WO1996014071A1 - Combination of chemical compounds used as a medicament intended to suppress the dependence of individuals to opioids - Google Patents

Combination of chemical compounds used as a medicament intended to suppress the dependence of individuals to opioids Download PDF

Info

Publication number
WO1996014071A1
WO1996014071A1 PCT/ES1994/000108 ES9400108W WO9614071A1 WO 1996014071 A1 WO1996014071 A1 WO 1996014071A1 ES 9400108 W ES9400108 W ES 9400108W WO 9614071 A1 WO9614071 A1 WO 9614071A1
Authority
WO
WIPO (PCT)
Prior art keywords
combination
drugs
dose
milligrams
dependence
Prior art date
Application number
PCT/ES1994/000108
Other languages
Spanish (es)
French (fr)
Inventor
Juan José Legarda Ibañez
Original Assignee
Legarda Ibanez Juan Jose
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Legarda Ibanez Juan Jose filed Critical Legarda Ibanez Juan Jose
Priority to CA002180117A priority Critical patent/CA2180117A1/en
Priority to HU9601835A priority patent/HUT75938A/en
Priority to US08/666,533 priority patent/US6103734A/en
Priority to BR9408488A priority patent/BR9408488A/en
Priority to PCT/ES1994/000108 priority patent/WO1996014071A1/en
Priority to JP8515069A priority patent/JPH09507865A/en
Priority claimed from BR9408488A external-priority patent/BR9408488A/en
Publication of WO1996014071A1 publication Critical patent/WO1996014071A1/en
Priority to NO962740A priority patent/NO962740L/en
Priority to FI962728A priority patent/FI962728A/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine

Definitions

  • the present description deals with an invention based on the combination of certain chemical compounds or drugs through which the detoxification of drug addicts is carried out to opioid substances in a period of less than 24 hours.
  • abstinence is treated in various documents such as the article "Substance abuse disorders: a psychiatric priority" in Am. J. Psychiatry 148, concentrated on pages 1291 to 1300 written by the Group for the advancement of the Psychiatry Committee for Alcoholism and Addictions in 1991.
  • Detoxification methods may include drug substitution, using an opioid agonist such as methadone as indicated in the article by M. Gossop et al 1989 "Opiate withdrawal responses to 10-day and 21-day methadone withdrawal programs "(10 and 21 day methadone withdrawal programs) from British Journal Psychiatry 154, or through the use of partial opioid agonists such as Buprenorphine as indicated in” Human pharmacology and abuse potential of the analgesic buprenorphine "(Human Pharmacology and potential abuse of analgesic buprenorphine) by Jasinski et al in Arch. Gen. Psychiatry 35 in 1978.
  • an opioid agonist such as methadone as indicated in the article by M. Gossop et al 1989 "Opiate withdrawal responses to 10-day and 21-day methadone withdrawal programs "(10 and 21 day methadone withdrawal programs) from British Journal Psychiatry 154
  • partial opioid agonists such as Buprenorphine as indicated
  • adrenergic agonists such as clonidine or guanfacine as indicated in the articles "clonidine in opiate withdrawal” ( Clonidine in opioid withdrawal) from Ms Gold and others of 1978 in Lancet i, and in "Preliminary results of guanfacine treatment of acute opiate withdrawal” by Schubert et al in American Journal Psychiatry 141.
  • Psychiatry 148 as "Techniq ⁇ e for greatly shortening the transition from methadone to naltrexone maintenance of patients addicts to opiates" (Technique to minimize the transition in the maintenance of methadone to naltrexone in patients with opioid addiction). More recently, a new treatment route has been used with twenty individuals addicted to heroin. The procedure was non-invasive, that is, all medication was given orally and began twelve hours after the last heroin use as extracted from the article by N. Loimer and others of 1993 "ultrashort non invasive opiate detoxification” (Detoxification ultra short opioid non-invasive) published in Am. J. Psychiatry 150.
  • This procedure consisted of using the same sedative as in the previous experience, midazolam, but at even higher doses than in the previous case.
  • This procedure also included an alpha-adrenergic agonist, a clonidine that enhances sedation and decreases the symptoms of opioid withdrawal syndrome and an antiemetic, ondansetron.
  • an opioid antagonists naloxone and naltrexone, were used in very high doses, 4 and 50 milligrams respectively in a single dose.
  • the present invention represents a combination of drugs that allows an ultra-rapid pattern for the detoxification of drug illuminators addicted to heroin and / or methadone or other opiates.
  • the use of certain compounds will be carried out according to guidelines that, in the first place, can begin, unlike other guidelines, immediately after the patient has made his last opioid consumption, therefore, it is not necessary to wait as he puts in practice according to other treaties, just as it is not necessary to substitute an opioid for another before starting the application of the detoxification products provided for in the present invention, an additional novelty is the incorporation of one of the anesthetic sleep inductors used, the Propofol, a product that has never been used by other specialists in this field and both this and any other, for example midazolam, can be supplied in the recommended therapeutic doses without the need to dangerously increase its dosage.
  • patient monitoring must necessarily include blood pressure, cardiac activity and oxygen saturation in arterial blood. This last parameter has not been previously used by Other specialists in this field. Additionally, it should be mentioned that the products of the invention are used by invasive procedures. Likewise, sedation and / or anesthesia is maintained with monitoring for a minimum period of three hours. In addition, there are minimum requirements necessary to perform this type of intervention, a secretion aspirator and an apparatus for assisted breathing. The application of the drugs, therefore, must be carried out in the vicinity of an intensive care unit or in it, or in a hospital cabin that meets the necessary requirements.
  • the optional intake, one day before admission, of a laxative is required in order to perform as well as possible intestinal cleansing, the patient fasting at least eight hours before the intervention.
  • a complete medical and psychological examination will be carried out, discarding any type of pathology that contraindicates the treatment and the necessary analytical determinations such as blood count, biochemistry, pregnancy test will be performed in the case in which the patient is a woman in fertile age, and other complementary examinations directed according to the semiology found in the physical examination, such as chest x-ray, computerized axial tomography, electrocardiogram and electroencephalogram.
  • alpha adrenergic agents such as guanfacine or clomdine
  • guanfacine or clomdine will be administered at the time of admission, ensuring tension Blood pressure is not less than 90-60 mmHg or the heart rate is less than 55 systoles per minute, once the patient's examination is finished, the intervention can begin.
  • a peripheral venous route will be taken and, in the absence thereof, a central route, antiemetics such as ondansetron, and gastric protectors such as H2 antihistamines are administered, among which ranitidine and / or pump inhibitors can be found.
  • protons such as omeprazole and the patient is sedated or anesthetized with anesthetic agents such as propofol or propofol and a benzodiazepine such as midazolan and which will be kept in constant infusion at a dose adjusted to the patient's response and not higher than recommended by the pharmaceutical laboratory.
  • the opioid antagonist, naloxone and / or naltrexone is then given.
  • the administration of opioid antagonist will be repeated as appropriate and at doses that depend on the amount of heroin to which the patient is accustomed.
  • Each dose of naltrexone should never exceed 40 milligrams, nor will the total dose exceed 50 milligrams.
  • a naloxone test consisting of the intravenous administration of 0.8 milligrams of said substance is performed. If this test is negative, that is, no signs of withdrawal appear, the anesthetic administration is suspended, the patient is awakened, and the administration of an analgesic such as ketorolac, an H2 antihistamine such as ranitidine, a benzodiazepine such as ketazolam and an adrenergic agonist such as guanfacine.
  • an analgesic such as ketorolac, an H2 antihistamine such as ranitidine, a benzodiazepine such as ketazolam and an adrenergic agonist such as guanfacine.

