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WO2012009823A1 - Formulation pharmaceutique tranquilisante/sédative à base de neurostéréoïdes et dérivé phénotiazinique destinés à une utilisation chez les mammifères - Google Patents

Formulation pharmaceutique tranquilisante/sédative à base de neurostéréoïdes et dérivé phénotiazinique destinés à une utilisation chez les mammifères Download PDF

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Publication number
WO2012009823A1
WO2012009823A1 PCT/CL2011/000040 CL2011000040W WO2012009823A1 WO 2012009823 A1 WO2012009823 A1 WO 2012009823A1 CL 2011000040 W CL2011000040 W CL 2011000040W WO 2012009823 A1 WO2012009823 A1 WO 2012009823A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical formulation
acepromazine
activity
add
tranquilizer
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CL2011/000040
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English (en)
Spanish (es)
Inventor
Luis Aguayo Hernandez
Mario Silva Osorio
José BECERRA ALLENDE
Jorge Fuentealba Arcos
Claudia Perez Manriquez
Antonio Bizama Reyes
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Universidad de Concepcion
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Universidad de Concepcion
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 Universidad de Concepcion filed Critical Universidad de Concepcion
Publication of WO2012009823A1 publication Critical patent/WO2012009823A1/fr
Anticipated expiration legal-status Critical
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Classifications

