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WO2002001956A1 - Histidyl-proline diketopiperazine et procede d'utilisation associe - Google Patents

Histidyl-proline diketopiperazine et procede d'utilisation associe Download PDF

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Publication number
WO2002001956A1
WO2002001956A1 PCT/US2000/018123 US0018123W WO0201956A1 WO 2002001956 A1 WO2002001956 A1 WO 2002001956A1 US 0018123 W US0018123 W US 0018123W WO 0201956 A1 WO0201956 A1 WO 0201956A1
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administered
alcohol
histidyl
composition
stereoisomer
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PCT/US2000/018123
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English (en)
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Chandan Prasad
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Priority to PCT/US2000/018123 priority Critical patent/WO2002001956A1/fr
Priority to AU2000259049A priority patent/AU2000259049A1/en
Publication of WO2002001956A1 publication Critical patent/WO2002001956A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K38/05—Dipeptides
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines

Definitions

  • This invention relates to the composition and use of histidyl-proline diketopiperazine and analogues thereof for attenuating the desire for alcohol.
  • Alcoholism is a major public health problem responsible for large scale morbidity and mortality and can be defined as a chronic psychiatric disorder in which a pattern of pathological alcohol use leads to serious personal and physical distress. Alcohol addiction or dependence implies a loss of control over the desire to consume ethanol. Between 80% and 90% of the population in the United States drink alcohol at some time during their lives and 30% to 40% of these may develop some temporary alcohol related problems.
  • Treatments that are used may be classified as either psychotherapy or psychopharmacology.
  • Psychotherapies include counseling, participation in self help groups such as Alcoholics Anonymous, and the like.
  • the generally recognized psychopharmacological treatment of ethanol withdrawal symptoms and physical changes is the administration of a mild tranquilizer such as chlordiazepoxide.
  • vitamins, in particular the B vitamins are administered.
  • magnesium sulfate and/or glucose are also administered. While alcohol withdrawal rarely precipitates a major medical problem, alcoholic relapse after discharge of a patient from the controlled setting is very frequent.
  • long term pharmacotherapies generally include an alcohol deterring agent in the treatment of alcoholics.
  • Disulfiram functions as an aldehyde dehydrogenase inhibitor.
  • disulfiram When taken with alcohol, disulfiram induces a highly unpleasant condition called the disulfiram-alcohol reaction (DAR).
  • DAR disulfiram-alcohol reaction
  • This highly unpleasant condition is due to the accumulation of acetaldehyde, an intermediate metabolite of alcohol.
  • the symptoms of DAR include altered blood pressure, pulse rate, respiration rate, flushing, heat sensation, nausea, vomiting , palpitations, breathlessness and headaches.
  • the cyclic dipeptide endogenous to mammals, is ubiquitously distributed throughout the central nervous system and has been shown to elicit a number of endocrine and central nervous system-related biological functions including: elevation of brain cyclic GMP concentrations; inhibition of ethanol induced sleep; decrease in food intake; hypothermia in rats; attenuation of ketamine-induced anesthesia; inhibition of dopamine uptake by rat brain striatal synaptosomes; and inhibition of prolactin secretions in vitro.
  • histidyl-proline diketopiperazine can be useful for treating the cessation or withdrawal from the use of alcohol.
  • histidyl-proline diketopiperazine has been found to reduce the desire for alcohol.
  • the dosages required to attenuate the desire for alcohol are generally less than those dosages used for effecting appetite or water suppression.
  • the present invention is directed to a method for attenuating the desire for alcohol in a mammal comprising administering to such mammal in need thereof, a composition comprising histidyl-proline diketopiperazine and analogues thereof in an amount effective to attenuate the desire for alcohol.
  • Histidyl-proline diketopiperazine and analogues thereof are easily administered, safe to use and without any of the deleterious side effects associated with alcohol deterrents, i.e. disulfiram.
  • the composition may be administered in combination with alcohol deterrents, such as disulfiram, at doses lower than traditionally prescribed, thereby avoiding the problems associated with taking those drugs alone.
  • a method of attenuating the desire for alcohol comprises administering to a mammal in need thereof, an alcohol attenuating composition comprising histidyl-proline diketopiperazine in an amount wherein the appetite is not suppressed.
