WO1991019508A1 - Regenerateur des nerfs - Google Patents

Regenerateur des nerfs Download PDF

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Publication number
WO1991019508A1
WO1991019508A1 PCT/DE1991/000501 DE9100501W WO9119508A1 WO 1991019508 A1 WO1991019508 A1 WO 1991019508A1 DE 9100501 W DE9100501 W DE 9100501W WO 9119508 A1 WO9119508 A1 WO 9119508A1
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WO
WIPO (PCT)
Prior art keywords
use according
medicament
nerve
interleukin
messenger
Prior art date
Application number
PCT/DE1991/000501
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German (de)
English (en)
Inventor
Peter Wehling
Original Assignee
Peter Wehling
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.)
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Publication date
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Publication of WO1991019508A1 publication Critical patent/WO1991019508A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2006—IL-1

Definitions

  • the invention relates to the manufacture of a medicament for the regeneration of nerves, the function of which is impaired due to a traumatic event or otherwise, for example due to burns or radiation damage.
  • nerve cells In mammals and also in humans, many more nerve cells initially develop than are later used in the development of the nervous system. So-called neurotrophic factors then decide in the further course of development which nerve cell remains alive and which does not. It can only survive if a nerve cell makes contact with a target tissue via its axons - the stimulating cell processes - in which the neurotrophic substance necessary for its growth is contained or is produced. If this contact, e.g. interrupted by a traumatic event, the cell dies.
  • the longest known neurotrophic factor is the peptide NGF (nerve growth factor). NGF keeps both sympathetic and some types of sensory cells alive. In addition to the nerve growth factor NGF, other proteins have recently been discovered that enable the survival of the respective nerve cells. For example, the peptide BDNF (brain-derived neurotrophic factor), which is primarily responsible for the functionality of sensory nerve cells and neurons that are involved in the visual process. As well as factors not specified in more detail, such as the fibroblast growth factor FGF, the ciliary neurotrophic factor CNTF, the purpurin and the activin, for which a survival effect has so far only been demonstrated in vitro, that is to say in cell culture. The starting point for the task was investigations by Lindholm et al. (Nature, Vol.
  • the object of the invention is to provide a medicament which promotes the regeneration of nerves after a traumatic event, such as a severing of the nerve, or in the event of burns and radiation damage.
  • a traumatic event such as a severing of the nerve, or in the event of burns and radiation damage.
  • This object is achieved according to claim 1 by the use of messenger substances from the immune system for the manufacture of a medicament for the regeneration of nerves.
  • the messenger substances are advantageously selected from the group of kinins, in particular cytokines and lyphokines, that is to say leukotrienes, prostaglandins, interleukins and interferons, and combinations thereof.
  • Interleukin-1 is very particularly preferred.
  • kinins such as interleukin-1, which is mainly produced by macrophages and monocytes but also by other cells, have healing properties as well as tissue-destroying effects.
  • This opposite effect can, however, be explained by the pathophysiology of the inflammation and the diverse properties and functions of the messenger substances of the immune system.
  • interleukin has a variety of biological functions in the immune response: it activates the T cells by inducing the production of interleukin-2 and its receptor; it induces fever; it increases connective tissue absorption and stimulates fibroblasts and synovial cells (e.g. synovial cells HIG-82, synovial skin cells), which themselves also produce interleukin-1, for the release of protaglandins.
  • synovial cells e.g. synovial cells HIG-82, synovial skin cells
  • Interleukin contains two related proteins, the alpha and the beta form of interleukin 1, both of which react with the same receptor. However, due to this structural relationship, both interleukins should be particularly suitable for the production of a medicament for the regeneration of nerve cells. With regard to the treatment of people, the use of genetically derived, human inter - I _
  • the interleukin-1 is advantageously contained in the medicament between 50 and 5000 units / ml if the medicament is not subsequently diluted.
  • the nerve severance leads to two competing pathophysiological processes at the severing site: on the one hand, the amputated neuron tries to regain its old extent by sprouting appendages in the distal part of the injury (cellular regeneration) - the number of However, nerve cells remain unchanged - on the other hand, this is countered by injury-related fibroplasia and scar formation, whereby the number of connective tissue cells increases. The new connective tissue cells then block the free space distal to the injury and thus the nerve regeneration.
  • the process of wound healing can be inhibited at various levels.
  • Preferred here is, among other things, the addition of connective tissue-dissolving and / or scar-destroying substances to the medicament:
  • Such substances are, for example, collagenases and / or peptidases, such as chymopapain, papain, chymotrypsin, trypsin, etc.
  • the addition of collagenase in a concentration between is very particularly preferred 100 - 10,000 U / ml.
  • substances such as proline derivatives, in particular cis-hydroxyproline, is also advantageous 7 -
  • hormones and factors which promote nerve growth and / or delay wound healing are also advantageous.
  • Corticosteroids and their derivatives, progesterone, estrogen, methyl-prednisolone, triamzinolone acetate, as well as insulin, PDGF (platelet-derived growth factor), GH (growth hormone), FGF (fibroblast growth factor), CNTF (ciliary neurotrophic factor) are recommended for this ), Purple, activin, and descendants thereof.
  • steroids have an anti-inflammatory effect for weeks and suppress wound healing.
  • Estrogen and progesterone also show a similar effect in wound healing.
  • the topical application of triamzinolone acetate also shows an improvement in nerve regeneration.
  • the medicament additionally contains a fibrin glue made of aprotinin-CaCl ⁇ ; Thrombin and fibrinogen; Tissucol W2 (Red List: 47047).
  • the medicament can additionally have surfactants, solvents, solubilizers, stabilizers, antioxidants, such as dithioerythritol, in order to ensure the durability and effectiveness of the composition.
  • the form of administration of the medicament is advantageously adapted to the treatment method. Due to the different possible uses, the following forms of application of the drug appear to be advantageous: as an injection solution, as an infusion solution for local and / or systemic infusions, as a therapeutic system, e.g. as a dispenser implant, dispenser balls, as a solution and jelly for spreading or as an intermediate filling.
  • Figure 1 is a scheme for performing animal experiments
  • FIG. 2 shows the clinical evaluation of the animal experiments with regard to the average motor power of the right hind paw
  • FIG. 3 shows the representative derivation of the evoked spinal potential and the evoked muscle activity in the intrinsic foot muscles after irritation of the sciatic nerve proximal or distal to the severing point on a test animal, whereby in addition to the epidural suture and fibrin seal, the medicament according to the invention was used;
  • FIG. 4 analogously to FIG. 3, a representative derivation of the evoked spinal potential and the evoked muscle activity in the intrinsic foot muscles after irritation of the sciatic nerve, only one animal from the control group was used;
  • FIG. 5 shows the change in the amplitude of the evoked spinal potential in the test and control group as a function of the time after the operation;
  • FIG. 6 shows the height of the amplitudes in the intrinsic foot muscles measured after stimulation of the sciatic nerve proximal to the nerve severing in the control and test group;
  • FIG. 7 shows the average values of the measured nerve conduction speed (NLG) in the control and experimental group.
  • Figure 8b their relative frequency as a function of the total fiber diameter of the myelinated nerve fibers.
  • the surgical procedure was as follows: In nembutal anesthesia (40-50 mg / kg body weight), the right sciatic nerve of the Wistar rat was exposed laterally up to the branching in the tibial and peroneal nerves. Then 3 marker threads (9-0 Ethilon W2 , BV-4, monofilament, polyamide, from Ethicon) were placed epineurally in the longitudinal direction to prevent the nerves from rotating. The nerve was severed with a smooth cut about 1 cm proximal to branching with the aid of microscissors.
  • the epineural suture was made with 6 threads of 9-0 Ethilon. Approx. 1mm proximal and distal of the separation point between the nerve slowly injected with 0.05 ml of dissolved IL-beta (50 U; from Genzy e) at a concentration of 1000 U / ml. The injection was slow, so that the continuation of the 11-1 solution into the severing area could be followed under the surgical microscope.
  • the rat interleukin-1 beta used had a molecular weight of 17,000 daltons; it was dissolved in buffer solution shortly before the injection.
  • the seam area was then treated with 0.05 ml of fibrin glue (100 IU aprotinin calcium chloride / ml + 50 IU thrombin and fibrinogen; Tissucol TM) coated, in order to prevent escapes that the interleukin-1 from the tions Symposiumt Transsek-.
  • fibrin glue 100 IU aprotinin calcium chloride / ml + 50 IU thrombin and fibrinogen; Tissucol TM coated
  • the control group (6 animals) was treated and examined immediately. However, no interleukin-1 but physiological saline was injected.
  • the animals in the experimental and control group were observed over a period of 3 months.
  • the animals were completely neurophysiologically examined before the operation as well as 7, 12, 15, 25, 32, 40, 60 (80th, for IL-1) and 90 days after the operation.
  • In order to be able to rule out an autonomous denervation behavior (biting the hind paw) of the animals they were photographed in the same interval.
  • After 3 months, all test animals and 3 control animals were assessed "clinically" and ⁇ torphometrically. The course of the experiment and the analyzes is shown schematically in FIG. 1.
  • the clinical findings are shown graphically in FIG. 2.
  • the SFI according to de Medinacelli is plotted in percent and the ordinate shows the postoperative time.
  • the graphic shows the Average motor performance of the right hind paw in the experimental (11-1 + suture / fibrin) and control group (suture / fibrin only).
  • the experimental group comprises 5 animals and the control group 6 animals. In the test group, the clinical motor performance is increased on average. The under- . difference is significant (p ⁇ 0.05).
  • a weakened toe spread reflex was to be triggered in all animals after 90 days. In the control group, however, only 3 animals showed this reflex, the others not. '
  • the evoked spinal potentials were carried out at the level L1 after simultaneous irritation of the tibial nerve distal to the severance at the level of the Achilles tendon insertion.
  • CAMP intrinsic foot muscles
  • Figure 3 shows the representative derivative of . evoked spinal potential (SSEP L1, left lane) and the evoked muscle activity in the intrinsic foot muscles (CAMP, right lane) after irritation of the proximal sciatic nerve (CAMP) or distal (SSEP) of the severed parts on a test animal e 'iner epidural seam and Fibrinab ⁇ seal and using the invention Medika ⁇ management.
  • the animal in question developed complete foot paresis immediately after severing the nerve, which improved significantly from the 60th clinical day.
  • the filter setting was LF: 10 Hz + HF: 10 kHz
  • the SSEP (left lane) corresponds to 64 averaged answers.
  • the CAMP (right lane) corresponds to a unique irritation of the nerve. Supramaximal stimuli were used. If it was not possible to determine the threshold value due to complete paresis, the irritation was caused by applying 40 mV.
  • FIG. 4 shows an analogous investigation on a control animal. The severed parts were only treated by epidural suture and fibrin sealing, but no treatment with interleukin was carried out.
  • the control animal also developed a complete foot paresis immediately after severing the nerve, which only improved slightly over time.
  • the filter setting was LF: 10 Hz + HF: 10 kHz.
  • the SSEP on the left corresponds to 64 averaged answers.
  • the CAMP corresponds to a unique irritation of the nerve.
  • Supramaximal stimuli were used.
  • FIG. 5 shows the amplitude values (SSEP-Ll) of the evoked spinal nerve potentials in ⁇ V at level L1 in the test and control group as a function of the time after the operation.
  • the irritation occurs in the right tibial nerve distal to the nerve severance at the level of the Achilles tendon. The point of irritation was thus approx. 3.5 cm from the severing point.
  • the evoked muscle response of the intrinsic foot muscles in the aforementioned experiment on the treated side showed a high level of reproducibility with an intra- and inter-individual constant increase in the amplitude of the CMAP to be observed in the two groups from the 40th to 60th postoperative day. Up to the 32nd postoperative day, no potential in the dependent foot muscles could be derived in both groups on the treated side. From the 40th postoperative day in the experimental group (11-1, 5 animals) a potential could be derived in 2 animals. In contrast, this was not possible with any of the animals in the control group.
  • FIG. 7 graphically shows and evaluates the height of the motor NLG in m / s (vertical axis) preoperatively and 90 days postoperatively in the test and control group.
  • the average values with standard deviation of the measured nerve conduction velocity (NLG) are shown.
  • the NLG was determined from the derivation of the muscle response after irritation of the sciatic nerve. ximal and distal of the nerve severing area. If a CAMP was not detectable at two different stimulation sites, this animal was not included in the static calculation of the NLG.
  • the NLG could be determined in one animal in the control group; in the test group (with interleukin-1), however, in all. After 90 days, the NLG could be measured in all animals of both groups. The difference in motor nerve conduction speed after 90 days of treatment is significant.
  • FIGS. 8a and b The result of the morphometric examination in the test and control group is shown in FIGS. 8a and b.
  • FIG. 8a shows the total number of myelinated fibers 5 mm distal to the nerve severing site 12 weeks after the severing.
  • the counting shows that in the group protests ⁇ the total fiber number (m: 13336) is significantly higher relative to the Kon ⁇ roller (9685 m). This difference has a significance level of p ⁇ 0.004.
  • the total nerve fiber diameter is indicated on the horizontal axis in steps of 0.5 ⁇ m.
  • the mean diameter of the axon was 2.108 ⁇ m (sd: 1.032) in the test group and 2.271 ⁇ m in the control group (sd: 1.068).
  • results show, compared to a control group, a significant improvement in neurophysiological parameters and clinically functional values, the total number of myelinated axons 5 mm distal to the transection was increased, the morphometric parameters remained unchanged.
  • the pathophysiological mechanism behind this improved functional nerve regeneration result can only be assessed hypothetically.
  • the membrane properties of the nerve fibers are possibly stabilized in the sense of improved resistance to damaging influences which take place in the submicroscopic range.

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  • Health & Medical Sciences (AREA)
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  • Gastroenterology & Hepatology (AREA)
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Abstract

Une composition stimule la régénération des nerfs après un évènement traumatisant, tel que le sectionnement d'un nerf, ou lors de lésions dues à des brûlures ou à des rayonnements. A cet effet, on utilise les substances messagères du système immunitaire, de préférence des substances sélectionnées dans le groupe des kinines, notamment des cytokines et des lymphokines, des leucotriènes, des prostaglandines, des interleukines et des interférons, ainsi que des combinaisons de celles-ci.
PCT/DE1991/000501 1990-06-15 1991-06-17 Regenerateur des nerfs WO1991019508A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4019208.3 1990-06-15
DE19904019208 DE4019208A1 (de) 1990-06-15 1990-06-15 Nervenregenerationsmittel

Publications (1)

Publication Number Publication Date
WO1991019508A1 true WO1991019508A1 (fr) 1991-12-26

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PCT/DE1991/000501 WO1991019508A1 (fr) 1990-06-15 1991-06-17 Regenerateur des nerfs

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EP (1) EP0548083A1 (fr)
AU (1) AU7968491A (fr)
DE (1) DE4019208A1 (fr)
WO (1) WO1991019508A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999015192A1 (fr) * 1997-09-19 1999-04-01 Auckland Uniservices Limited Agent de sauvetage neuronal
EP1374898A1 (fr) * 2001-03-12 2004-01-02 Institute of Gene and Brain Science Remedes pour lesions nerveuses
US7235255B2 (en) * 2000-06-22 2007-06-26 Spinal Restoration, Inc. Biological bioadhesive compositions and methods of preparation and use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0412554A2 (fr) * 1989-08-10 1991-02-13 Sumitomo Pharmaceuticals Company, Limited Préparation à libération retardée À  administrer dans le cerveau
WO1991002067A1 (fr) * 1989-07-27 1991-02-21 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Regulation de la synthese du facteur de croissance nerveuse dans le systeme nerveux central

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991002067A1 (fr) * 1989-07-27 1991-02-21 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Regulation de la synthese du facteur de croissance nerveuse dans le systeme nerveux central
EP0412554A2 (fr) * 1989-08-10 1991-02-13 Sumitomo Pharmaceuticals Company, Limited Préparation à libération retardée À  administrer dans le cerveau

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH, Volume 23, 1990, Ribeirao Prieto, Brasil, pages 981-984, DA-SILVA C.F., "Local Administration of Interleukin-1 Increases Sensory Neuron Regeneration in Vivo". *
NATURE, Volume 330, 17 December 1987, London, GB, pages 658-659, LINDHOLM D. et al., "Interleukin-1 Regulates Synthesis of Nerve Growth Factor in Non-neuronal Cells of Rat Sciatic Nerve". *
PROC. NATL. ACAD. SCI. U.S.A., Volume 83, December 1986, Washington, US, pages 9231-9235, WILLIAMS L.R., "Continuous Infusion of Nerve Growth Factor Prevents Basal Forebrain Neuronal Death After Fimbria Fornix Transection". *
SCIENCE, Volume 228, 26 April 1985, Lancaster, PA, US, pages 497-499, GIULIAN A. et al., "Interleukin-1 Stimulation of Astroglial Proliferation After Brain Injury". *
SOCIETY FOR NEUROSCIENCE ABSTRACTS, Volume 15, No. 1, 1989, page 18, OTTEN U., "Interleukin-1 Injected Into Neostriatum of Adult Rat Brain Stimulates Synthesis of Nerve Growth Factor". *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999015192A1 (fr) * 1997-09-19 1999-04-01 Auckland Uniservices Limited Agent de sauvetage neuronal
US7235255B2 (en) * 2000-06-22 2007-06-26 Spinal Restoration, Inc. Biological bioadhesive compositions and methods of preparation and use
EP1374898A1 (fr) * 2001-03-12 2004-01-02 Institute of Gene and Brain Science Remedes pour lesions nerveuses
EP1374898A4 (fr) * 2001-03-12 2004-07-28 Inst Of Gene And Brain Science Remedes pour lesions nerveuses

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Publication number Publication date
EP0548083A1 (fr) 1993-06-30
DE4019208A1 (de) 1992-03-05
AU7968491A (en) 1992-01-07

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