Abstract

Combination of chemical compounds used as a medicament intended to suppress the dependence of individuals to opioids, the combination comprising a laxative or enema of irrigation, repeated doses of alpha-adrenergic agents, antiemetic agents, gastric protectors, optionally inhibitors of the proton pump, an anxiolytic compound, anaesthetic sleep inducing agent and determined doses of an opioid antagonist compound, such as naxalone or naltrexone.

Description

COMBINACION DE FARMACOS COMO MEDICAMENTO DESTINADO SUPRESION DE DEPENDENCIA DE INDIVIDUOS A OPIACEOS COMBINATION OF PHARMACOS AS A MEDICINAL INTENDED SUPPRESSION OF DEPENDENCY OF INDIVIDUALS TO OPIACEANS
La presente descripción trata de una invención basada en la combinación de determinados compuestos químicos o fármacos a través de los cuales la desintoxicación de drogodependientes se realiza a substancias opiáceas en un periodo de menos de 24 horas. The present description deals with an invention based on the combination of certain chemical compounds or drugs through which the detoxification of drug addicts is carried out to opioid substances in a period of less than 24 hours.
Uno de los principales objetivos en los tratamientos de la adicción a opiáceos es la abstinencia, la cual se trata en diversos documentos como el artículo "Substance abuse disorders: a psychiatric priority" (Desórdenes por abuso de substancias: Una prioridad psiquiátrica) en Am. J. Psychiatry 148, concentrado en las páginas 1291 a 1300 escrito por el Grupo para el avance de la Psiquiatría del comité para el alcoholismo y las adicciones en 1991. One of the main objectives in opioid addiction treatment is abstinence, which is treated in various documents such as the article "Substance abuse disorders: a psychiatric priority" in Am. J. Psychiatry 148, concentrated on pages 1291 to 1300 written by the Group for the advancement of the Psychiatry Committee for Alcoholism and Addictions in 1991.
Existen ciertos procedimientos de tipo rápido en los que la desintoxicación necesita de más de 10 días para ser completada, según se indica en diversas publicaciones, como son "Dependence clinical research and treatment unit, the Maυdsley and Bethlem Royal Hospital" (La unidad de tratamiento e investigación clínica de dependencia de droga de los hospitales reales de Maudsley y Bethlem) en Br. J. Addict 83 recogido en las páginas 1387 a 1394 por J.5. strang, M. Gossop y B. Bradley en 1988. There are certain rapid-type procedures in which detoxification needs more than 10 days to complete, as indicated in various publications, such as "Dependence clinical research and treatment unit, the Maυdsley and Bethlem Royal Hospital" (The treatment unit and clinical investigation of drug dependence of the royal hospitals of Maudsley and Bethlem) in Br. J. Addict 83, collected on pages 1387 to 1394 by J.5. Strang, M. Gossop and B. Bradley in 1988.
Una publicación en la misma linea fué escrita por T.R. Kosten, J.H. Kristal, D.5. Charney, L.H. Price, C.H. Morgan y H.D. Kleber en 1989 con el título "Rapid detoxification from opioid dependence" (Desintoxicación rápida de dependencia a opiáceos), en la American Journal Psychiatry 146, así como en otro artículo de los citados autores Kosten et al en 1991 como "Treatment of heroin addicts using buprenorphine" (Tratamiento de adictos a heroína usando buprenorfina) en Am.J. Drυg Alcohol Abuse 17. A publication in the same line was written by TR Kosten, JH Kristal, D.5. Charney, LH Price, CH Morgan and HD Kleber in 1989 with the title "Rapid detoxification from opioid dependence", in the American Journal Psychiatry 146, as well as in another article by the aforementioned authors Kosten et al in 1991 as "Treatment of heroin addicts using buprenorphine" in Am.J. Drυg Alcohol Abuse 17.
Dichos procedimientos descritos en los citados artículos son a menudo costosos, además de ser frustantes debido al alto porcentaje de abandonos. Para una desintoxicación hospitalaria el rango de abandonos oscila entre el 20% y el 30% como se indica en el artículo "Dropping out of substance abuse treatment: A clinically oriented review." (Abandonos durante el tratamiento de abuso de sustancias: una revisión orientada clínicamente) de la clin. Psychol .Rev.12 en sus páginas 93 a 116, llegándose en el caso de desintoxicación ambulatoria hasta el 80%, como se cita también en el artículo de M. Gossop, A. Johns y L. Green de 1986 con el título "Opiate withdrawal: impatient versus outpatient programmes and preferred versus random assignment to treatment" (Abstinencia de opiáceos: programas hospitalarios contra ambulatorios y asignaciones preferidas frente a asignaciones aleatorias del tratamiento) en Br. Me. J. 293. Los métodos de desintoxicación pueden incluir la sustitución de la droga, usando un agonista opiáceo tal como la metadona como se indica en el artículo de M. Gossop et al de 1989 " Opiate withdrawal responses to 10-day and 21-day methadone withdrawal programmes" (Respuestas de abstinencia a opiáceos mediante programas de abstinencia de metadona de 10 y 21 dias) de British Journal Psychiatry 154, o bien mediante la utilización de agonistas parciales opiáceos tales como la Buprenorfina como se indica en "Human pharmacology and abuse potential of the analgesic buprenorphine" (Farmacología humana y potencial abuso de la buprenorfina analgésica) de Jasinski et al en la Arch. Gen. Psychiatry 35 en 1978. otra pauta implica el uso de agonistas adrenérgicos tales como la clonidina o la guanfacina como se indica en los articulos "clonidine in opiate withdrawal" (Clonidina en abstinencias opiáceas) de