  • an alcohol attenuating composition comprising histidyl-proline diketopiperazine in an amount wherein the appetite is not suppressed.
  • Proper diet is generally encouraged in patients for effectively treating alcohol abuse.
  • compositions comprising histidyl- proline diketopiperazine are process selective in that it can reduce dependence on alcohol, but not food and water consumption.
  • the inventive composition can be administered by those methods known to those skilled in the art.
  • Methods of administration include, but are not limited to, enteral, parenteral, oral, nasal or transdermal administration.
  • Histidyl-proline diketopiperazine and analogues thereof are comprised of amino acids and as such exhibit a low immunogenic response and are considered generally nontoxic.
  • the composition can be safely administered in an amount ranging from about 1 g/kg of body weight per day to about 1,000,000 g/kg of body weight per day for reducing alcohol desire. More preferably the composition is administered orally from about 1 g/kg of body weight per day to about 50000 g/kg of body weight per day for reducing alcohol desire wherein appetite is not suppressed.
  • Parenteral administration is generally 20-30% less than the oral dosage amounts as would be known to those of ordinary skill in the art in view of this disclosure.
  • the present invention relates to a method for attenuating the desire for alcohol in a mammal by administering to such mammal in need thereof, an effective amount of histidyl-proline diketopiperazine and a pharmaceutical carrier to attenuate the desire for alcohol.
  • Histidyl-proline diketopiperazine also known as cyclo (His-Pro) or CHP, is a cyclic dipeptide of histidine and proline and is derived in the mammalian body by limited proteolysis of thyrotropin releasing hormone (TRH) through the action of the brain enzyme pyroglutamyl peptidase.
  • TRH thyrotropin releasing hormone
  • the cyclic dipeptide can be obtained by synthesis from the requisite amino acids as is known to those of ordinary skill in the art, for example, as disclosed in C. Prasad, T. Matsui, A. Peterkofsky, Antagonism of Ethanol Narcosis by Histidyl-Proline Diketopiperazine, Nature, Lond. 268: 142-144, 1977, incorporated herein by reference.
  • CHP is structurally unrelated to any presently used agent in the treatment of alcoholism and has been demonstrated in the present invention to attenuate the desire for alcohol in rats and mice. It will be apparent to those of ordinary skill in the art that the results obtained from these models are useful in predicting pharmacological or behavioral effects of drugs in humans.
  • CHP CHP on alcohol desire
  • the effect of CHP on alcohol desire is not from a generalized suppression of ingestion of food, but rather from the interaction of CHP with the serotonergic and/or dopamanergic receptors in the brain.
  • One of the major sites for the control of appetite behavior in the brain is the hypothalmus.
  • the desire for alcohol is believed to be controlled by other areas in the brain such as the ventral tegmental area or nucleus accumbens.
  • mice were obtained from Jackson Laboratories and housed individually in light controlled rooms for a period of at least twenty-one days after arrival with free access to Purina Chow and water. The lights were cycled on and off every twelve hour period.
  • the mice included eight C57BL, six DBA/2 F x - hybrid and six DBA/2 strains.
  • C57BL strain is an inbred black mouse which exhibits a high degree of preference for alcohol in a free choice paradigm.
  • DBA/F j strains are inbred mice which exhibit an intermediate level of preference for alcohol.
  • DBA/2 are inbred mice which exhibit no preference for alcohol.
  • the mice were sacrificed without anesthesia and the brains removed and processed for CHP radioimmunoassay.
  • the radioimmunoassay involved incubating at 4-5° C a mixture containing 0.1ml of various dilutions of brain sample, 0.1 ml of 0.25% bovine serum albumin in phosphate buffered saline, 0.1ml of rabbit CHP antibody and 0.1ml of I 125 - CHP. After 48 hours incubation, free and antibody bound tracers were separated by adding 1 ml of 17.5% polyethylene glycol, MW 6000 containing bovine gamma-globulin (4mg/ml) followed by centrifugation for 20 minutes. The supernatant was discarded and the pellet was counted for radioactivity.
  • Results shown in Table I indicate that the levels of CHP in the brain are lower in strains that have a preference for alcohol and further support the belief that an increase in alcohol preference is due to a decrease in brain CHP content. Moreover, the data suggests that increasing CHP levels in the brain may decrease preference for alcohol.
  • One way to increase brain CHP levels is through exogenous administration of
  • CHP The cyclic dipeptide is known to resist enzymatic degradation and readily cross the blood brain barrier. Moreover, the measurement of CHP in serum has been obtained for mice and further supports the viability of exogenous CHP administration in humans.
