Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
• • 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
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to the use of a stable gaseous composition based on nitrogen monoxide (NO) and carbon dioxide
• Nitric oxide is produced naturally in mammals by an enzyme, NO-synthase, which is expressed constitutively in endothelial cells, in platelets, and in the central and peripheral nervous systems. Another form of calcium-independent NO-synthase can be induced by different stimuli (notably liposaccharides) in many cells such as macrophages, lymphocytes, myocardial cells, endothelial cells and smooth muscle cells. Nitric oxide is an important biological messenger in mammals and this molecule plays a decisive role in the local control of hemodynamics.
• Nitric oxide also controls post-capillary venous permeability.
• Nitric oxide also participates in hormonal regulation mechanisms, at the kidney level by inhibiting the release of renin, at the cardiovascular level, by antagonizing the release of natriuretic factor (ANF).
• NAF natriuretic factor
• platelet activation is under the permanent control of endothelial nitric oxide, and to a lesser extent under that of platelet NO synthase.
• the platelets release nucleotides (ATP, ADP), serotonin, PAF, thromboxane A2 and vasopressin; they can also initiate the coagulation cascade by releasing thrombin.
• ATP nucleotides
• ADP serotonin
• PAF thromboxane A2
• vasopressin vasopressin
• endothelial cells release NO and prostacyclin which act synergistically to prevent and counter the platelet aggregation process.
• vasodilators have been developed to date: these substances known under the designation of nitrovasodilators produce NO in vivo and thus compensate for a defect in endogenous NO. There may be mentioned, for example, molsidomine or sodium nitroprusside, which make it possible to prevent the phenomena of adhesion and platelet aggregation.
• L-arginine In order to compensate for an insufficient production of NO, the administration of L-arginine or of analogues of L-arginine has also been proposed, L-arginine intervening directly in the biosynthesis of nitrogen monoxide, in as a substrate for NO-synthase.
• Surgical procedures by laparoscopy are more and more practiced because they allow, compared to the conventional techniques of open laparotomies, to reduce not only the duration of hospitalization, but also the healing time and thereby postoperative pain.
• the laparoscopy technique is usually accompanied by insufflation in the abdomen (intra or extra-peritoneal insufflation) of a gas, such as C0 2 , which insufflation causes an increase in the pressure exerted at l inside the abdomen.
• a gas such as C0 2
• the purpose of the present invention is therefore to alleviate the problems set out above.
• the invention then relates to the use of a gaseous composition containing nitrogen monoxide (NO) and carbon dioxide (C0 2 ) for the manufacture of a gaseous medicament intended for the treatment or prophylaxis by intra-abdominal hypoperfusions of the abdominal organs.
• intra-abdominal route is meant intra or extra-peritoneal route.
• the drug NO / C0 2 mixture of the invention is particularly suitable for administration by intra-abdominal insufflation during a laparoscopic or laparoscopic intervention; the peritoneum designating the serous membrane lining the cavity of the abdomen.
• the gaseous medicament of the invention preferably consists of the only mixture of carbon dioxide and nitrogen monoxide; however, the addition of at least one gas chosen from the group formed by xenon, krypton, nitrous oxide and their mixtures, to said mixture of C0 2 and NO is conceivable.
• the concentration of NO in the NO + C0 2 gas mixture is an effective concentration, preferably between 1 and 100 ppm.
• a concentration of less than 1 ppm is not desirable and a concentration of more than 100 ppm results in a progressive disappearance of the therapeutic effect.
• the reasons for the low activity observed at such concentrations are still unknown, but could be linked to local toxicity or possibly to saturation of the nitrogen monoxide receptors.
• the concentration of NO in the drug mixture is between 15 and 30 ppm.
• the stability of the gaseous medicament of the invention allows it to be stored under pressure in conventional containers of the type steel bottles or light alloy based on aluminum. In order to avoid any risk of contamination, we will advantageously opt for light alloy based on aluminum.
• the preferred storage conditions ensuring stability greater than 2 years are a temperature between 15 and 30 ° C, preferably 20 and 25 ° C, and a pressure between 20 and 30 bars.
