing the undersirable side effects associated with the previously employed anorexigenic agents, and hence is highly effective in the treatment of obesity.
The histidine, which is preferably L-histidine but may also be D-histidine, DL-histidine or mixtures thereof, may be employed either as the free base or in the form of various pharmaceutically acceptable, non-toxic, water-soluble salts thereof. Examples of such salts are the mono- or di-hydrochlorides, sulphates and phosphates, and such non-toxic alkaline metal salts as the potassium and sodium salts.
Anorexigenic pharmaceutical preparations may conveniently and easily be produced by compounding the histidine or a pharmaceutically acceptable salt thereof with conventional inert pharmaceutical carriers into dosage forms which are suitable for oral or parenteral administration, in accordance with conventional manufacturing processes common in the art. Such dosage forms include tablets, capsules, suspensions, solutions, and the like. Among the various pharmaceutical carriers that may be employed for this purpose are lactose, starch, gelatin, talc, magnesium stearate, stearic acid, gums, water, saline solution, glucose solution, and the like.
The daily dosage of histidine which are effective in producing anorexia may be varied within a relatively wide range and, to some extent, are dependent upon the needs and requirements of the individual patient. It has been found, however, that as a general rule, the daily administration of from about 1 to about 32 grams of histidine, calculated as free base, will prove to be effective. Preferably the histidine is orally administered to the patient in suitable dosage forms containing from about 0.5 to about 16 grams of histidine per dosage unit, one to three times a day as conditions demand, desirably before meals. Under ordinary circumstances, a suitable oral dosage form containing about 8.1 grams of histidine, administered twice a day before meals for a total daily dose of about 16.2 grams, will prove to be effective for producing anorexia without any undesirable side effects. Moreover, at this dosage level, normal appetite will generally return within 24 to 48 hours following discontinuation of the treatment.
Although the precise mechanism by which the administration of histidine produces anorexia is not fully understood, it is believed to be at least in part related to the ability of histidine to complex loosely bound zinc in the plasma, thereby upsetting normal zinc transport and storage processes in the body. Such reaction is evidenced by increased urinary zinc excretion observed in patients treated with histidine in accordance with the invention.
As illustrative embodiments of the invention, the following examples are presented to illustrate the anorexigenic effect produced in patients treated with histidine in accordance with this invention.
Example 1
A patient was placed on a constant 9 mEq Na + diet with 100 mEq of Na + added in a salt shaker and a fixed amount of distilled water, the daily amount set by the patient. The patient was then studied for two control days during which two daily blood samples and total excretion of urine for all 24 hour periods were collected and zinc and copper measured. Mean control values for serum zinc and copper concentrations were 85 and 130 μg/ 100 ml, respectively; mean control values for urinary zinc and copper excretion were 950 and 35 μg/24 hours, respectively. On the third and fourth days of the study 8.1 gm L-histidine was administered orally, once daily, in pears, without any resultant change in either serum zinc or copper concentrations but with a significant increase in urinary zinc excretion to 1123 μg/24 hours. No change in any clinical parameters occurred at the end of these two days. On the fifth and sixth days of the study, 8.1 gm L-histidine was administered orally, twice daily, in pears, for a total daily dose of 16.2 gm, without any significant change in either serum zinc or copper concentrations but with a further increase in urinary zinc excretion to 1,490 μg/24 hours. On the morning of the sixth day of the study, at breakfast, the patient became aware of a marked loss of appetite resulting in his wish to avoid food. This symptom was very unusual for him. Following discontinuation of the L-histidine, urinary zinc excretion and appetite returned to normal within 24-48 hours. No other side effects were noted.
Example 2
A patient was placed on a constant 9 mEq NA + diet with 100 mEq of Na + added in a salt shaker and a fixed amount of distilled water, the daily amount set by the patient. The patient was then studied for two control days during which two daily blood samples and total excretion of urine for all 24 hour periods were collected and zinc and copper measured. Mean control values for serum zinc and copper concentrations were 77 and 90 μg/100 ml, respectively; mean control values for urinary zinc and copper excretion were 550 and 34 μg/24 hours, respectively. On the third and fourth days of the study, 8.1 gm L-histidine was administered orally, once daily, in pears, without any resultant change in either serum zinc or copper concentrations but with a significant increase in urinary zinc excretion to 765 μg/24 hours. On the fourth day of the study, while on 8.1 gm L-histidine daily, the patient at lunchtime noted the onset of anorexia which caused him to omit eating his potatoes, something he had never done before, while well, in his life. On the fifth and sixth days of the study, 8.1 gm L-histidine was administered orally, twice daily, in pears, for a total daily dose of 16.2 gm, without any significant change in either serum zinc or copper concentrations but with a further increase in urinary zinc excretion to 1,100 μg/24 hours. The patient's anorexia persisted during these two days of the study but did not increase in severity. Following discontinuation of the L-histidine urinary zinc excretion and appetite returned to normal within 24-48 hours. No other side effects were noted.
Example 3
A patient was placed on a constant 9 mEq Na + diet with 100 mEq of Na + added in a salt shaker and a fixed amount of distilled water, the daily amount set by the patient. The patient was then studied for two control days during which two daily blood samples and total excretion of urine for all 24 hour periods were collected and zinc and copper measured. Mean control values for serum zinc and copper concentrations were 100 and 102 μg/100 ml, respectively; mean control values for urinary zinc and copper excretion were 315 and 41 μg/24 hours, respectively. On the third and fourth days of the study, 8.1 gm L-histidine was administered orally, once daily, in pears, with a decrease in serum zinc concentration to 89 μg/100 ml and an increase in urinary zinc excretion to 630 μg/24 hours. No change in any clinical parameters occured at the end of these two days. On the fifth and sixth days of the study, 8.1 gm L-histidine was administered orally, twice daily, in pears, for a total daily dose of 16.2 gm, without any significant change in serum zinc concentration to 87 μg/100 ml and a further increase in urinary zinc excretion to 950 μg/24 hours. On the evening of the sixth day of the study, at dinner, the patient became aware of a marked loss of appetite resulting in his wish to avoid food. This symptom was very unusual for him. Following discontinuation of the L-histidine urinary zinc excretion and appetite returned to normal within 24-48 hours. No other side effects were noted.
In addition to the mechanism previously stated with respect to the manner by whic histidine functions in the product of anorexia histidine also accumulates in hypothalamic regions of the brain in and near area which exercise some control over appetite and food intake. In this sense histidine may suppress appetite and food intake either by a direct inhibitor effect on these brain centers or through an indirect effect on zinc levels in these areas of the brain.