    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the invention corresponds to a pharmaceutical formulation, tranquilizer / sedative, comprising at least one neurosteroid and a tranquilizer of the phenothiazine derivative type, which is used as a pre-anesthetic in mammals.
  • drugs with a calming and sedative effect are used to facilitate patient management in procedures such as: placement of probes, radiography, animal transfers, capture of wild animals, among others.
  • the term tranquilizer and sedative are used as synonyms, however, the former does not produce a depression of the degree of consciousness by increasing the dose, instead the sedatives, by increasing the dose, significantly depress the central nervous system.
  • the researchers define the term sedation / reassurance, as the decrease in the degree of consciousness characterized by a decrease in motor activity and a slower response time to a stimulus. Sedatives generate depression of the central nervous system at high doses, instead high doses of tranquilizers, give rise to extrapyramidal signs such as muscle tremors.
  • sedative doses of propofol mainly reduce the activity of neurons in the cerebral cortex, while hypnotic doses significantly decrease blood flow and metabolism of subcortical structures such as thalamus, midbrain, reticular formation.
  • a significant number of drugs including tranquilizers, sedatives and general anesthetics, modulate GABA ionotropic receptors A) prolonging the opening of chloride channels that mediate rapid synaptic inhibition, generating inhibitory postsynaptic currents. It has also been related to processes such as regulation of wakefulness, anxiety, muscle tension, memory and epileptiform seizures.
  • GABA is one of the main inhibitory neurotransmitters of the central nervous system. In mammals, it has a hyperpolarizing action by increasing the influence of IC " on the postsynaptic neuron; approximately 70% to 90% of the neostriate uses GABA as an inhibitory neurotransmitter and there is a complex and close relationship between GABAergic and dopaminergic neurons, where GABA acts by depressing the dopaminergic pathway.
  • Diazepam is the drug widely used for its sedative, anxiolytic, and hypnotic effects.
  • the sedative action of this benzodiazepine whose molecular target is the GABAA receptor; It is scarce in small animals and its use independently is not useful in performing diagnostic or therapeutic procedures; On the other hand, the muscle relaxation that it produces, makes it the agent of choice in dissociative anesthesia.
  • Xylazine is 2 (2,6-dimethiphenylamino) -4H-5,6-dihydro-1, 3-thiazine hydrochloride and, pharmacologically, is classified as an analgesic and sedative.
  • Xylazine is an adrenergic agonist at 2 , although it has also been observed that it acts on cholinergic, serotorinergic, H2 histamine and opioid receptors.
  • the administration of xylazine causes depression of the heart rate due to first and second degree atrioventricular block.
  • Xylazine should be used with caution or avoided in animals with: gastrointestinal problems, liver disease, respiratory depression or pharyngeal or laryngeal dysfunction, patients with heart disease or diseases in the urinary tract.
  • Accepromazine is probably the most common tranquilizer used in veterinary medicine and corresponds to 2-acetyl-10 - (- 3-dimethylaminopropyl). Its effect is based on the central blockade of excitatory dopaminergic receptors, which results in tranquilizing, antihemetic and hypothermic effects. In addition to causing a decrease in motor activity in all animals, at high doses, they cause extrapyramidal or cataleptic effects.
  • the central catecolamine blockade produces a peripheral ⁇ -adrenergic block that causes peripheral vasodilation and hypotension, so its use in hypovolemic patients with cardiac alterations should be avoided. It causes a mild anticholinergic effect, which explains that at the digestive level there is a depression of gastrointestinal motility. It also produces a decrease in body temperature in all animal species and a significant decrease in respiratory rate.
  • Accepromazine can be administered intravenously, intramuscularly, subcutaneously or orally in dogs, cats and horses. Being a liver metabolizing drug should be avoided in patients with problems in this organ and, particularly, should be avoided in breeds of brachycephalic dogs such as boxer, Pekingese, buldog since they are especially sensitive to it.
  • Neuroactive steroids according to the present invention are suitable for the treatment of those states controlled by the action of the neurotransmitter (gamma) -aminobutyric acid (GABA), as substances that exhibit activity against pain, anxiety and insomnia and also as anesthetics.
  • GABA neurotransmitter
  • the difference with our technology is that it is not a new molecule that we want to safeguard, and its structure differs with our initiative.
  • Some pharmacological antecedents of steroidal derivatives that act on the central nervous system show that they are capable of interacting with membrane receptors, mainly in neurons and produce a rapid change in the excitability of the central nervous system, causing a depressing effect on it.
  • the present technology comprises a veterinary tranquilizer / sedative formulation comprising at least one neurosteroid with tranquilizing activity, preferably but not exclusively 1,4-androstadien-3,17-dione (ADD), a tranquilizer of the phenothiazine derivative type, preferably but not exclusively acepromazine maleate; and pharmaceutically acceptable excipients.
  • ADD 1,4-androstadien-3,17-dione
  • a tranquilizer of the phenothiazine derivative type preferably but not exclusively acepromazine maleate
  • pharmaceutically acceptable excipients pharmaceutically acceptable excipients.
  • acepromazine in a concentration range between 1-100 mg / Kg, approximately
  • 1,4-androstadien-3,17-dione in a concentration range between 50-100 mg / Kg, approximately
  • the combined use of these two molecules manages to significantly reduce the motor activity of the individual, unlike the effect caused by the individual use of said molecules.
  • ADD 1,4-androstadiene-3,17-dione
  • the anxiolytic capacity of ADD is evaluated in male rats.
  • the light / dark test is carried out, which consists in measuring the residence time of the individuals both in the dark compartment and in the light compartment of a box enabled for it, for 15 min for each treatment group.
  • Figure 1 shows the effects of ADD (50-100 mg / kg) compared to the anxiolytic effects of diazepam (0.5 mg / kg).
  • the control group (animals without treatment), has a homogeneous behavior that is characterized by the permanence of the animals in the field of darkness almost 100% of the observation time (15 min), recording a time of exploration of the light field of 10 ⁇ 3.5 seconds, which is equivalent to less than 1.2% of the total duration of the experiment. Animals treated with diazepam, two minutes after the drug is administered, begin to perform intermittent scans to the light field, registering a significantly longer time in the light field at the end of the experiment (p ⁇ 0.001) than the control group (close to 2000%).
  • Animals treated with ADD do not modify the behavior of permanence in the dark light areas of the box. As the dose increases, no behavioral changes are observed, however unlike the control group, animals treated with ADD have visible degrees of immobility in the dark sector of the experimental box. Unlike diazepam, ADD shows no anxiolytic effect.
  • n number of rats per group.
  • the intramuscular route is used to administer steroids, in order to simulate a real clinical situation, but it can also be administered intravenously.
  • the effect of ADD starts on average at 5 minutes post administration in all animals, therefore the measurements start from that moment to not interfere with the results. Preliminary tests show that the duration of the ADD effect is approximately 30 minutes and the maximum effect is reached 10 minutes after administration.
  • the rats Five minutes after the administration of the respective treatments, the rats are placed in a transparent acrylic box (47 x 35 x 30 cm). Spontaneous mobility is measured by direct observation, recording the number of lifts and grooming time for 10 min.
  • This group has an average of 23.5 ⁇ 3.9 quadrant changes during the measurement period, which is combined with some vertical movements where the rats stand on their hind limbs and rest their hands on the vertical part of the box ( raised), sniffing and exploring its perimeter.
  • the average number of lifts observed is 18.8 ⁇ 2.7. All this activity is associated with grooming intervals, which consist of stereotyped cleaning movements performed by individuals. This activity is observed in a total time of 112.5 ⁇ 8 seconds.
  • Accepromazine produces bradycardia and direct myocardial depression, which can aggravate hypotension and even decompensate those patients with congestive heart failure.
  • acepromazine and 1,4-androstadien-3,17-dione, allows to reduce the dose of acepromazine by 50% and achieve considerable calming effects, as observed in rats, which has a direct impact on the reduction of adverse effects presented by acepromazine and that restrict its clinical use.
  • the patch-clamp technique is performed in full cell mode.
  • ADD registration by this technique shows potentiating effects of GABA evoked currents (2.5 ⁇ ) in hippocampal neurons of rat embryos, as shown in Figure No. 5A.
  • ADD modulation was rapidly and completely reversible.
  • ADD induces a potentiation of GABAergic currents of approximately 30%, which translates into a significant reduction in GABA EC 50 from 8.9 to 6.2 ⁇ .
  • the steroids were obtained by biotransformation processes, they were grown in fungal strains in liquid medium for 120 h, with agitation of 120 rpm. After 96 h of culture, the steroidal substrate of plant origin was added at a concentration that ranged between 500-2000 mg / l. Samples of 20 ml were taken daily, in order to assess the biotransformer capacity of the strains. The hydroxylation effect of steroids was evaluated by parameters; pH of initial medium, temperature, etc.
  • the culture is filtered by separating the mycelium from the liquid medium.
  • the liquid solution was extracted with ethyl acetate subsequently evaporated, finally obtaining a total extract with the biotransformation products.
  • the spheroid for experimentation was dissolved in a solution of 10% polyethoxylated castor oil and 90% physiological serum, and then microagitated at a temperature of 45 ° C for 10 minutes.
  • Accepromazine was used as a reference drug to compare tranquilizer and sedative activity and Diazepam as a control drug to assess the anxiolytic effect.
  • the steroid administration route was intramuscular (i.m) and the doses used were determined by preliminary tests. Doses were administered in a range between 30 to 150 mg / kg, without exceeding a final injection volume of 1 ml.
  • Spontaneous motor activity Five minutes after administration of the steroid the rats were placed in a transparent acrylic box of dimensions 47 x 35 x 30 cm. Spontaneous mobility was measured by direct observation, recording the number of lifts and grooming time for 10 min.
  • Light / Dark Scan This test has been widely used to measure anxiety in rodents. It consists of using an acrylic box of dimensions 60 x 50 x 30cm, which is divided into two zones, one of darkness and another of light, communicated by a 10 x 7cm door, which allows easy movement in both fields. The residence time in each field was recorded, before and after administration of the steroid, and of the drugs, for 15 minutes. After each test, the box was carefully cleaned with 70% alcohol.
  • Locomotive activity This test was performed to evaluate the locomotive activity of individuals. A 47 x 25 cm box was used, which was divided into four quadrants of equal dimensions. Five minutes after administration of the steroid, the total number of quadrant changes was recorded by direct observation for a time of 10 min.
  • Hippocampal neurons from rat embryos (C57BL / j6) of 18 days gestation were cultured. Neurons were used, in electrophysiological tests, at 12 days of culture. Culture medium with 80% MEM was used; 10% fetal bovine serum, 10% horse serum, 1 ml of supplementary nutrients.
  • Electrophysiological tests The full-cell patch-clamp technique was used to obtain records of the effects of all steroids, with an Axon 200-B amplifier.
  • the micropipettes were filled with: 140 mM KCI, 10 mM BAPTA, 10 mM HEPES (pH 7.4), 4 mM MgCI 2 , 0.3 mM GTP and 2 mM ATP-Na 2 , 300 mOSM.
  • the external solution contained: 150 mM NaCI, 5.4 mM KCI, 2.0 mM CaCI 2 , 1.0 mM MgCI 2 , 10 mM HEPES (pH 7.4) and 10 mM glucose.
  • the fixing potential was -60 mV.
  • the records were made with a 5 kHz low pass bessel filter and a gain of 5 mV / pA.
  • the currents were measured in the presence of 2.5 ⁇ of GABA alone and co-applied with 10 ⁇ of different ADDs. Variations were represented as a percentage of the control ( * p ⁇ 0.05; * * p ⁇ 0.01)