  • twenty adult male C57BL mice obtained from Jackson Laboratories were housed individually in light controlled rooms for a period of at least ten days after arrival with free access to Purina Chow and water. The lights were cycled on and off every twelve hour period. Each room was fitted with 250ml bottles having drip proof drinking spouts on both sides of a food bin containing Purina Chow. For the experiment, rats were divided into four groups of five mice each.
  • mice were sacrificed and trunk blood was collected in glass test tubes. The blood was stored on ice and allowed to clot for 2 hours and centrifuged at 5°C for 30 minutes at 2000 rpm. The serum was then collected and stored at -70°C until processed for CHP radioimmunoassay.
  • the radioimmunoassay involved incubating at 4-5° C a mixture containing 0.1ml of various dilutions of brain sample, 0.1 ml of 0.25% bovine serum albumin in phosphate buffered saline, 0.1ml of rabbit CHP antibody and 0.1ml of I 125 - CHP. After 48 hours incubation, free and antibody bound tracers were separated by adding 1 ml of 17.5% polyethylene glycol, MW 6000 containing bovine gamma- globulin (4mg/ml) followed by centrifugation for 20 minutes. The supernatant was discarded and the pellet was counted for radioactivity. TABLE II
  • CHP is comprised of amino acids and as such is expected to exhibit a low immunogenic response allowing a wider range of dosages.
  • the method of treatment according to the invention involves administration of histidyl-proline diketopiperazine and a pharmaceutical carrier in therapeutically effective amounts for attenuating the desire for alcohol.
  • CHP is administered in an amount wherein the appetite is not suppressed.
  • Therapeutically effective amounts expressed in ⁇ g/kg of body weight per day, range from about 1 to about 1,000,000. More preferably CHP administration is from about 1 to about 50000 ⁇ g/kg of body weight per day.
  • Parenteral administration generally requires lower amounts as is known to those of ordinary skill in the art.
  • CHP is preferably used in an amount of from about 1 to about 30,000 ⁇ g/kg of body weight per day. It is expected that the defined therapeutic ranges for attenuating the desire for alcohol in mice and rats will be the same or somewhat similar when the material is administered to humans.
  • CHP and analogues thereof may be administered in combination with alcoholic deterrents.
  • Alcoholic deterrents such as disulfiram, generally exhibit deleterious side effects that result in the patient terminating treatment.
  • a combination of an alcoholic deterrent and CHP lowers the effective dose required for each drug.
  • Histidyl-proline diketopiperazine and analogues thereof may accordingly be expected to be administered to a human patient in need of such treatment corresponding to the usual routes of administration and in the usual forms.
  • These include solutions, suspensions, emulsions, tablets, capsules and powders prepared in pharmaceutically acceptable carriers for oral administration or sterile solutions for parenteral administration.
  • CHP and analogues thereof can be formulated into solid or liquid preparations such as tablets, granules, pills, powders, lozenges, sachets, cachets, elixirs, emulsions, solutions, syrups, suspensions, aerosols (as a solid or in liquid form) and soft and hard capsules.
  • Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, mannitol, sucrose and cornstarch.
  • they can be prepared in depot, sustained release or other formulations.
  • the the depot and sustained release formulations are preferably prepared in the manner described in U.S. Pat. Appln. Serial Nos. 08/800,924 filed February 13, 1997 and 09/181,204 filed
  • sustained release delivery systems include both controlled release and prolonged release.
  • sustained release systems include any drug delivery system that achieves the slow release of drug over an extended period of time. When the system maintains constant drug levels in the blood or target tissue, it is considered a controlled release system.
  • CHP can be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders, such as acacia, cornstarch, gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate.
  • Liquid preparations are prepared by dissolving histidyl-proline diketopiperazine in an aqueous or non aqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring agents and preservative agents as are known in the art.
  • histidyl-proline diketopiperazine and analogues thereof may be dissolved in a physiologically and pharmaceutically acceptable carrier and administered as either a solution or a suspension.
  • Suitable pharmaceutically acceptable carriers are water, saline, dextrose solutions, fructose solutions or oils of animal, vegetative, or synthetic origin.
  • the pharmaceutical carrier may also contain preservatives, buffers, etc. as is known in the art.
  • Synthetic benzyloxycarbonyl-L-histidyl-L-prolineamide was prepared by coupling benzyloxcarbonyl-L-histidine (20mmol, ICN) with L-prolineamide (20mmol, Aldrich Chemicals), N-ethylmorpholine (20mmol, Aldrich Chemicals) and dicyclohexylcarbodiimide (20mmol., Pierce Chemicals).
  • L-prolineamide 20mmol, Aldrich Chemicals
  • N-ethylmorpholine 20mmol, Aldrich Chemicals
  • dicyclohexylcarbodiimide 20mmol., Pierce Chemicals
  • Benzyloxycarbonyl-L-histidyl-L-prolineamide (500mg) was dissolved in a solution containing methanol (10ml), H2O (0.3ml) and glacial acetic acid (0.3ml). After adding palladium black catalyst (lOOmg), the suspension was hydrogenated under 40 pounds of pressure for 2 hours. The catalyst was then filtered and the resultant solution was heated in boiling water for 30 minutes, then dried in vacuo.
  • Mass spectrographic analysis showed prominent ions at m/e 234, m/e 154, m/e 81 and m/e 70.
  • Proton NMR showed chemical shifts at 1.95, 2.2, 3.4, 3.5, 4.65, 7.4, 8.25 ppm downfield from trimethylsilane.
  • Amino acid analysis showed the presence of ninhydrin-positive material corresponding to only proline and histidine with a ratio of 1.1 to 1.
  • EXAMPLE 2 Effect of CHP Administration on Voluntary Alcohol Consumption in Alcohol Naive Mice
  • Forty adult male C57BL mice were obtained from Jackson Laboratories and housed individually in light controlled rooms for a period of at least ten days after arrival with free access to Purina Chow and water. The lights were cycled on and off every twelve hour period. Mice were divided into four groups often.
  • Each room was fitted with two 250ml bottles having drip proof drinking spouts on both sides of a food bin containing Purina Chow.
  • One bottle contained 6% (V/V) ethanol in water whereas the other bottle contained water.
  • Increasing concentrations of CHP were added to each bottle and distributed according to group. The two bottles were frequently exchanged with each other to minimize positional preference. Fluid intake from each bottle was recorded after 7 days.
  • Ethanol preference was calculated as ethanol intake/(ethanol intake + water intake) x 100.
  • the group receiving the highest amounts of CHP showed the lowest ethanol preference.
  • the group receiving the highest amounts of CHP had comparable fluid intakes as the other groups receiving lower amounts of or no CHP.
  • EXAMPLE 3 Effect of CHP Administration on Voluntary Alcohol Consumption in Alcohol Experienced Mice Forty adult male C57BL mice were obtained from Jackson Laboratories and housed individually in light controlled rooms for a period of at least ten days prior to beginning the experiment with free access to Purina Chow and water. The lights were cycled on and off every twelve hour period. The mice were divided into four groups often. Each room was fitted with two 250ml bottles having drip proof drinking spouts on both sides of a food bin containing Purina Chow. Both bottles contained 6% (V/V) ethanol in water and were the only source of fluid available. Mice were allowed to drink for seven days. On the eighth day, one bottle containing ethanol in water was removed and replaced with a 250ml bottle containing water. Increasing concentrations of CHP were added to each bottle and distributed according to group. The bottles were frequently exchanged to discourage positional preference. Fluid intake from each bottle was recorded after an additional 7 days. % Ethanol preference was calculated for each group.
  • EXAMPLE 4 Effect of Intraperitoneal and Oral Administration of CHP on Food Intake
  • Thirty-six outbred adult male Sprague-Dawley rats, certified virus free, obtained from Hilltop Laboratories, New York, New York were housed in a temperature and light controlled room for a period of at least seven days after arrival.
  • Sprague-Dawley rats are white albino outbred rats.
  • the temperature of the room was maintained at about 20-21 °C.
  • the lights in the room were cycled between on and off every twelve hours.
  • the rats were allowed free access to Purina Chow food and water prior to beginning the experiment.
  • rats were divided into six groups of six rats each.
  • Each group was treated with a different dosage of CHP dissolved in 0.5 milliliters of sterile water.
  • the amount of CHP in each dose was based on the body weight of the individual rat. Rats were fasted for about 21 hours from food but not water. Oral dosages of CHP were administered using a gavage tube according to each rat group. The rats were then given access to Purina Chow and water for the next seven hours. Food intake during the seven hours was measured in grams per rat and averaged for each group. The rats were then allowed to rest for 10 days to eliminate from the body any residual CHP. At the end of this period, the experiment was repeated using peritoneal administration.
  • a preferred embodiment is a method for attenuating the desire for alcohol in a mammal by administering an effective amount of histidyl-proline diketopiperazine and a pharmaceutical carrier.
  • histidyl-proline diketopiperazine is useful for reducing the desire for alcohol.
  • exogenous administration is process selective in that it reduces desire for alcohol, but not food and water consumption.

