US20160008301A1 - Use of Adelmidrol in the Treatment of Epithelial Dysfunctions - Google Patents

Use of Adelmidrol in the Treatment of Epithelial Dysfunctions Download PDF

Info

Publication number
US20160008301A1
US20160008301A1 US14/793,165 US201514793165A US2016008301A1 US 20160008301 A1 US20160008301 A1 US 20160008301A1 US 201514793165 A US201514793165 A US 201514793165A US 2016008301 A1 US2016008301 A1 US 2016008301A1
Authority
US
United States
Prior art keywords
adelmidrol
chronic
use according
dog
acute
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.)
Abandoned
Application number
US14/793,165
Other languages
English (en)
Inventor
Maria Federica Della Valle
Francesco Della Valle
Vincenzo Di Marzo
Stefania PETROSINO
Barbara Costa
Gabriele Marcolongo
Daniele GRASSI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Epitech Group SpA
Original Assignee
Epitech Group SpA
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 Epitech Group SpA filed Critical Epitech Group SpA
Assigned to EPITECH GROUP S.R.L. reassignment EPITECH GROUP S.R.L. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DI MARZO, VINCENZO, PETROSINO, STEFANIA, DELLA VALLE, FRANCESCO, DELLA VALLE, MARIA FEDERICA, COSTA, BARBARA, GRASSI, DANIELE, MARCOLONGO, GABRIELE
Publication of US20160008301A1 publication Critical patent/US20160008301A1/en
Priority to US15/482,129 priority Critical patent/US20170209395A1/en
Priority to US16/374,912 priority patent/US11491122B2/en
Abandoned legal-status Critical Current