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Anesthesiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

La présente invention concerne une technologie orientée vers le secteur vétérinaire, laquelle correspond à une formulation pharmaceutique tranquilisante/sédative pour diminuer l'activité motrice comprenant au moins un neurostéréoïdes ayant une activité tranquilisante et un tranquilisant de type dérivé phénotiazinique, utilisé en tant qu'agent pré-anesthésique chez des mammifères, de préférence, des animaux de petites tailles et chez des patients à risque.
PCT/CL2011/000040 2010-07-19 2011-07-15 Formulation pharmaceutique tranquilisante/sédative à base de neurostéréoïdes et dérivé phénotiazinique destinés à une utilisation chez les mammifères Ceased WO2012009823A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CL764-2010 2010-07-19
CL2010000764A CL2010000764A1 (es) 2010-07-19 2010-07-19 Formulacion farmaceutica veterinaria que comprende un neuroesteroide con actividad tranquilizante como 1,4-androstadien-3,17-diona y un tranquilizante fenotiazinico como acepromazina; y su uso como pre-anestesico, preferentemente en pacientes de alto riesgo como hipotensos e hipovolemicos, y/o con problemas cardiovasculares.

Publications (1)

Publication Number Publication Date
WO2012009823A1 true WO2012009823A1 (fr) 2012-01-26

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PCT/CL2011/000040 Ceased WO2012009823A1 (fr) 2010-07-19 2011-07-15 Formulation pharmaceutique tranquilisante/sédative à base de neurostéréoïdes et dérivé phénotiazinique destinés à une utilisation chez les mammifères

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CL (1) CL2010000764A1 (fr)
WO (1) WO2012009823A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4213981A (en) * 1978-09-13 1980-07-22 American Home Products Corporation Injectable anesthetic
WO2009082039A1 (fr) * 2007-12-26 2009-07-02 Eisai R & D Management Co., Ltd. Antagonistes des récepteurs ampa pour le traitement de l'épilepsie, de troubles mentaux ou de déficits de l'organe sensoriel

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4213981A (en) * 1978-09-13 1980-07-22 American Home Products Corporation Injectable anesthetic
WO2009082039A1 (fr) * 2007-12-26 2009-07-02 Eisai R & D Management Co., Ltd. Antagonistes des récepteurs ampa pour le traitement de l'épilepsie, de troubles mentaux ou de déficits de l'organe sensoriel

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
EVANS A. T. ET AL.: "Anesthesia of Ferrets", SEMINARS IN AVIAN AND EXOTIC PET MEDICINE, vol. 7, no. 1, 1998, pages 48 - 52, XP005466234 *
SHALES, C. J. ET AL.: "Care Report: Dorso-medial antebrachiocarpal luxation with radio-ulna luxation in a domestic shorthair", JOURNAL OF FELINE MEDICINE AND SURGERY, vol. 8, 2006, pages 197 - 202 *

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CL2010000764A1 (es) 2010-10-29

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