M.s. Gold y otros de 1978 en Lancet i, y en "Preliminary results of guanfacine treatment of acute opiate withdrawal" (Resultados preliminares de tratamiento con guanfacina de la abstinencia aguda de opiáceos) de Schubert et al en American Journal Psychiatry 141. Such procedures described in the aforementioned articles are often expensive, in addition to being frustrating due to the high percentage of dropouts. For a hospital detoxification the range of dropouts ranges from 20% to 30% as indicated in the article "Dropping out of substance abuse treatment: A clinically oriented review." (Abandonment during substance abuse treatment: a clinically oriented review) of the clin. Psychol. Rev. 12 on pages 93 to 116, reaching up to 80% in the case of outpatient detoxification, as also cited in the article by M. Gossop, A. Johns and L. Green of 1986 with the title "Opiate withdrawal: impatient versus outpatient programs and preferred versus random assignment to treatment "in Br. Me. J. 293. Detoxification methods may include drug substitution, using an opioid agonist such as methadone as indicated in the article by M. Gossop et al 1989 "Opiate withdrawal responses to 10-day and 21-day methadone withdrawal programs "(10 and 21 day methadone withdrawal programs) from British Journal Psychiatry 154, or through the use of partial opioid agonists such as Buprenorphine as indicated in" Human pharmacology and abuse potential of the analgesic buprenorphine "(Human Pharmacology and potential abuse of analgesic buprenorphine) by Jasinski et al in Arch. Gen. Psychiatry 35 in 1978. Another pattern involves the use of adrenergic agonists such as clonidine or guanfacine as indicated in the articles "clonidine in opiate withdrawal" ( Clonidine in opioid withdrawal) from Ms Gold and others of 1978 in Lancet i, and in "Preliminary results of guanfacine treatment of acute opiate withdrawal" by Schubert et al in American Journal Psychiatry 141.
Recientemente existe un creciente interés por los tratamientos de bloqueo usando antagonistas opiáceos como la naloxona o la naltrexona asociados a agonistas adrenérgicos, como bien se indica en las publicaciones "Rapid opiate detoxification with clonidine and naltrexone" (Desintoxicación de opiáceos rápida mediante clonidina y naltrexona) de Riordan y otros en 1980 recogido en Lancet i, y en "The combined use of clonidine and naltrexone as a safe, rapid and effective treatment of abrupt withdrawal from methadone" (El uso combinado de clonidina y naltrexona como un tratamiento efectivo, rápido y seguro de abstinencias abruptas de metadona) publicada en Am. J. Psychiatry por charney et al en 1989, consiguiéndose realizar los tratamientos terapéuticos derivados de la utilización de dichos compuestos, en un corto periodo de tiempo, entre 48 horas y 4-5 días como se indica en los artículos "opioid withdrawal and naltrexone induction in 48-72 h. with minimal dropout using a modification of the naltrexone-clonidine technique" (Abstinencia opiácea e inducción a naltrexona en un periodo de 48-72 horas con mínimo abandono usando una modificación de la técnica naltrexona-clonidina) en Br. J. Psychiatry 153 realizado por Brewer et al en 1988 y "Clinical utility of rapid clonidine-naltrexone detoxification for opioíd abusers." (Utilidad clínica de desintoxicación rápida de clomdina-naltrexona para dependientes de opiáceos) en Br. J.Psychiatry 83 por E.vimng, T.Kosten y H.Kleber en 1988. Recently there is a growing interest in blocking treatments using opioid antagonists such as naloxone or naltrexone associated with adrenergic agonists, as indicated in the publications "Rapid opiate detoxification with clonidine and naltrexone." by Riordan et al. in 1980 collected in Lancet i, and in "The combined use of clonidine and naltrexone as a safe, rapid and effective treatment of abrupt withdrawal from methadone" as the combined, rapid and rapid treatment of methadone abrupt abstinence insurance) published in Am. J. Psychiatry by charney et al in 1989, achieving therapeutic treatments derived from the use of said compounds, in a short period of time, between 48 hours and 4-5 days as indicated in the articles "opioid withdrawal and naltrexone induction in 48-72 h. with minimal dropout using a modi fication of the naltrexone-clonidine technique "(Opioid withdrawal and induction to naltrexone in a period of 48-72 hours with minimal abandonment using a modification of the naltrexone-clonidine technique) in Br. J. Psychiatry 153 conducted by Brewer et al in 1988 Y "Clinical utility of rapid clonidine-naltrexone detoxification for opioid abusers." (Clinical utility of rapid detoxification of clomdine-naltrexone for opioid dependents) in Br. J. Psychiatry 83 by E.vimng, T. Kosten and H.Kleber in 1988.
Dada la información publicada hasta ahora, la cual hemos citado anteriormente, se observa que existe un problema en la desintoxicación, especialmente en la sustitución con metadona, siendo éste el síndrome de abstinencia más prolongado. El uso de antagonistas permite una importante reducción en la duración del proceso de desmtoxicación. En esta linea, una experiencia de tratamiento con siete individuos en mantenimiento con metadona, incluyó la incorporación de un antagonista opiáceo, la naloxona, un sedante, midazolam, en dosis muy superiores a las recomendadas así como la utilización de un antagonista del sedante, flυmazeml, para revertir la sedación. Durante el tratamiento se monitorizó pulso cardiaco y presión arterial según las instrucciones comentadas en el artículo de Loimer y otros de 1991 aparecido en Am. J. Psychiatry 148 como "Techniqυe