Links

Images

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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/062—Ascomycota
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the object of the present invention is Adelmidrol in the treatment of epithelial dysfunctions.
  • Palmitoylethanolamide is an endogenous lipid N-acylamidic substance of which an effect on neuroinflammation and pain has been widely demonstrated [Calignano A. et al Europ. J. Pharmacol. 2001; 419:191-198; Skaper S. D. et al Mol Neurobiol. 2013; 48:340-352; Skaper S. D. et al. Inflammopharmacology. 2014; 22:79-94].
  • the increase in the endogenous levels of PEA is currently considered important to determine the control of the neuroinflammation and pain mechanism due to different etiopathogenetic causes and associated with many diseases both of human beings and animals [Petrosino S.
  • the first method is based on the systemic oral or sublingual administration of PEA: in this case, PEA must be administered in micronized (particle size in the range between 2 and 10 microns) or ultra-micronized (particle size in the range between 0.8 and 6 microns) form due to the high insolubility in water of the lipid molecule [EP 1207870 B1; WO 2011/027373 A1].
  • the second method is based on the inhibition of the activity of the specific PEA-degrading enzyme activity, i.e. FAAH (Fatty Acid Amide Hydrolase) and NAAA (N-Acylethanolamine Acid Amidase); this inhibition was obtained with the systemic administration of synthetic inhibitors of said hydrolases [Piomelli D. et al CNS Drug Reviews 2006; 12:21-38; Fiasella A. Chem Med Chem 2014 Epub of Print] able to block the degradation of PEA.
  • FAAH Food Acid Amide Hydrolase
  • NAAA N-Acylethanolamine Acid Amidase
  • Adelmidrol is a synthetic N-acylamidic molecule as well (N,N′-Bis(2-hydroxyethyl)nonandiamide) with a high solubility in water as well as a good solubility in lipids.
  • the inventors of the present patent have surprisingly found that Adelmidrol, when brought in contact with epithelial cells such as keratinocytes, is able to cause an important increase of the endogenous levels of PEA while not interfering with the activity of the PEA-degrading enzymes (FAAH and/or NAAA).
  • FAH PEA-degrading enzymes
  • an object of the present invention therefore is Adelmidrol for use in the treatment of epithelial tissue dysfunctions in a human being or animal.
  • a further object of the invention is a pharmaceutical formulation for use in the treatment of epithelial tissue dysfunctions in a human being or animal, the formulation containing Adelmidrol, optionally in association with an active ingredient selected from the group consisting of an oxazoline derivative of Palmitoylethanolamide, an anti-microbial agent, trans-traumatic acid, and hyaluronic acid or derivatives thereof.
  • FIG. 1 shows the endogenous levels of AEA, 2-AG, PEA and OEA in HaCaT cells stimulated for 24 hours with 10 ⁇ M Adelmidrol;
  • FIG. 2 shows the evaluation of knee edema using a digital caliper—From left to right: non OA: OA+saline; OA+Adelmidrol 1.5 microgr/25 microL; OA+Adelmidrol 15 microgr/25 microL; OA+Adelmidrol 150 microgr/25 microL;
  • FIG. 3 shows the evaluation of the biochemical marker TNF- ⁇ in the synovial fluid.
  • the invention relates to Adelmidrol for use in the treatment of epithelial tissue dysfunctions in a human being or animal.
  • Adelmidrol is the International Non-proprietary Name (INN) of a synthetic derivative of azelaic acid, a naturally-occurring saturated dicarboxylic acid.
  • azelaic acid has been found in the human body and its plasma levels are in the range between 20-80 ng/ml.
  • Adelmidrol is N,N′-bis(2-hydroxyethyl)nonandiamide; the molecule has an amphiphile behavior as it has both hydrophilic and lipophilic properties able to promote solubility both in water and in organic solvents.
  • Epithelial dysfunctions treated with Adelmidrol according to the present invention are preferably selected from the group consisting of: oropharyngeal and esophageal Dysphagia with different etiology; gastroesophageal reflux; Cricopharyngeal Achalasia; esophageal Achalasia; stomatites with different etiology; Presbiphagia in the elderly; feline gingivostomatitis; periodontal disease also related to endodontics/orthodontics and dental implantology interventions; Burning Mouth Syndrome (BMS); Eyelid Edema; Blepharitis, Blepharoconjunctivitis; inward turning (entropion) and eversion (ectropion) of the eyelid; keratitis and keratitoconjunctivitis with different etiology (e.g., superficial punctate keratitoconjunctivitis); corneal lesions with different etiology; quali-quant
  • the concentration of Adelmidrol in pharmaceutical forms for topical application (creams, gels, patches) intended for use in a human being and in an animal is in the range between 0.2% and 7.0%.
  • Adelmidrol should be used in a concentration in the range between 0.3% and 5.0%.
  • the amounts of pharmaceutical forms for topical application are in the range between 0.01 and 0.5 ml per cm 2 of epithelium (e.g. skin, mucous membranes); thereby, the administered dose of Adelmidrol does not exceed the LD 50 of the molecule by more than 10%, which is calculated in experimental animals and by oral administration, in 2-3 g/kg body weight.
