WO2005027942A1 - Principe actif pharmaceutique provenant de venin de serpent, ce principe actif servant a traiter les melanomes - Google Patents

Principe actif pharmaceutique provenant de venin de serpent, ce principe actif servant a traiter les melanomes Download PDF

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Publication number
WO2005027942A1
WO2005027942A1 PCT/DE2004/002058 DE2004002058W WO2005027942A1 WO 2005027942 A1 WO2005027942 A1 WO 2005027942A1 DE 2004002058 W DE2004002058 W DE 2004002058W WO 2005027942 A1 WO2005027942 A1 WO 2005027942A1
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substance
substances
active
penetrating
kda
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PCT/DE2004/002058
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German (de)
English (en)
Inventor
Dirk Weickmann
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Toximed Gmbh
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Publication date
Application filed by Toximed Gmbh filed Critical Toximed Gmbh
Priority to DE112004002332T priority Critical patent/DE112004002332D2/de
Publication of WO2005027942A1 publication Critical patent/WO2005027942A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/58—Reptiles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • biogenic poisons Needs coordinated, so-called biogenic, poisons. These biogenic poisons have found their place in the interplay of different types of life in the course of long development periods.
  • Plants or animals can have a primarily toxic effect through the production of toxins or can only acquire secondary toxicity by ingesting toxic substances from the living or inanimate environment.
  • Tumors the most dangerous and feared diseases of our time, are currently being combated in a very radical and less environmentally friendly way.
  • the following can be used as simple, characteristic keywords: steel, radiation and chemotherapy.
  • a pharmaceutical active ingredient is known from DE 199 61 141 A1, in which it has been found that components of the spider venom from spiders of the Sicaridae family can be used for the treatment of tumor diseases. Mainly, a peptide toxin from the poison of this type of spider, a further antagonistic substance obtained from the poison and / or a combination of these components are used medically.
  • This active ingredient can be used for the treatment of tumor diseases and in parallel or in support of tumor operations and residual tumor tissue can be destroyed.
  • genetically modified body cells tumor cells
  • the active ingredient in question recognizes the changed surface structure of such cells and kills them without complications. cannot be used pharmaceutically.
  • this known active ingredient does not act in combination against melanomas in vivo.
  • Malignant melanoma is a malignant tumor that originates from the pigment cells of the skin.
  • the most important risk factors for developing melanoma are a healthy skin type and exposure to UV rays, whereby sunburns in childhood are of particular importance.
  • the warning symptoms of liver spots include an increase in size, a change in color, itching, easy vulnerability with a tendency to bleed, as well as an irregular limitation of the pigmented skin area. Since the chances of a cure are only good with early diagnosis and therapy, people at risk should be examined by a dermatologist once a year.
  • the first step in the treatment is surgical removal of the melanoma, and further therapy depends on the stage of the disease.
  • the number of diseases among the black population is only one sixth of that of the fair-skinned population.
  • the black population especially the less pigmented parts of the body such as mucous membranes, as well as hand and
  • melanoma In terms of appearance, four main types of melanoma can be distinguished: the superficial spreading melanoma, the nodular melanoma, the
  • the superficial spreading melanoma is the most common type of melanoma with 70%. It grows only on the surface over a long period of time and forms flat, irregularly shaped stoves with different colors from black, gray, blue and brown to white. Sometimes it turns into a nodular shape after years, combined with vertical growth.
  • nodular melanoma The frequency of nodular melanoma is approximately 15%. It bulges hemispherically beyond the skin level and is from gray-brown to reddish - blue-black
  • Acral - nodular melanoma is present in about 7% of the cases. It mostly appears on the palms of the hands and feet and in the nail area. It is in the
  • Lentigo - malignant melanoma is less common in about 5% of cases.
  • Amelanotic melanoma is rare. It is not colored and therefore particularly difficult to see.
  • Malignant melanoma starts from the pigment-forming cells (melanocytes) that lie on the epidermis.
  • the tumor cells grow both in the horizontal direction and in the vertical direction.
  • the horizontal growth leads to a visible increase in the size of the melanoma on the skin.
  • the vertical growth is important for the forecast.
  • the basement membrane as the lowest layer of the epidermis temporarily represents a certain barrier to the blood and lymphatic vessels of the epidermis. If it is penetrated, the cancer cells can spread throughout the body via the blood and lymph channels, attach to other organs and multiply there. This scattering, also known as metastasis, may have already taken place in the case of very small tumors.
  • the suspicious skin must always be removed completely by surgery, taking at least three centimeters of healthy skin on the outside. The skin is then examined under the microscope (histology). The tumor thickness and the tumor penetration depth are the most important prognostic factors in the assessment. The entire body must be examined to determine the extent of the tumor. X-rays, sonography and computed tomography are mostly used. Infection of the lymph nodes or other organs can be demonstrated.
  • Active substances from the poison and oral secretions of vipers are preferably used: a) Vipera berus, b) Vipera wagneri, c) Vipera ursini, and d) Vipera aspis.
  • the snakes are divided into two main groups. 1. Vipers (Viperidae) or otters and 2. Poisonous snakes (Elapidae). The group of vipers is divided into two subgroups, the real vipers, which is why
  • Vipera berus (adder) and the Vipera aspis (Juraviper) belong to, and the
  • Viperidae differ from pit vipers by the absence of the "pit," a sensory organ in front of the eyes.
  • the European vipers have a rather strong body with a short tail and often a triangular head.
  • the back scales are strongly keeled and often almost all signs on the top of the head are divided.
  • the relatively small eyes have vertical pupils.
  • the after shield is undivided among the vipers. With some species it comes down to the
  • Snout tip to form a soft, scaly snout horn.
  • the food consists mainly of small mammals (mice, voles, shrews), birds or lizards.
  • Vipera berus is also known as adder. It is a small, relatively slender venomous snake in which the elongated head is only slightly separated from the body. It grows to a size of 60 cm to 85 cm in the wild.
  • the copper-red iris is characteristic of the adder.
  • the basic color of her body is variable. The color palette ranges from beige and all shades of brown to yellow and gray to reddish. On the back there is usually an uninterrupted zigzag band which stands out from the basic color and whose appearance is a distinguishing feature for the different subspecies.
  • the snake's body sides are adorned with a series of round spots at regular intervals. The basic color of the male animals is always much lighter than that of the female animals. Rare red-brown adores without a back label are rare.
  • Vipera wagneri also called Wagner's Bergotter, comes from northeastern Turkey and Azerbaijan. It is a 70 cm to 90 cm long, muscular snake and has a strikingly short tail.
  • the body color of the male animals is light gray, while the female animals are colored light brown. There are ocher-colored spots on the back that touch in the middle of the back. These have a dark brown or black border and are separated from each other by light crossbeams. The tip of the snout is lighter in the female animals than in the male animals.
  • Wagner's mountain otters like to stay close to the water, especially on small streams or rivulets. Depending on the season, they are day or night active. These animals are actually very shy, but when they are in danger they hiss loudly, raise their front bodies at an angle and bite.
  • Vipera ursini are found in southern locations up to an altitude of 3000 meters. These snakes prefer the steppes and meadows. In principle, they inhabit the ground, but can also climb well. Most of these animals are active during the day. They reach a body length of 35 cm to 50 cm and show similarities Adder on. The oval head is relatively little separated from the body. The snout is narrower and more pointed than the adder. The eyes have vertically slit pupils. Strongly keeled back scales give a roughened overall impression at this point.
  • Vipera aspis also known as aspis viper, is also known as the actual European venomous snake because it only occurs here. It is 60 cm to 70 cm long and has a typical square head, with the body narrowing sharply towards the neck. The body coloration is very variable and can be stone gray, brown, reddish brown, brick red and orange. Vipera aspis has a typical viper-like stocky body. However, the male animals are longer and slimmer than their female counterparts and have a dark back pattern, consisting of mutually transverse spots that can merge into a zigzag or wavy band. The eyes have vertically slit pupils in bright light,
  • the substances obtained have a certain molecular weight, which can be 28 kDa, 32 kDa or 35 kDa.
  • the active ingredient according to the invention can optionally contain an antagonistic or synergistic and / or penetrating substance from the total poison cocktail or oral secretion of the relevant animal species to the respective peptide toxin or oral secretion.
  • the antagonistic or synergistic substance is preferably a phospholipase or a hyaluronidase or a combination of both substances.
  • the antagonistic or synergistic substance is a mixture of the phospholipases and hyaluronidases and / or toxins present in other types of animals.
  • the peptide toxin and the substance which is antagonistic and / or synergistically active are preferably obtained from the viper total poison cocktail by a fractionation process, and it is further preferred that the pharmaceutical active substance contains a peptide toxin and a substance which has an antagonistic or synergistic effect which consists of different fractions.
  • the effect of the pharmaceutical active ingredient can advantageously be tailored to the type and / or size of tumor to be treated.
  • the peptide toxin, or the oral secretion, and the substance having an antagonistic and / or synergistic effect can be obtained by known fractionation processes for the separation of proteins from the total poison raw mixture or the mouth saliva. It is preferred that the peptide toxin and the substance having an antagonistic or synergistic effect thereof are obtained by gel chromatography, HPC, affinity chromatography and / or ion exchange chromatography.
  • the peptide toxin is present as an active pharmaceutical ingredient in such an amount that the active ingredient has a destructive effect on tumor cells.
  • the required proportions are chosen so that the active ingredient according to the invention has no or only a slight toxic effect in the patient to be treated.
  • the amounts of the active pharmaceutical ingredients must also be matched to the type of tumor to be treated and the physical, possibly also psychological, circumstances of the respective patient.
  • the preliminary tests required for such a coordination are to be carried out by the person skilled in the art in the context of animal tests and / or ethically justifiable tests on the patient on the basis of his specialist knowledge and ability.
  • a pharmaceutical active ingredient in which the amount of peptide toxin or oral secretion and the substance having an antagonistic or synergistic effect thereon comprises an amount of peptide toxin or oral secretion and antagonistic or synergistic substance which depends on the one to be treated Tumor is chosen.
  • the pharmaceutical active ingredient according to the invention contains conventional carriers and auxiliary substances, such as antibiotics, antifungals, antituberculotics, agents against parasites, cytostatics, amino acids, enzymes which promote wound healing and / or mitotic inhibitors.
  • antibiotics such as antibiotics, antifungals, antituberculotics, agents against parasites, cytostatics, amino acids, enzymes which promote wound healing and / or mitotic inhibitors.
  • the peptide toxin or the oral secretion and the antagonistic or synergistic substance are used in combination.
  • the present invention also includes derivatives and salts of the substances provided according to the invention.
  • the peptide toxin can comprise one or more additions, substitutions and / or deletions of amino acids, it naturally having to be ensured that the medicinal effect according to the invention is retained.
  • a preferred process for the preparation of an active ingredient according to the invention comprising at least one peptide toxin and / or at least one substance having an antagonistic or synergistic effect, at least one peptide toxin and / or at least one antagonistic or synergistic substance from the poison of animals of the above under a) to d) mentioned species, has the following steps:
  • the poisons in question contain various peptide toxins and various substances which have an antagonistic or synergistic effect thereon, and other active substances which are also of medical and therapeutic relevance. All of these substances can be used therapeutically in a specific ratio, to be determined by the person skilled in the art, in a medical active substance.
  • fractionation process shows, by way of example only, a possibility of obtaining the peptide toxins and the substances having an antagonistic or synergistic effect. Further configurations are possible.
  • the raw poison mixture used, or the. Mouth saliva is obtained from female animals of the type mentioned.
  • the process for obtaining poison and oral secretions from the vipers mentioned under a) to d) is carried out for the animals in a species-appropriate and gentle manner in the following form: a) the viper is fixed and a hand is held behind the head, b) with the other hand approach the viper with a sterile sponge, c) the sponge is held upright and the viper is brought closer, d) at a certain distance the viper bites into the sponge and you pull yourself with the sponge back from the viper.
  • the substances obtained are removed from the sponge, collected and then cleaned.
  • the raw poison mixture or the oral secretion is homogenized before the fractionation, and it is further preferred that the fractions are deep-frozen before further processing and more preferably lyophilized.
  • peptide toxins or oral secretions contained in the animal venom and counter-directed (for this purpose antagonistic or synergistic) enzymes or peptide toxins in combination with oral secretions, in appropriate concentrations and proportions for the treatment of tumor diseases and in parallel or in support of tumor operations and (residual) tumor tissue is destroyed.
  • at least one peptide toxin or at least one substance acting antagonistically or synergistically comes from the poison of animals of the species mentioned.
  • the destruction of tumor tissue not recorded during the operation and the prevention of local tumor metastasis in the organism can be achieved.
  • genetically defective body cells tumor cells
  • the phospholipases used according to the invention can recognize or selectively bind and lyse these tumor cells which have changed their surface structure.
  • tissue in desired, locally delimited areas - here tumor tissue-predestined tissue areas - can be killed without complications.
  • the mode of operation is based on the native, mutually influencing modes of action of the peptide toxins and the substances present in the animal poison, which have an antagonistic or synergistic effect, as follows:
  • Phospholipases hyaluronidases are also described as so-called penetrating enzymes. It is the case that the enzymes mentioned make tissue more permeable to the active ingredient according to the invention via digestive functions. In addition, they can recognize genetically defective body cells (tumor cells) and these themselves or by infiltration of necrotic or cytotoxic peptides coupled to them are killing.
  • antagonistic or synergistic substances are understood to mean, for example, phospholipases and hyaluronidases or peptide toxins from animals of the aforementioned genera, although it is not excluded that other antagonistic or synergistic substances are present in the animal venom, which can also be used according to the invention.
  • a comparison with respect to absolute and relative amounts of the components of the active ingredient according to the invention can be carried out in vitro on living human cells (healthy and tumorous). of the tissue type to be treated. Attention to the tendency to spread is of the greatest importance. This can be clarified in preliminary tests in comparison of the tumor tissue strength to the tissue surrounding the tumor.
  • the mode of action of the total poison cocktail, or individual substances separated therefrom by column chromatography and characterized by the molecular weight, can be carried out by testing them in corresponding healthy and tumorous human cell lines.
  • the peptide toxins preferably originate from the same organism as the substances which have an antagonistic or synergistic effect thereon and / or further active substances optionally present. In this way, the effective interaction or counterplay of these substances developed by nature can be exploited.
  • the pharmaceutical active substances according to the invention can be produced in such a way that first a crude poison mixture is obtained by methods known per se and fractionation of the crude poison mixture is carried out by fractionation methods, likewise known per se, for the separation of proteins. This serves the purpose of obtaining the peptide toxins and the substances which act antagonistically or synergistically in a form which is as separate as possible from one another or in separate fractions. Subsequently, different fractions can be combined to produce a pharmaceutical active ingredient, or individual fractions can be combined with peptide toxins originating from other organisms or substances having an antagonistic or synergistic effect. Individual fractions can also be used to produce an active pharmaceutical ingredient.
  • Hyaluronidases from snake venoms can preferably be used as antagonistic substances. This can be combined with one or more fractions from substances obtained from vipers of the types mentioned under a) to d). It is also possible according to the invention to combine the fractions with other suitable active ingredients and / or with carriers and auxiliaries customary in pharmacy for the production of pharmaceutical active ingredients.
  • specific poison components necrotic and cytotoxic peptide toxins
  • natural substances having an antagonistic effect stop substances of the phospholipase and hyaluronidase type
  • stop substances of the phospholipase and hyaluronidase type can be selected from the animal venom, for example by purification by column chromatography.
  • a new syringe with a new cannula was used for each animal.
  • the cannula was then closed again with the cannula protective cover.
  • the sealed syringe and the drawn-up poison were then immediately placed in a desiccator. This was then kept in a freezer at at least 14 degrees Celsius for at least 12 hours.
  • the cannula protective cover was removed after removal from the freezer.
  • the cannula was placed in solvent, e.g. Protein solvent (solvent for protein column chromatography: 0.25 M Tris / HCL, pH 6.5 to 7.3, 1, 92 M glycine, in distilled, deionized water) and immersed in 1 ml.
  • solvent e.g. Protein solvent (solvent for protein column chromatography: 0.25 M Tris / HCL, pH 6.5 to 7.3, 1, 92 M glycine, in distilled, deionized water) and immersed in 1 ml.
  • the entire solution was placed in a standing transparent plexiglass column using a perspex funnel (to avoid contamination) had an inner diameter of 1.5 cm, a wall thickness of 2 mm and a height of 50 cm and was tapered at the bottom to 1.5 mm, was filled with 20 ml of gel.
  • a perspex funnel to avoid contamination
  • the poison solution thus introduced ran through the gel and displaced the buffer contained in the gel.
  • Rot Load 1 + 2 (Carl Roth GmbH & Co KG, Düsseldorf: SDS, glycerol, bromophenol blue, phosphate buffer, Roi Load 1 with mercaptoethanol, Roti Load 2 without mercaptoethanol) was used as the application buffer for peptide binding and protein protection.
  • the individual fractions were collected separately in sterile, screwable 5 ml Teflon vials. The quality control of the individual fractions was carried out by means of electrophoresis.
  • Fractions with the same composition can be collected together.
  • the individual fractions were freeze-dried for further processing and storage, for example with the following parameters:
  • the fraction to be lyophilized was cooled in an open teflon vial loosely covered with perforated aluminum foil to minus 22 degrees Celsius. to A freezing time of the sample allowed a cooling time of 11 hours. Then a vacuum of 0.200 mbar was applied. After the vacuum had been reached, the fraction was heated to plus 4 degrees Celsius and kept at this temperature for at least 24 hours while maintaining the vacuum. After the freeze-drying process, the teflon vial was screwed airtight with the lyophilized fraction. The storage time is approx. 6 months at room temperature, approx. 1 year at plus 7 degrees Celsius and approx. 15 years at minus 14 degrees Celsius.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un principe actif pharmaceutique servant à traiter les mélanomes, ce principe actif étant composé d'une association de substances provenant de venins biogènes ou de sécrétions buccales de certaines espèces de vipères.
PCT/DE2004/002058 2003-09-16 2004-09-15 Principe actif pharmaceutique provenant de venin de serpent, ce principe actif servant a traiter les melanomes WO2005027942A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE112004002332T DE112004002332D2 (de) 2003-09-16 2004-09-15 Pharmazeutischer Wirkstoff aus Schlangengift gegen Melanome

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10342747.3 2003-09-16
DE10342747A DE10342747A1 (de) 2003-09-16 2003-09-16 Pharmazeutischer Wirkstoff gegen Melanome

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WO2005027942A1 true WO2005027942A1 (fr) 2005-03-31

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006114652A1 (fr) * 2005-04-27 2006-11-02 Christos Karametas Extrait ethanolique d'origine animale combine a des enzymes ayant un effet therapeutique sur des tumeurs et autres maladies

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CN1098293A (zh) * 1993-08-02 1995-02-08 程满温 蝎毒注射液及其制法和用法
US5565431A (en) * 1994-06-20 1996-10-15 Lipps; Binie V. Cancer cell inhibitors and method
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WO2001075103A1 (fr) * 2000-01-28 2001-10-11 Biodoor Gene Technology Ltd. Shanghai Nouveau polypeptide, proteine humaine 9 de toxine de scorpion a chaine courte, et polynucleotide codant pour ce polypeptide
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006114652A1 (fr) * 2005-04-27 2006-11-02 Christos Karametas Extrait ethanolique d'origine animale combine a des enzymes ayant un effet therapeutique sur des tumeurs et autres maladies

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DE112004002332D2 (de) 2006-08-10

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