• compositions of the invention can be administered by intra-abdominal insufflation, and more particularly by intraperitoneal insufflation. To do this, we will proceed in a manner known per se. After abdominal incision, the NO / C0 2 composition is injected into the abdominal cavity by means of a needle connected to an insufflator such as a Medicam 900 MP type video insufflator. During the entire duration of the intervention, an internal pressure of 10 to 20 mm of Hg is maintained in the abdominal cavity. Note that the blowing of a mixture of C0 2 and nitrogen monoxide is neither described nor suggested in the literature.
• the vasodilating and anti-aggregating activity of NO platelets makes the composition of the invention particularly suitable for the treatment of side effects linked to a reduction in the vascularization of the intra-abdominal organs during laparoscopic procedures.
• the amount of drug composition to be administered depends, for its part, on the age of the patient, the severity of the condition from which he suffers and the NO concentration of the gaseous composition injected. Examples 1 to 3 which follow illustrate the stability of the compositions of the invention, as well as their therapeutic utility, with reference to Figures 1 and 2 appended.
• the value of the NO concentration is measured by a chemiluminescence analyzer in the range from 0 to 100 ppm, calibrated before each measurement using a standard NO / N 2 mixture at 90 ppm.
• the chemiluminescence analyzer used is the TOPAZE 2020 manufactured by COSMA.
• This example aims to demonstrate the effectiveness of the composition NO / C0 2 of the invention, administered by intraperitoneal insufflation, in the fight against hypoperfusion of the abdominal organs, and in particular of the kidneys.
• Doppler ⁇ sensors are implanted on the renal artery so as to measure the diameter of the arterial vessel and the speed of the blood in order to assess the average renal blood flow.
• a urinary catheter is installed in the urethra in order to measure the urine flow.
• the 8 pigs are divided into 2 groups of 4 pigs each. These 2 groups of 4 pigs undergo intraperitoneal insufflation, for 2 hours and at a pressure of 15 mm Hg, of:
• a drop in blood flow and diuresis is observed in the 2 groups of pigs, from the start of insufflation. However, the drop is less for group 2 (NO / C0 2 blown). In fact, after insufflation, the blood flow and diuresis values obtained for group 2 are 20% to 30% higher than those obtained for group 1.
• the gaseous composition of N0 / C0 2 of the invention does indeed make it possible to combat hypoperfusions of the abdominal organs, when it is administered intra-abdominally, that is to say extra or intra-peritoneal, in allowing in particular an increase in blood flow to the abdominal organs.

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• Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Heart & Thoracic Surgery (AREA)
• Inorganic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Cardiology (AREA)
• Epidemiology (AREA)
• Organic Chemistry (AREA)
• Urology & Nephrology (AREA)
• Vascular Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 1996
  • 1996-10-15 AT AT96934916T patent/ATE209922T1/de not_active IP Right Cessation
  • 1996-10-15 ES ES96934916T patent/ES2167608T3/es not_active Expired - Lifetime
  • 1996-10-15 JP JP9516340A patent/JPH11513703A/ja not_active Ceased
  • 1996-10-15 DE DE69617719T patent/DE69617719D1/de not_active Expired - Lifetime
  • 1996-10-15 WO PCT/FR1996/001610 patent/WO1997015311A1/fr active IP Right Grant
  • 1996-10-15 AU AU73051/96A patent/AU701760B2/en not_active Ceased
  • 1996-10-15 EP EP96934916A patent/EP0855912B1/de not_active Expired - Lifetime
  • 1996-10-17 AU AU73058/96A patent/AU7305896A/en not_active Abandoned
  • 1996-10-17 US US09/051,641 patent/US6051241A/en not_active Expired - Fee Related
  • 1996-10-17 EP EP96934928A patent/EP0859620A1/de not_active Ceased
  • 1996-10-17 WO PCT/FR1996/001624 patent/WO1997015312A1/fr not_active Application Discontinuation
  • 1996-10-17 JP JP9516344A patent/JPH11513705A/ja active Pending
  • 1996-10-18 US US08/733,919 patent/US5670177A/en not_active Expired - Fee Related
  • 1996-10-18 CA CA002188238A patent/CA2188238A1/fr not_active Abandoned

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