  • the amount of Adelmidrol to be administered in the form of solutions intended for internal epithelia is in the range between 0.5 and 20 mg/Kg body weight.
  • Adelmidrol may be administered in combination with an active ingredient selected from the group consisting of an oxazoline derivative of palmitoylethanolamide, an anti-microbial agent, trans-traumatic acid and hyaluronic acid or derivatives thereof.
  • the anti-microbial agent is preferably selected from Echinacea purpurea extract, Usnea barbata extract, usnic acid, phytosphingosine, bronopol and mixtures thereof.
  • Adelmidrol is administered in combination with an active substance as defined above, a joint (i.e. in the same pharmaceutical formulation), separate or sequential administration may be provided.
  • a pharmaceutical formulation according to the invention may have the following composition by weight, the balance being related only to the active ingredients (thus, excluding carriers and excipients):
  • the treatment with Adelmidrol is topical (on external epithelia or internal epithelia).
  • the inventive formulation can thus contain pharmaceutically acceptable, additives and excipients, selected according to the selected pharmaceutical form, such as solvents, viscous carriers, tackifying agents (acrylic polymers), buffering agents, preservatives, antioxidants, gelling agents, thickeners and so on.
  • pharmaceutically acceptable, additives and excipients selected according to the selected pharmaceutical form, such as solvents, viscous carriers, tackifying agents (acrylic polymers), buffering agents, preservatives, antioxidants, gelling agents, thickeners and so on.
  • compositions suitable for both human and veterinarian use can be preferably selected from: instillation solutions, solutions for inclusion in the joint capsule, gels for internal or external use, spray solutions, eye drops, creams, salves, patches and ointments.
  • the compounds can also be formulated as rectal formulations such as suppositories, retention enemas or micro-enemas, for example containing the basic components of common suppositories such as cocoa butter or other glycerides.
  • the compounds may also be formulated as deposition preparations.
  • Such long-acting formulations may be administered by implantation (e.g. subcutaneously or by transdermal or intramuscular route). Therefore, for example, the compounds according to the present invention may be formulated with appropriate hydrophobic or polymeric materials (e.g. in the form of an emulsion in a suitable oil) or ion exchange resins or as minimally soluble derivatives, for example as minimally soluble salt.
  • formulations described above may be prepared according to conventional methods, such as those described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., N.Y., USA.
  • the chloroform/methanol 90:10 fraction containing AEA, 2-AG, PEA and OEA was analyzed by liquid chromatography coupled to mass spectrometry using chemical ionization at atmospheric pressure (LC-APCI-MS) (Marsicano et al., 2002).
  • the equipment used includes a Shimadzu HPLC (LC-10ADVP) coupled with a Shimadzu spectrometer (LCMS-2010) via a Shimadzu APCI interface.
  • the ionization source temperature is 400° C. and a Phenomenex reverse phase HPLC column (C-18, 5 microns, 150 ⁇ 4.6 mm) is used.
  • the mobile phase consisting of a mixture of methanol/water/acetic acid (85/15/0.1%), passes through the column at a rate of 1 ml/min.
  • the mass spectrum determination is carried out according to the selected ion monitoring (SIM) [Di Marzo et al. Nature 2001; 410:822-825].
  • Selected ions correspond to mass/charge values (m/z) of 356 and 348 (molecular ions of deuterated and non-deuterated AEA), 384.35 and 379.35 (molecular ions of deuterated and non-deuterated 2-AG), 304 and 300 (molecular ions of deuterated and non-deuterated PEA), 328 and 326 (molecular ions of deuterated and non-deuterated OEA).
  • the quantity expressed as pmol/mg of lipid extract were compared using ANOVA followed by the Student-Newman-Keuls test.
  • Adelmidrol does not inhibit the activity of catabolic enzymes for PEA (FAAH and NAAA).
  • mice were conducted using adult male rats of the Wistar strain (weight 200-250 grams) supplied by Harlan Italy, put in enclosures for a week in standard dietary and environmental conditions (temperature 21 ⁇ 1° C., humidity 60 ⁇ 10%, light 12 hours a day and water and food ad libitum) before being used in the experiments.
  • Knee osteoarthritis was induced in rats by a single intra-articular injection of monosodium iodoacetate (MIA) at a dose of 2 mg/25 ⁇ L in the infrapatellar area of the right knee, based on the method suggested by Kolbhen but revisited.
  • MIA acts locally by inhibiting glycolysis, destroying the metabolism of chondrocytes and producing cartilage degeneration.
  • MIA osteoarthritic
  • the Von Frey test Ugo Basile, Varese, Italy
  • a tactile stimulator that can be moved on a base Perspex platform, a metal grid supported by four columns placed at the corners of the base platform, two compartments further subdivided into which the animals are placed at least 15-30 minutes before the measurement, and an electronic microprocessor.