for greatly shortening the transition from methadone to naltrexone maintenance of patients adicts to opiates" (Técnica para reducir al máximo la transición en el mantenimiento de metadona a naltrexona en pacientes adictos a opiáceos). Más recientemente se ha utilizado una nueva vía de tratamiento con veinte individuos adictos a la heroína. El procedimiento fué de tipo no invasivo, es decir, toda medicación se suministró por ruta oral y comenzó doce horas después del último consumo de heroína como se extrae del artículo de N. Loimer y otros de 1993 "ultrashort non invasive opiate detoxification " (Desintoxicación ultracorta de opiáceos no invasiva) publicado en Am. J.Psychiatry 150. Dicho procedimiento consistió en utilizar el mismo sedante que en la experiencia anterior, midazolam, pero a dosis aún más elevadas que en el caso anterior. Dicho procedimiento incluía también un agonista alfa-adrenérgico, clonidina que potencia la sedación y disminuye la sintomatología del sindrome de abstinencia a opiáceos y un antiemético, ondansetrón. Para acelerar la desintoxicación se utilizaron dos antagonistas opiáceos, naloxona y naltrexona, en dosis muy elevadas, 4 y 50 miligramos respectivamente en una sola dosis. Given the information published so far, which we have cited above, it is observed that there is a problem in detoxification, especially in substitution with methadone, this being the most prolonged withdrawal syndrome. The use of antagonists allows a significant reduction in the duration of the detoxification process. In this line, a treatment experience with seven individuals in methadone maintenance, included the incorporation of an opioid antagonist, naloxone, a sedative, midazolam, at doses much higher than recommended as well as the use of a sedative antagonist, flυmazeml , to reverse sedation. During the treatment, heart rate and blood pressure were monitored according to the instructions commented in the Loimer et al. Article of 1991, which appeared in Am. J. Psychiatry 148 as "Techniqυe for greatly shortening the transition from methadone to naltrexone maintenance of patients addicts to opiates" (Technique to minimize the transition in the maintenance of methadone to naltrexone in patients with opioid addiction). More recently, a new treatment route has been used with twenty individuals addicted to heroin. The procedure was non-invasive, that is, all medication was given orally and began twelve hours after the last heroin use as extracted from the article by N. Loimer and others of 1993 "ultrashort non invasive opiate detoxification" (Detoxification ultra short opioid non-invasive) published in Am. J. Psychiatry 150. This procedure consisted of using the same sedative as in the previous experience, midazolam, but at even higher doses than in the previous case. This procedure also included an alpha-adrenergic agonist, a clonidine that enhances sedation and decreases the symptoms of opioid withdrawal syndrome and an antiemetic, ondansetron. To accelerate detoxification, two opioid antagonists, naloxone and naltrexone, were used in very high doses, 4 and 50 milligrams respectively in a single dose.
Estas dos últimas formas de desintoxicar representan, en la experiencia que ha llevado a la utilización del conjunto de compuestos objeto de la invención, un grave riesgo para la vida del individuo y son impracticables con las dosis de antagonistas y de sedantes utilizados, así como con el tipo de sedantes utilizados, sin, además, una monitorización adecuada. como última publicación aparecida sobre este campo de la medicina terapéutica, comentamos el artículo "A 24-h impatient treatment for heroin addicts: a preliminary investigation" (Un tratamiento hospitalario de 24 horas para adictos a la heroína: investigación preliminar" del titular de la presente solicitud, publicada en Drug and Alcohol Dependence en 1994. En dicho artículo se indican ciertas pautas y productos en la linea de lo comentado hasta ahora, habiendo determinadas diferencias con los productos y el uso de dichos productos que se desarrollarán en la presente descripción. Dichas diferencias se basan en la utilización de ciertos sedantes y antagonistas en dosis menos elevadas que hasta entonces, por lo que se aportan al organismo las dosis recomendadas de utilización del producto, las cuales en el caso de la utilización de los antagonistas se centran en un rango entre 6 y 40, preferentemente entre 10 y 30 miligramos y aún más preferentemente entre 12 '5 y 18'5 miligramos, en el caso de utilizar dosis de naltrexona, pudiendo utilizarse igualmente como antagonista, dosis de naloxona en un rango de 0'4 a 1'5 miligramo por hora, por vía venosa, otra diferencia, hasta ahora mantenida por vanos autores como Loymer etc.. se basará en la utilización de monitorización y sedación en un periodo superior a 2 horas. These last two forms of detoxifying represent, in the experience that has led to the use of the set of compounds object of the invention, a serious risk to the life of the individual and are impracticable with the doses of antagonists and sedatives used, as well as with the type of sedatives used, without, in addition, adequate monitoring. As the latest publication on this field of therapeutic medicine, we comment on the article "A 24-h impatient treatment for heroin addicts: a preliminary investigation" (A 24-hour hospital treatment for heroin addicts: preliminary investigation) of the head of the This application, published in Drug and Alcohol Dependence in 1994. This article indicates certain guidelines and products in line with what has been commented so far, there being certain differences with the products and the use of said products that will be developed in this description. These differences are based on the use of certain sedatives and antagonists at lower doses than before, so the recommended doses of product use are provided to the body, which in the case of Antagonists use focus on a range between 6 and 40, preferably between 10 and 30 milligrams and even more preferably between 12 '5 and 18.5 milligrams, in the case of using naltrexone dose, and can also be used as an antagonist, dose of naloxone in a range of 0.4 to 1.5 milligrams per hour, by venous route, another difference, until now maintained by vain authors such as Loymer etc ... will be based on the use of monitoring and sedation in a period greater than 2 hours.
La presente invención representa una combinación de fármacos que permite una pauta ultra rápida para la desintoxicación de pol íconsumindores de drogas adictos a la heroína y/o a la metadona u otros opiáceos. La utilización de ciertos compuestos se realizará según unas pautas que en primer lugar, pueden comenzar, a diferencia de otras pautas, inmediatamente después de que el paciente haya realizado su último consumo de opiáceos, por lo tanto, no es necesaria la espera como se pone en práctica según otros tratados, así como no es necesario substituir un opiáceo por otro antes de comenzar la aplicación de los productos para des intoxicación previstos en la presente invención, una novedad adicional es la incorporación de uno de los inductores del sueño anestésico utilizados, el propofol, producto que nunca ha sido usado por otros especialistas en este campo y tanto éste como cualquier otro, por ejemplo el midazolam, se puede suministrar en las dosis terapéuticas recomendadas sin necesidad de incrementar peligrosamente su dosificación. The present invention represents a combination of drugs that allows an ultra-rapid pattern for the detoxification of drug illuminators addicted to heroin and / or methadone or other opiates. The use of certain compounds will be carried out according to guidelines that, in the first place, can begin, unlike other guidelines, immediately after the patient has made his last opioid consumption, therefore, it is not necessary to wait as he puts in practice according to other treaties, just as it is not necessary to substitute an opioid for another before starting the application of the detoxification products provided for in the present invention, an additional novelty is the incorporation of one of the anesthetic sleep inductors used, the Propofol, a product that has never been used by other specialists in this field and both this and any other, for example midazolam, can be supplied in the recommended therapeutic doses without the need to dangerously increase its dosage.
Por otra parte, la monitorización del paciente ha de incluir necesariamente presión arterial, actividad cardíaca y saturación de oxígeno en sangre arterial. Este último parámetro no ha sido utilizado anteriormente por otros especialistas en este campo. Adicionalmente se ha de citar el hecho de que los productos de la invención se utilizan mediante procedimientos de tipo invasivo. Asimismo, la sedacción y/o anestesia se mantiene con monitorización durante un periodo mínimo de tres horas, son, además, mínimos requisitos necesarios para realizar este tipo de intervención un aspirador de secreciones y un aparato para respiración asistida. La aplicación de los fármacos, por lo tanto, ha de realizarse en la proximidad de una unidad de cuidados intensivos o en ella misma, o en un habitáculo hospitalario que reúna los requisitos necesarios. On the other hand, patient monitoring must necessarily include blood pressure, cardiac activity and oxygen saturation in arterial blood. This last parameter has not been previously used by Other specialists in this field. Additionally, it should be mentioned that the products of the invention are used by invasive procedures. Likewise, sedation and / or anesthesia is maintained with monitoring for a minimum period of three hours. In addition, there are minimum requirements necessary to perform this type of intervention, a secretion aspirator and an apparatus for assisted breathing. The application of the drugs, therefore, must be carried out in the vicinity of an intensive care unit or in it, or in a hospital cabin that meets the necessary requirements.
Para comprender la combinación de los productos reunidos en la invención y su finalidad en la consecución de la desintoxicación, se irá desarrollando el procedimiento en el que se encuentran inmersos. To understand the combination of the products gathered in the invention and their purpose in achieving detoxification, the procedure in which they are immersed will be developed.
En primera instancia, se requiré la toma opcional, un día antes del ingreso, de un laxante con el fin de realizar una limpieza intestinal lo más adecuada posible, sometiéndose el paciente a ayuno al menos ocho horas antes de la intervención. Asimismo se llevará a cabo un completo examen médico y psicológico, descartando cualquier tipo de patología que contraindique el tratamiento y se practicarán las determinaciones analíticas necesarias tales como hemograma, bioquímica, test de gestación en el caso en que el paciente se trate de una mujer en edad fértil, y otras exploraciones complementarias dirigidas según la semiología encontrada en la exploración física, como por ejemplo, radiografía de tórax, tomografía axial computerizada, electrocardiograma y electroencefalograma. En momentos próximos al ingreso se administrarán dosis repetidas de alfa adrenérgicos, tales como la guanfacina o clomdina, procurando que la tensión arterial no sea inferior a 90-60 mmHg ni que la frecuencia cardíaca sea inferior a 55 sístoles por minuto, una vez finalizada la exploración del paciente se puede comenzar la intervención. En este caso, se cogerá una vía venosa periférica y en su defecto una vía central, se administran antieméticos tales como el ondansetrón, y protectores gástricos tales como antihistamínicos H2, entre los que se puede encontrar la ranitidina y/o inhibidores de la bomba de protones como omeprazol y se procede a la sedación o anestesia del paciente con agentes anestésicos como propofol o bien el propofol y una benzodiacepina como el midazolan y que se mantendrán en perfusión constante a una dosis ajustada a la respuesta del paciente y no superior a las recomendadas por el laboratorio farmacéutico. A continuación se suministra el antagonista opiáceo, naloxona y/o naltrexona. Durante el periodo de sedación o anestesia se repetirá la administración de antagonista opiáceo según corresponda y a dosis que dependen de la cantidad de heroína a la que esté habituado el paciente. cada dosis de naltrexona nunca deberá exceder de 40 miligramos, ni la dosis total excederá de 50 miligramos. cuando el individuo a tratar deja de mostrar signos de abstinencia a opiáceos tales como piloercción, rinorrea y agitación motora, generalmente a las cuatro horas de la inducción del suefío. se realiza un test de naloxona consistente en la administración intravenosa de 0,8 miligramos de dicha sustancia. Si este test es negativo, es decir no aparecen signos de abstinencia, se procede a suspender la administración de anestésico, se despierta al paciente, y se recomienda la administración de un analgésico tal como ketorolaco, un antihistamínico H2 como la ranitidina, un benzodiacepina como el ketazolam y un agonista adrenérgico como la guanfacina. Finalizando la administración de fármacos, a las 24 horas del ingreso inicial, se puede dar el alta al paciente administrando de nuevo un antagonista opiáceo de vida media larga tal como la naltrexona. Una vez descrita suficientemente la naturaleza de la presente invención, así como una forma o disposición de llevarlo a la práctica, solo nos queda por afiadir que el sistema de la invención puede sufrir una serie de variaciones en partes de su contenido, habida cuenta que dichas alteraciones no varien sustancialmente las características que se reivindican a continuación. In the first instance, the optional intake, one day before admission, of a laxative is required in order to perform as well as possible intestinal cleansing, the patient fasting at least eight hours before the intervention. Likewise, a complete medical and psychological examination will be carried out, discarding any type of pathology that contraindicates the treatment and the necessary analytical determinations such as blood count, biochemistry, pregnancy test will be performed in the case in which the patient is a woman in fertile age, and other complementary examinations directed according to the semiology found in the physical examination, such as chest x-ray, computerized axial tomography, electrocardiogram and electroencephalogram. Repeated doses of alpha adrenergic agents, such as guanfacine or clomdine, will be administered at the time of admission, ensuring tension Blood pressure is not less than 90-60 mmHg or the heart rate is less than 55 systoles per minute, once the patient's examination is finished, the intervention can begin. In this case, a peripheral venous route will be taken and, in the absence thereof, a central route, antiemetics such as ondansetron, and gastric protectors such as H2 antihistamines are administered, among which ranitidine and / or pump inhibitors can be found. protons such as omeprazole and the patient is sedated or anesthetized with anesthetic agents such as propofol or propofol and a benzodiazepine such as midazolan and which will be kept in constant infusion at a dose adjusted to the patient's response and not higher than recommended by the pharmaceutical laboratory. The opioid antagonist, naloxone and / or naltrexone is then given. During the period of sedation or anesthesia the administration of opioid antagonist will be repeated as appropriate and at doses that depend on the amount of heroin to which the patient is accustomed. Each dose of naltrexone should never exceed 40 milligrams, nor will the total dose exceed 50 milligrams. when the individual to be treated ceases to show signs of opioid withdrawal such as piloerction, rhinorrhea and motor agitation, usually four hours after the induction of sleep. a naloxone test consisting of the intravenous administration of 0.8 milligrams of said substance is performed. If this test is negative, that is, no signs of withdrawal appear, the anesthetic administration is suspended, the patient is awakened, and the administration of an analgesic such as ketorolac, an H2 antihistamine such as ranitidine, a benzodiazepine such as ketazolam and an adrenergic agonist such as guanfacine. Ending drug administration, 24 hours after admission Initially, the patient can be discharged by re-administering a long-lived opioid antagonist such as naltrexone. Once the nature of the present invention has been sufficiently described, as well as a way or arrangement to put it into practice, it remains only to be added that the system of the invention may undergo a series of variations in parts of its content, given that said Alterations do not substantially vary the characteristics claimed below.

Claims

REIVINDICACIONES
1.- Combinación de fármacos como medicamento destinada a la supresión de dependencia de individuos a opiáceos, caracterizada por constar de: - Un laxante o enema de irrigación. 1.- Combination of drugs as a medicine for the suppression of dependence of individuals to opiates, characterized by consisting of: - A laxative or irrigation enema.
- Dosis repetidas de alfa-adrenérgicos. - Al menos una dosis de antieméticos.  - Repeated doses of alpha-adrenergic. - At least one dose of antiemetics.
- Protectores gástricos.  - Gastric protectors.
- Opcionalmente inhibidores de la bomba de protones,  - Optionally proton pump inhibitors,
Al menos una dosis de ansiolítico.  At least one dose of anxiolytic.
Al menos una dosis de inductores del sueño anestésico,  At least one dose of anesthetic sleep inducers,
Al menos una dosis de un fármaco antagonista opiáceo.  At least one dose of an opioid antagonist drug.
2.- Combinación de fármacos, según la primera reivindicación, caracterizada porque los alfa-adrenáergicos son guanfacina o clonidina. 2.- Combination of drugs, according to the first claim, characterized in that the alpha-adrenergic agents are guanfacine or clonidine.
3.- combinación de fármacos, según la primera reivindicación, caracterizada porque el antiemético es ondansetrón. 3.- combination of drugs, according to the first claim, characterized in that the antiemetic is ondansetron.
4.- Combinación de fármacos, según la primera reivindicación, caracterizada porque los protectores gástricos son antihistamínicos H2, como por ejemplo, ranitidina. 4.- Combination of drugs, according to the first claim, characterized in that the gastric protectors are H2 antihistamines, such as ranitidine.
5.- combinación de fármacos, según la primera reivindicación, caracterizada porque el inhibidor de la bomba de protones es omeprazol. 5.- combination of drugs, according to the first claim, characterized in that the inhibitor of Proton pump is omeprazole.
6.- Combinación de fármacos, según la primera reivindicación, caracterizada porque el ansiolítico es midazolam. 6.- Combination of drugs, according to the first claim, characterized in that the anxiolytic is midazolam.
7.- Combinación de fármacos, según la primera reivindicación, caracterizada porque los inductores del sueño anestésico son propofol o propofol y una benzodiacepina como el midazolam. 7.- Combination of drugs, according to the first claim, characterized in that the inducers of anesthetic sleep are propofol or propofol and a benzodiazepine such as midazolam.
8.- Combinación de fármacos, según la primera reivindicación, caracterizada porque el fármaco antagonista opiáceo es naloxona entre 0,4 y 1,5 miligramos por hora; o naltrexona entre 6 y 40 miligramos, preferentemente entre 10 y 30 miligramos y aún más preferentemente entre 12,5 y 18,5 miligramos. 8.- Combination of drugs, according to the first claim, characterized in that the opioid antagonist drug is naloxone between 0.4 and 1.5 milligrams per hour; or naltrexone between 6 and 40 milligrams, preferably between 10 and 30 milligrams and even more preferably between 12.5 and 18.5 milligrams.
9.- Combinación de fármacos, según la primera reivindicación, caracterizada por utilizar una sene de compuestos adicionales con posterioridad a los fármacos, siendo éstos un agonista alfa-adrenérgico, un protector gástrico y una benzodiacepina. 9.- Combination of drugs, according to the first claim, characterized by using a sene of additional compounds after the drugs, these being an alpha-adrenergic agonist, a gastric protector and a benzodiazepine.
PCT/ES1994/000108 1994-11-04 1994-11-04 Combination of chemical compounds used as a medicament intended to suppress the dependence of individuals to opioids WO1996014071A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
CA002180117A CA2180117A1 (en) 1994-11-04 1994-11-04 Combination of chemical compounds used as a medicament intended to suppress the dependence of individuals to opioids
HU9601835A HUT75938A (en) 1994-11-04 1994-11-04 Combination of chemical compounds used as a medicament intended to suppress the dependence of individuals to opioids
US08/666,533 US6103734A (en) 1994-11-04 1994-11-04 Drug combination as a medicament to suppress the dependence of individuals to opiates
BR9408488A BR9408488A (en) 1994-11-04 1994-11-04 Combination of drugs as a medicine to suppress opiate addiction in individuals
PCT/ES1994/000108 WO1996014071A1 (en) 1994-11-04 1994-11-04 Combination of chemical compounds used as a medicament intended to suppress the dependence of individuals to opioids
JP8515069A JPH09507865A (en) 1994-11-04 1994-11-04 Drug combinations as agents that suppress an individual's dependence on narcotics
NO962740A NO962740L (en) 1994-11-04 1996-06-28 Medication combination intended as a drug to suppress individuals' opiate addiction
FI962728A FI962728A (en) 1994-11-04 1996-07-02 Drug composition for use as a medicine that prevents individuals' dependence on optiates

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BR9408488A BR9408488A (en) 1994-11-04 1994-11-04 Combination of drugs as a medicine to suppress opiate addiction in individuals
PCT/ES1994/000108 WO1996014071A1 (en) 1994-11-04 1994-11-04 Combination of chemical compounds used as a medicament intended to suppress the dependence of individuals to opioids

Publications (1)

Publication Number Publication Date
WO1996014071A1 true WO1996014071A1 (en) 1996-05-17

Family

ID=25664647

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/ES1994/000108 WO1996014071A1 (en) 1994-11-04 1994-11-04 Combination of chemical compounds used as a medicament intended to suppress the dependence of individuals to opioids

Country Status (1)

Country Link
WO (1) WO1996014071A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998047481A1 (en) * 1997-04-18 1998-10-29 Janssen Pharmaceutica N.V. Use of 5ht3 antagonists for promoting intestinal lavage
WO2001064201A2 (en) * 2000-02-28 2001-09-07 Britannia Pharmaceuticals Limited Restricting reinstatement of drug use
WO2001068080A2 (en) * 2000-03-15 2001-09-20 Wolfgang Sadee Neutral antagonists and use thereof in treating drug abuse