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Abstract

L'invention concerne une composition et un procédé permettant d'atténuer le désir d'alcool chez un mammifère. Ce procédé consiste à administrer à un tel mammifère une quantité efficace pour atténuer le désir d'alcool d'une substance renfermant une histidyl-proline dikétopipérazine et un support de celle-ci acceptable sur le plan pharmaceutique.
PCT/US2000/018123 2000-06-30 2000-06-30 Histidyl-proline diketopiperazine et procede d'utilisation associe Ceased WO2002001956A1 (fr)

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PCT/US2000/018123 WO2002001956A1 (fr) 2000-06-30 2000-06-30 Histidyl-proline diketopiperazine et procede d'utilisation associe
AU2000259049A AU2000259049A1 (en) 2000-06-30 2000-06-30 Histidyl-proline diketopiperazine and method of use

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102133151B1 (ko) * 2019-03-28 2020-07-13 주식회사 노브메타파마 Chp(사이클로-히스프로)를 포함하는 복막 섬유증의 예방, 개선 또는 치료용 조성물
CN112424215A (zh) * 2018-07-10 2021-02-26 诺麦塔制药有限公司 环(-his-pro)的新多晶型形式
WO2024049204A1 (fr) * 2022-08-31 2024-03-07 주식회사 노브메타파마 Utilisation d'une composition contenant un sel de zinc et du cyclo(his-pro) pour la prévention, le soulagement ou le traitement des maladies respiratoires
US12053467B2 (en) 2020-12-18 2024-08-06 NovMeta Pharma Co., Ltd. Method of treating fibrosis

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5418218A (en) * 1992-07-10 1995-05-23 The University Of Maryland At Baltimore Histidyl-proline diketopiperazine (cyclo his-pro) a cns-active pharmacologic agent

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5418218A (en) * 1992-07-10 1995-05-23 The University Of Maryland At Baltimore Histidyl-proline diketopiperazine (cyclo his-pro) a cns-active pharmacologic agent

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112424215A (zh) * 2018-07-10 2021-02-26 诺麦塔制药有限公司 环(-his-pro)的新多晶型形式
KR102133151B1 (ko) * 2019-03-28 2020-07-13 주식회사 노브메타파마 Chp(사이클로-히스프로)를 포함하는 복막 섬유증의 예방, 개선 또는 치료용 조성물
WO2020197359A1 (fr) * 2019-03-28 2020-10-01 주식회사 노브메타파마 Utilisation de cyclo-his-pro (chp) pour prévenir, améliorer ou traiter la fibrose
US12053467B2 (en) 2020-12-18 2024-08-06 NovMeta Pharma Co., Ltd. Method of treating fibrosis
WO2024049204A1 (fr) * 2022-08-31 2024-03-07 주식회사 노브메타파마 Utilisation d'une composition contenant un sel de zinc et du cyclo(his-pro) pour la prévention, le soulagement ou le traitement des maladies respiratoires

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