  • the tactile stimulator is positioned inside an aluminum cylinder provided with a handle that allows the operator to move it on the platform.
  • the activation button of this mechanism is located on both sides of the handle Thanks to a mirror positioned above the cylinder, alongside the filament, the stimulation can be applied in the correct point of the plantar surface and the movements of the foot can be monitored.
  • the microprocessor is provided with an LCD display that shows the latency time (in seconds) up to the removal of the paw from the mechanical stimulation and the force applied by the filament on the paw (in grams). For measurements in mice, a maximum latency time of 20 seconds and a maximum force corresponding to 5 grams were set.
  • a digital manual slide caliper (measuring capacity 0-150 mm; resolution: 0.01 mm; ROHS Compliant Electronic Digital Caliper—2 Biological Instruments SNC, Italy) was used. The measurement was done manually by evaluating the diameter (expressed in mm) of the left and right knees of each animal at the kneecap. The edema was calculated as the difference between the volume of the right knee and left knee. The data are shown in FIG. 2 .
  • TNF- ⁇ Tumor Necrosis Factor
  • TNF- ⁇ levels in the synovial fluid was made using an ELISA (Enzyme Linked Immuno-Sorbent-Assay) immunoenzymatic assay using a commercial kit from Biosource International Inc.
  • the method uses a procedure in which the antigen is trapped between two layers of antibodies and for this reason it is called an ELISA sandwich.
  • the sample and the biotinylated antibody are added to the wells of a microtitration plate coated with specific antibodies to TNF- ⁇ and the first incubation is carried out, during which the specific cytokine in the sample interacts with both the antigen binding site exposed by the immobilized antibodies on the plate, and with the site of the biotinylated antibody present in solution.
  • the enzyme streptavidin peroxidase is added, which binds to the biotinylated antibody.
  • a solution containing the substrate (Stabilized Chromogen) is added.
  • Stabilized Chromogen is added.
  • a product is generated whose staining intensity is measured spectrophotometrically and is directly proportional to the concentration of TNF- ⁇ in the samples.
  • the various parameters are measured at different times in relation to the parameter itself (e.g. inflammatory parameters are evaluated only in the first week since the MIA, pain is always evaluated before and 60 min after the administration of Adelmidrol).
  • the effect on edema is accompanied by a reduction in the levels of TNF- ⁇ in the synovial fluid ( FIG. 3 ).
  • a sterile solution containing 2% Adelmidrol and 0.1% hyaluronic acid sodium salt was instilled into the bladder of no. 7 female patients through catheter after the complete emptying of the bladder itself. All patients had a confirmed diagnosis of BPS (Bladder Pain Syndrome). Most of the times, the patients had comorbidity with other pelvic diseases (vulvar vestibulitis 4/7; IBS (irritable bowel syndrome) 2/7; Fibromyalgia Syndrome 1/7, Recurrent Urinary Tract Infections (RUTI) 3/7).
  • the frequency of urination (measured as the number of urinations in 12 hours), both during the day and at night, and the discomfort with bladder full were controlled, analyzing the pain, the feeling of weight and the burning in the pelvic area (all three parameters were measured by means of numerical scale VAS, before treatment, at the end of the attack therapy and at the end of the maintenance therapy).
  • Pat 01 Pat 02 Pat 03 Pat 04 Patient's 35 27 28 45 age years old years old years old years old Treatment Attack phase 1 1 1 instill/week ⁇ instill/week ⁇ instill/week ⁇ instill/week ⁇ 8 weeks 8 weeks 8 weeks 8 weeks 8 weeks 8 weeks 8 weeks 8 weeks Maintenance phase 1 1 1 1 instill/month ⁇ instill/month ⁇ instill/month ⁇ instill/month ⁇ instill/month ⁇ 6 months 6 months 6 months 6 months Urination frequency Before Day 8x 7x 7x 8x treatment Night 2x 0x 1x 0x At the end of Day 6x 6x 6x 7x attack phase Night 0x 0x 0x 0x At the end of Day 4x 5x 4x 5x maintm.
  • phase Pat 05 Pat 06 Pat 07 Patient's 72 39 46 age years old years old years old Treatment Attack phase 1 1 1 instill/week ⁇ instill/week ⁇ instill/week ⁇ 8 weeks 8 weeks 8 weeks Maintenance phase 1 1 1 instill/month ⁇ instill/month ⁇ instill/month ⁇ 6 months 6 months 6 months Urination frequency Before Day 10x 18x 12x treatment Night 1x 6x 2x At the end of Day 7x 7x 7x attack phase Night 0x 1x 1x At the end of Day 5x 5x 5x maintm. phase Night 0x 0x 0x Discomfort Pain in the Before treatm. 9 9 9 8.5 with bladder full pelvic area At the end of 3 3 2 attack phase At the end of 2 2 1 maintm.
  • phase Feeling of Before treatm. 6 9 9 weight in the At the end of 4 4 5 pelvic area attack phase At the end of 3 2 3 maintm.
  • phase Burning in the Before treatm. 7 9 9 pelvic area At the end of 4 5 5 attack phase At the end of 2 1 1 maintm. phase
  • Each 50 ml vial contains:
  • a 500 ml tube contains:
  • a 10 ml micro-enema contains:
  • a 10 ml single dose squeezable container contains:
  • a 2 ml vial contains:
  • a 100 ml spray bottle contains:
  • Each 1 ml single dose squeezable container contains:
  • Each 250 ml container contains:
  • Each 10 ml tube contains:
  • Each 5 ml sterile vial contains:

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Pulmonology (AREA)
  • Dermatology (AREA)
  • Mycology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Urology & Nephrology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Botany (AREA)
  • Biotechnology (AREA)
  • Cardiology (AREA)
  • Otolaryngology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Immunology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Vascular Medicine (AREA)
  • Neurosurgery (AREA)
US14/793,165 2014-07-08 2015-07-07 Use of Adelmidrol in the Treatment of Epithelial Dysfunctions Abandoned US20160008301A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US15/482,129 US20170209395A1 (en) 2014-07-08 2017-04-07 Use of Adelmidrol in the Treatment of Epithelial Dysfunctions
US16/374,912 US11491122B2 (en) 2014-07-08 2019-04-04 Use of a combination of Adelmidrol and hyaluronic acid in the treatment of pain caused by osteoarthritis and epithelial dysfunctions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI20141245 2014-07-08
ITMI2014A001245 2014-07-08

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/482,129 Continuation US20170209395A1 (en) 2014-07-08 2017-04-07 Use of Adelmidrol in the Treatment of Epithelial Dysfunctions

Publications (1)

Publication Number Publication Date
US20160008301A1 true US20160008301A1 (en) 2016-01-14

Family

ID=51904027

Family Applications (3)

Application Number Title Priority Date Filing Date
US14/793,165 Abandoned US20160008301A1 (en) 2014-07-08 2015-07-07 Use of Adelmidrol in the Treatment of Epithelial Dysfunctions
US15/482,129 Abandoned US20170209395A1 (en) 2014-07-08 2017-04-07 Use of Adelmidrol in the Treatment of Epithelial Dysfunctions
US16/374,912 Active 2035-08-30 US11491122B2 (en) 2014-07-08 2019-04-04 Use of a combination of Adelmidrol and hyaluronic acid in the treatment of pain caused by osteoarthritis and epithelial dysfunctions

Family Applications After (2)

Application Number Title Priority Date Filing Date
US15/482,129 Abandoned US20170209395A1 (en) 2014-07-08 2017-04-07 Use of Adelmidrol in the Treatment of Epithelial Dysfunctions
US16/374,912 Active 2035-08-30 US11491122B2 (en) 2014-07-08 2019-04-04 Use of a combination of Adelmidrol and hyaluronic acid in the treatment of pain caused by osteoarthritis and epithelial dysfunctions

Country Status (14)

Country Link
US (3) US20160008301A1 (de)
EP (1) EP2965765B1 (de)
JP (1) JP6752001B2 (de)
KR (1) KR102490825B1 (de)
CN (1) CN105250252A (de)
AU (1) AU2015203809B2 (de)
CA (1) CA2896435C (de)
CY (1) CY1121957T1 (de)
DK (1) DK2965765T3 (de)
ES (1) ES2740928T3 (de)
HK (1) HK1217913A1 (de)
HU (1) HUE044801T2 (de)
PL (1) PL2965765T3 (de)
PT (1) PT2965765T (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITUB20154849A1 (it) * 2015-10-30 2017-04-30 Epitech Group S P A ADELMIDROL PER L'USO NELLE PATOLOGIE CARATTERIZZATE DA INSUFFICIENTE AGONISMO DEL RECETTORE PPAR-gamma
RU2610557C1 (ru) * 2016-01-13 2017-02-13 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт глазных болезней" Способ профилактики избыточного рубцевания дакриостомы после дакриоцисториностомии
CN113082029B (zh) * 2021-03-02 2022-07-15 浙大宁波理工学院 一种伤口清洗消毒剂

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060257510A1 (en) * 2005-04-19 2006-11-16 Innovet Italia S.R.L. Pharmaceutical compositions for the treatment of ulcerations
WO2013121449A1 (en) * 2012-02-17 2013-08-22 Epitech Group S.R.L. Compositions and methods for the modulation of specific amidases for n-acylethanolamines for use in the therapy of inflammatory diseases

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1252866B (it) * 1991-12-31 1995-06-28 Lifegroup Spa N-acilderivati di aminoalcooli con acidi policarbossilici atti alla modulazione dei mastociti nei processi infiammatori su base neuroimmunogenica
US6548550B1 (en) 1999-08-06 2003-04-15 Innovet Italia S.R.L. Pharmaceutical compositions containing N-palmitoylethanolamide and use thereof in the veterinary field
PT1207849E (pt) * 1999-08-06 2005-05-31 Innovet Italia Srl A utilizacao de n, n'-bis (2-hidroxietil) nomandiamida como composicao cosmetica
DK1374903T3 (da) * 2002-06-26 2007-07-30 Innovet Italia Srl Farmaceutisk sammensætning til forebyggelse af udvikling og progression af mykotiske hudoverfladesygdomme
ES2344920T3 (es) * 2006-03-28 2010-09-09 Epitech Group S.R.L. Composicion farmaceutica para el tratamiento de patologias provocadas por la respuesta general del sistema inmutario.
CA2738117C (en) 2009-09-07 2016-12-06 Epitech Group S.R.L. Composition containing ultra-micronized palmitoyl-ethanolamide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060257510A1 (en) * 2005-04-19 2006-11-16 Innovet Italia S.R.L. Pharmaceutical compositions for the treatment of ulcerations
WO2013121449A1 (en) * 2012-02-17 2013-08-22 Epitech Group S.R.L. Compositions and methods for the modulation of specific amidases for n-acylethanolamines for use in the therapy of inflammatory diseases