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
C. BREWER: "Opioid withdrawal and naltrexone induction in 48-72 hours with minimal drop-out, using a modification of the naltrexone-clonidine technique.", BR. J. PSICHIATRY, vol. 153, 1988, pages 340 - 343 *
E. VINING: "Clinical utility of rapid clonidine-naltrexone detoxificarion for opioid abusers", BR. J. ADDICT., vol. 83, no. 5, 1988, pages 567 - 575 *
J. FLOREZ: "Farmacología Humana", 1992, EDICIONES CIENTIFICAS Y TECNICAS, S.A., BARCELONA *
J.J. LEGARDA: "A 24-h inpatient detoxification treatment for heroin addicts: a preliminary investigation.", DRUG AND ALCOHOL DEPENDENCE, vol. 35, no. 2, May 1994 (1994-05-01), pages 91 - 93 *
N. LOIMER: "Ultrashort nonivasive opiate detoxification", AM J PSICHIATRY, vol. 150, no. 5, 1993, pages 839 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998047481A1 (en) * 1997-04-18 1998-10-29 Janssen Pharmaceutica N.V. Use of 5ht3 antagonists for promoting intestinal lavage
US6235745B1 (en) 1997-04-18 2001-05-22 Janssen Pharmaceutica N.V. Use of 5HT3, antagonists for promoting intestinal lavage
US6555546B2 (en) 1997-04-18 2003-04-29 Janssen Pharmaceutics, N.V. Use of 5HT3 antagonists for promoting intestinal lavage
WO2001064201A2 (en) * 2000-02-28 2001-09-07 Britannia Pharmaceuticals Limited Restricting reinstatement of drug use
WO2001064201A3 (en) * 2000-02-28 2002-07-18 Britannia Pharmaceuticals Ltd Restricting reinstatement of drug use
WO2001068080A2 (en) * 2000-03-15 2001-09-20 Wolfgang Sadee Neutral antagonists and use thereof in treating drug abuse
WO2001068080A3 (en) * 2000-03-15 2002-07-04 Wolfgang Sadee Neutral antagonists and use thereof in treating drug abuse
US6713488B2 (en) 2000-03-15 2004-03-30 Sadee Wolfgang Neutral antagonists and use thereof in treating drug abuse

Similar Documents

Publication Publication Date Title
Seoane et al. Efficacy and safety of two new methods of rapid intravenous detoxification in heroin addicts previously treated without success
Al-Zahrani et al. Comparison of oral midazolam with a combination of oral midazolam and nitrous oxide-oxygen inhalation in the effectiveness of dental sedation for young children
Hallonsten et al. EAPD guidelines on sedation in paediatric dentistry
Thompson et al. Nitrous oxide as an analgesic in acute myocardial infarction
Lee et al. Intranasal administration of dexmedetomidine (DEX) as a premedication for pediatric patients undergoing general anesthesia for dental treatment
US6103734A (en) Drug combination as a medicament to suppress the dependence of individuals to opiates
PT1378267E (en) Use of flumazenil to produce a medicament for the treatment of cocaine dependency
WO1996014071A1 (en) Combination of chemical compounds used as a medicament intended to suppress the dependence of individuals to opioids
Inagaki et al. The efficacy and safety of dexmedetomidine for procedural sedation in patients receiving local anesthesia outside the intensive care unit: a prospective, double-blind, randomized clinical phase III trial in Japan
Lund et al. Anesthetic challenges posed by heavy kratom users
Gillman et al. Analgesic nitrous oxide in neuropsychiatry: past, present and future
Varela et al. Intravenous sedation for the closed reduction of fractures in children.
Muthiah et al. Intravenous labetolol in treating hypertensive crisis following dexmedetomidine infusion for procedural sedation
Rehi et al. Comparison of Propofol Ketamine and Propofol Fentanyl Combinations to Make Patient Comfort and Psychologically Ease in Colonoscopy Procedures
Jorgensen et al. Premedication in dentistry
Lippmann et al. Butorphanol and promethazine as pre-anaesthetic medication
Patt Delayed postoperative respiratory depression associated with oxymorphone
Chrisman et al. Outpatient anesthesia
Ahlawat et al. DEXMEDETOMEDINE AND KETAMINE COMBINED SEDATION FOR PAEDIATRIC PATIENTS UNDERGOING MAGNETIC RESONANCE IMAGING-CASE SERIES
Farsani et al. Comparison of Blood Glucose Levels, Blood Pressure, Heart Rate and Oxygen Saturation among Diabetic Patients Undergoing General Anesthesia and Local Anesthesia with Sedation: A Cross-Sectional Study
Clark et al. Use of benzoctamine as sedative in patients with respiratory failure
Iniya Conscious Sedation for Cataract Surgery done Under Retrobulbar Block: A Comparative Study Evaluating the Effects of Midazolam and Dexmedetomidine
Jimin et al. Effects of remimazolam combined with sufentanil on hemodynamics during anesthetic induction in advanced-age patients with hypertension undergoing orthopedic surgery of the lower limbs: a randomized, controlled trial
RU2549474C1 (en) Method for preanaesthetic medication preceding gynaecological surgeries under general anaesthesia
Lomanto et al. Problems in diagnosing halothane hepatitis.

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): BR CA FI HU JP NO PL RO RU US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

WWE Wipo information: entry into national phase

Ref document number: 2180117

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 962728

Country of ref document: FI

WWE Wipo information: entry into national phase

Ref document number: 1994931598

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1994931598

Country of ref document: EP

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 08666533

Country of ref document: US

122 Ep: pct application non-entry in european phase