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Berenbaum (Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!), Osteoarthritis and Cartilage 21 (2013) 16-21). *
Filippis (Adelmidrol, a palmitoylethanolamide analogue, reduces chronic inflammation in a carrageenin-granuloma model in rats, J. Cell. Mol. Med. Vol 13, No 6, 2009 pp. 1086-1095) *
Yu (Anti-inflammatory effects of essential oil in Echinacea purpurea L., Pak J Pharm Sci. 2013 Mar;26(2):403-8. (Abstract only)) *

Also Published As

Publication number Publication date
US11491122B2 (en) 2022-11-08
EP2965765A1 (de) 2016-01-13
US20190224145A1 (en) 2019-07-25
JP6752001B2 (ja) 2020-09-09
EP2965765B1 (de) 2019-05-08
HUE044801T2 (hu) 2019-11-28
DK2965765T3 (da) 2019-07-22
BR102015016445A2 (pt) 2016-01-12
PT2965765T (pt) 2019-07-10
CA2896435C (en) 2023-08-22
KR20160006124A (ko) 2016-01-18
AU2015203809A1 (en) 2016-01-21
AU2015203809B2 (en) 2020-02-20
CA2896435A1 (en) 2016-01-08
PL2965765T3 (pl) 2019-11-29
CN105250252A (zh) 2016-01-20
JP2016028022A (ja) 2016-02-25
HK1217913A1 (zh) 2017-01-27
US20170209395A1 (en) 2017-07-27
KR102490825B1 (ko) 2023-01-20
ES2740928T3 (es) 2020-02-07
CY1121957T1 (el) 2020-10-14

Similar Documents

Publication Publication Date Title
US11491122B2 (en) Use of a combination of Adelmidrol and hyaluronic acid in the treatment of pain caused by osteoarthritis and epithelial dysfunctions
CA2604768C (en) Mucoadhesive xyloglucan-containing formulations useful in medical devices and in pharmaceutical formulations
RU2520034C2 (ru) Соединения для лечения воспаления
US9486402B2 (en) Compositions containing berberine or analogs thereof for treating rosacea or red face related skin disorders
CN107049947B (zh) 包含溶解度差的抗惊厥药的经鼻抗惊厥药物组合物
KR20160051676A (ko) 섬유증의 치료를 위한 치환된 방향족 화합물 및 관련 방법
EP2271332B1 (de) Verwendung von verbindungen bei der behandlung von tauopathy
US20070248702A1 (en) Use of CB2 receptors agonists for the treatment of Huntington's disease
CN115403546A (zh) 愈创木烷类倍半萜衍生物及其制药用途
US20190241498A1 (en) Resveratrol esters
JP2023508844A (ja) 左旋性二環式モルホリン及びその塩、その調製方法、医薬組成物、並びに使用
JP2023503373A (ja) 新規多機能オリゴペプチド
US20190117634A1 (en) Treatment of Vulvodynia
BR102015016445B1 (pt) Uso do adelmidrol
RU2819002C1 (ru) Левовращающий бициклический морфолин и его соль, способ его получения, его фармацевтическая композиция и применение
EP2456423A2 (de) Behandlung von hyperproliferativen erkrankungen
Liu et al. MPT0E028, a novel pan-HDAC inhibitor, prevents pulmonary fibrosis through inhibition of TGF-β-induced CTGF expression in human lung fibroblasts: involvement of MKP-1 activation
EP4340808A1 (de) Formulierungen von 3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluormethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5,5-dimethyl-1-(2-morpholinoethyl)imidazolidin-2,4-dion

Legal Events

Date Code Title Description
AS Assignment

Owner name: EPITECH GROUP S.R.L., ITALY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DELLA VALLE, MARIA FEDERICA;DELLA VALLE, FRANCESCO;DI MARZO, VINCENZO;AND OTHERS;SIGNING DATES FROM 20150724 TO 20150825;REEL/FRAME:036718/0255

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION