WO1998047495A1 - Nouvelle composition - Google Patents

Nouvelle composition Download PDF

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Publication number
WO1998047495A1
WO1998047495A1 PCT/SE1998/000301 SE9800301W WO9847495A1 WO 1998047495 A1 WO1998047495 A1 WO 1998047495A1 SE 9800301 W SE9800301 W SE 9800301W WO 9847495 A1 WO9847495 A1 WO 9847495A1
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WO
WIPO (PCT)
Prior art keywords
nitrate
urine
pharmaceutical composition
agent
reducing agent
Prior art date
Application number
PCT/SE1998/000301
Other languages
English (en)
Inventor
Kjell Alving
Jan M. Lundberg
Jon Lundberg
Eddie Weitzberg
Peter Wiklund
Original Assignee
Nitricare Kb
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 Nitricare Kb filed Critical Nitricare Kb
Priority to AU61283/98A priority Critical patent/AU6128398A/en
Publication of WO1998047495A1 publication Critical patent/WO1998047495A1/fr

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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
    • A61K33/24—Heavy metals; Compounds thereof
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/02—Ammonia; Compounds thereof
    • 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
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/32—Manganese; Compounds thereof
    • 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

Definitions

  • the present invention relates to the prevention and treatment of bacterial infections in mammals by inducing and/or enhancing the endogenous production of nitric oxide (NO) and/or other reactive nitrogen oxides in body fluids.
  • the present invention also relates to a pharmaceutical composition and the use of said composition in the prevention and treatment of bacterial infections in mammals.
  • SE 9404161-3 which concerns the diagnosis of inflammatory conditions in the intestines
  • WO 95/02181 which concerns the determination of NO levels in exhaled air for purposes of diagnosing inflammatory conditions in the upper airways
  • SE 9601369-3 which concerns the determination of NO levels in gas samples taken from the urogenital organs for purposes of diagnosing inflammatory conditions in said organs.
  • NO may serve protective functions by scavenging other, more toxic, radicals.
  • Nitric oxide is normally produced enzymatically by constitutive NO synthases in, e.g. nerves and endothelial cells; these enzymes yield the relatively small amounts of NO involved in physiological regulation of nerve transmission and vascular tone.
  • the inducible NO synthase found, e.g. in activated white blood cells produces NO at a high rate.
  • nitric oxide is also produced through a second route, i.e. through reduction of nitrite.
  • Nitrite is present in body fluids such as saliva and urine, in amounts depending on the individual's diet and health. For example, a diet rich in nitrate (such as certain vegetables) will result in high nitrate levels in saliva and urine.
  • the bacteria normally present in the oral cavity will reduce salivary nitrate to nitrite. Further reduction of nitrite to nitric oxide occurs normally in the acidic environment of the stomach (Lundberg et al. 1994, Gut, 35: 1543-46).
  • Nigel Benjamin et al. have in WO 95/22335 disclosed the use of acidified nitrate as an anti-microbial agent and further described a dosage form for use in the treatment of bacterial, viral or fungal conditions.
  • An important characteristic of that disclosure is the presence of an acidifying agent, adapted to reduce the pH at the environment of use to below pH 4.
  • the acidifying agent is salicylic acid.
  • bacterial infections in body fluids can be prevented and/or treated at physiological pH by the administration of a suitable reduction agent and a suitable acidifying agent.
  • a suitable reduction agent and a suitable acidifying agent Preferably said agents are administered in connection with, but not necessarily simultaneously or conjunctly with a nitrate source.
  • the inventive composition induces and/or significantly enhances the formation of nitric oxide and/or other reactive nitrogen oxides in nitrite-containing body fluids, in particular in urine.
  • the present invention is described in closer detail in the following description and examples, to be read as exemplifying and not limiting the scope of the invention, as set forth in the appended patent claims.
  • Fig. la shows urinary nitric oxide release from control urine (open bars), control urine with 100 ⁇ M sodium nitrite added (striped bars) and infected urine (containing 8-400 ⁇ M nitrite, hatched bars),
  • Fig. lb shows nitric oxide release from control urine (100 ⁇ M nitrite added) at different pH values, with and without 10 mM ascorbic acid (filled and striped bars, respectively), and
  • Fig. 2 shows the growth of E. coli following exposure to acidified nitrite-containing urine.
  • the experiments were performed using different concentrations of nitrite ( ⁇ M) at pH 5.0 (a in the figure) and with different pH using a fixed concentration of nitrite (100 ⁇ M, b in the figure, filled bars).
  • Optical density in figure b was measured at 4 h.
  • Fig. 3 shows the growth of E. coli in human urine with and without the addition of the different components of the invention
  • Fig. 4 shows the effect of ingested ammonium nitrate and vitamin C on bacterial growth in human urine.
  • the present invention introduces a new concept of prevention and/or treatment of bacterial infections in body fluids, according to which the local production of NO and/or other reactive nitrogen oxides in body fluids, such as urine, vaginal fluid and cerebrospinal fluid is induced and/or enhanced by the administration of a new pharmaceutical composition.
  • the present invention mainly concentrates on the treatment of manifest infections, in particular infections in the urinary tract, such as lower urinary tract infection, infectious cystitis etc.
  • the invention is naturally also useful in the long-term or short-term prevention of infections, given that the dosage, route of administration and composition is adjusted as necessary.
  • the present invention concerns a composition, comprising at least a reducing agent and an agent, capable of acidifying the urine.
  • the present invention also comprises a method for treating bacterial infections, in particular infections in the urogenital tract and especially in the urinary tract. Said method comprises the steps of acidifying the body fluid in question, e.g. the urine, the administration of a reducing agent and, optionally, the administration of a nitrate source.
  • Examples of urine acidifiers include, but are not limited to, the following: ammonium chloride, ammonium nitrate, metheneamine hippurate (sold under the trade mark Hiprex ® ), metolazone (sold under the trade mark Zaroxolyn ® ), diazoxide (sold under the trade mark Hyperstat ® ) and L-arginine hydrochloride. Further, preliminary tests show that L- arginine hydrochloride may have the additional effect of potentiating the enzymatic synthesis of reactive nitrogen oxides in the bladder.
  • reducing agents include, but are not limited to, the following compounds or groups of compounds: ascorbyl palmitate, vitamin C, vitamin E, manganese, selenium, beta-carothene, pro-anthocyanidins, polyp henols, urat, co-enzyme Q10, thioles and bioflavonoids.
  • the pharmaceutically suitable reducing agent is ascorbic acid. This compound has several advantages, for example that it is freely soluble in water and thus will be distributed to all body fluids, and that any excess amounts are excreted in the urine; it is non-toxic and it's physiological effect and behaviour are well documented. Additionally, ascorbic acid also functions as a weak acidifying agent.
  • the source of nitrogen is simultaneously a source of nitrate or nitrite.
  • a suitable source of nitrogen are various nitrate salts, for example sodium nitrate, NaNO 3 .
  • the MDL values (orally in rats) are 200 mg kg and 330 mg/kg for sodium nitrate and sodium nitrite, respectively.
  • the inventive composition is administered orally, in any of the following forms; a solution, a syrup, a chewable tablet, a tablet to be swallowed as a whole, a capsule to be swallowed, a water-soluble lozenge and a effervescent tablet to be dissolved in water.
  • care has to be taken in choosing the necessary excipients, such as tabletting agents, braking agents, lubricants etc. Any excipients must be chosen among agents accepted for use in pharmaceutical preparations or as food additives. Care has also to be taken in choosing the excipients so, that they do not react with or catalyse reactions between the constituents of the pharmaceutical preparation. In some cases, it may be suitable to employ microencapsulation techniques for ensuring the stability of the product.
  • the inventive composition is specially useful in the treatment of manifest urinary infections, such as urinary tract infections in post operative patients, catherized patients, cystectomized patients and patients with a urinary diversion. In the latter group of patients, where the bladder has been operatively removed and replaced with a section of the intestines, converted to a reservoir for urine, infections are a serious problem.
  • the present invention is highly useful in the treatment of such conditions and the inventive composition can be administered either orally or as a solution for flushing the surgically constructed reservoir. It is also contemplated by the present inventors, that the inventive pharmaceutical composition is administered as a prophylactic regimen to catherized patients or any patient, susceptible for infections in the urinary tract. Obviously, the inventive composition can be administered in conjunction with other treatments for bacterial infections in the urinary tract, potentiating these treatments.
  • the pharmaceutical composition according to the invention is to be directed specifically towards the prevention and/or treatment of infections in the urinary tract, the inclusion of a diuretic in said composition is possible.
  • diuretics potentially suitable in this application, are thiazide compounds, sulphonamid derivatives, phenoxi acetic acid derivatives, so called loop-diuretics and aldosterone antagonsists.
  • loop-diuretics and aldosterone antagonsists.
  • ammonium nitrate is included in the composition. This is specially preferred in compositions intended for the prevention and/or treatment of bacterial infections in the urinary tract.
  • the pharmaceutical composition is delivered in the form suitable for sublingual or buccal administration, e.g. as a lozenge or tablet.
  • Said lozenge or tablet comprises, in addition to the constituents described above, a water-soluble, direct compressible excipient and minor amounts of a lubricant.
  • This compressible excipient should be palatable or tasteless and water-soluble and accepted for use in pharmaceutical preparations or as a food additive.
  • Suitable excipients are those, conventionally used, for example dextrin compounds, various sugars and sugar alcohols, such as lactose, sorbitol, mannitol and xylitol.
  • Said lubricant is chosen among conventional lubricants, such as magnesium stearate.
  • excipient and lubricant have to be chosen so, and employed in such amounts, not to endanger the stability of the product, that is not to react with or catalyse a reaction between the constituents or substantially shorten the shelf-life of the pharmaceutical composition.
  • Example 1 Urine was collected from 10 healthy controls (age 26-42 years) and 8 patients (age 41-70 years) with bacteriuria as confirmed by urinary cultures. Nitrite concentration in infected urine was measured with capillary electrophoresis, and nitric oxide release was studied after adjusting pH to 4.5 or 5.0 with 1 M HCl. In control urine, nitric oxide formation was measured at different pH values (4-8) and with varying amounts of nitrite (10-500 ⁇ M).
  • nitric oxide release from acidified nitrite-containing urine would be influenced by the addition of ascorbate at a concentration (10 raM) resembling that found in urine (Brandt et aL, Am J Clin Pathol. 68(1977) 592-594) after daily ingestion of 1-2 gram. Similar measurements were also performed in urine from 5 healthy controls before and after ingestion of vitamin C (2 grams/day) for two days. In all experiments, urinary samples (10 ml) were incubated in a closed syringe at 37°C with a head space of 50 ml. After 30 min the head space gas was removed and immediately injected into a chemiluminescence nitric oxide analyser (Eco Physics, Switzerland). Ambient nitric oxide levels were below 4 parts per billion (ppb) in all experiments.
  • E. coli Escherichia coli ATCC 25922 was grown in Mueller- Hinton broth for 6 h at 37°C resulting in 3 x 10 8 CFU/ml.
  • the strain was diluted to a bacterial density of approximately 10 6 CFU/ml in acidified urine with or without the addition of nitrite and kept for 2 h at 37°C in a closed tube.
  • Bacterial growth was measured continuously in control urine medium for 10 h by vertical photometry in a computerised incubator for bacteria, Bioscreen C (Labsystems, Helsinki, Finland).
  • Basal nitric oxide formation was low both in control urine and in infected urine.
  • large amounts of nitric oxide were generated from infected urine (containing 8-400 ⁇ M nitrite) when the urine was acidified to pH 4.5 or 5.0 and from acidified non-infected urine if nitrite was added (Fig. la).
  • Urinary nitric oxide release was strongly pH dependent in the presence of nitrite and was greatly enhanced by the addition of ascorbic acid (Fig. lb). Also, nitric oxide formation increased with higher nitrite concentrations in urine.
  • ppb parts per billion nitric oxide was released from 10 ⁇ M nitrite, whereas 100, 250 and 500 ⁇ M yielded 400, 1500 and 4000 ppb nitric oxide, respectively.
  • ingestion of vitamin C urinary nitric oxide release (at pH 5.0, 100 ⁇ M nitrite) increased seven-fold compared to the control situation.
  • Example 2 The addition of nitrite to acidified urine (pH 5.0) dose-dependently reduced the growth of E. coli (Fig. 2a). The inhibition of bacterial growth was greater at lower urinary pH when using a fixed concentration of 100 ⁇ M nitrite (Fig. 2b).
  • Example 3 Escherichia coli (E. coli, strain ATCC 25922) was grown in Mueller- Hinton broth for 6 hours at 37 °C. The strain was then diluted to a bacterial density of approximately 10 6 CFU/ml in human urine. The bacteria were kept in a closed tube for 2 hours at variable pH with or without the addition of nitrate 10 mM and ascorbate 10 mM. Bacterial growth was then measured continuously in control urine medium for 20 hours by vertical photometry in a computerised incubator for bacteria, Bioscreen C (Labsystems, Helsinki, Finland). The growth rate is expressed as the time (hours) to reach 50% of the maximal growth found in control urine at pH 6 without addition of nitrate or ascorbate.
  • Urine was collected from a healthy male control. Urine was also collected after a ingestion of ammonium nitrate 4.5 gram daily for 3 days with or without simultaneous ingestion of 3 gram vitamin C (ascorbate).
  • Escherichia coli E. coli, strain ATCC 25922
  • the strain was then diluted to a bacterial density of approximately 10 6 CFU/ml in the urine collected from the healthy control and were kept in a closed tube for 2 hours.
  • Bacterial growth was then measured continuously in control urine medium (at pH 6 without nitrate and vitamin C) for 20 hours by vertical photometry in a computerised incubator for bacteria, Bioscreen C (Labsystems, Helsinki, Finland). Cf. figure 4.
  • A The growth in control urine at pH 5,
  • B the growth in urine (pH 5) after daily ingestion of ammonium nitrate 4.5 gram.
  • C daily ingestion of ammonium nitrate 4.5 gram and 3 gram vitamin C (ascorbate). Note the growth inhibitory effect after ingestion of ammonium nitrate (B) and the additive effect of simultaneous ingestion of vitamin C (C).

Abstract

La prévention et/ou le traitement d'infections bactériennes sont réalisées par l'administration d'une composition pharmaceutique qui induit et/ou augmente la formation de monoxyde d'azote (NO) dans les liquides de l'organisme, tels que l'urine et les sécrétions vaginales. La composition contient au moins un agent acidifiant pharmaceutiquement compatible, un agent de réduction et aussi, de préférence, une source de nitrate. Cette composition pharmaceutique peut être administrée, par ex. sous forme de pastille, de comprimé effervescent soluble dans l'eau, de solution etc.
PCT/SE1998/000301 1997-02-21 1998-02-20 Nouvelle composition WO1998047495A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU61283/98A AU6128398A (en) 1997-02-21 1998-02-20 New composition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9700617A SE9700617D0 (sv) 1997-02-21 1997-02-21 New composition
SE9700617-5 1997-04-22

Publications (1)

Publication Number Publication Date
WO1998047495A1 true WO1998047495A1 (fr) 1998-10-29

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Family Applications (1)

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PCT/SE1998/000301 WO1998047495A1 (fr) 1997-02-21 1998-02-20 Nouvelle composition

Country Status (3)

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AU (1) AU6128398A (fr)
SE (1) SE9700617D0 (fr)
WO (1) WO1998047495A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001089572A1 (fr) * 1998-06-10 2001-11-29 Nitric Oxide Solutions Systemes et methodes de traitement topique avec de l'oxyde nitrique
WO2002017881A2 (fr) * 2000-08-30 2002-03-07 Queen Mary & Westfield College Composition d'administration transdermique d'agent pharmaceutique
AU2001270631B2 (en) * 2000-07-11 2005-07-07 Bayer Aktiengesellschaft Use of strains of the parapox ovis virus for producing antiviral pharmaceuticals and anticancer pharmaceuticals

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2047878A1 (en) * 1969-06-13 1971-03-19 Chanteaud Laboratoires Treatment of pheasants using arginine, - ascorbic acid and mineral salts
EP0021984A1 (fr) * 1979-06-19 1981-01-07 Jean-Paul Begouen Médicament vétérinaire pour le traitement des jeunes veaux
EP0167191A1 (fr) * 1984-06-04 1986-01-08 Jan Willem Bins Préparation thérapeutique contenant le nitrate d'ammonium comme substance active
US4595591A (en) * 1979-09-27 1986-06-17 Solco Basel Ag Use of dilute nitric acid solutions for treating certain skin lesions
DD281543A5 (de) * 1988-06-17 1990-08-15 Univ Leipzig Herstellungsverfahren fuer ein mittel zur verbesserung der muskulaeren aeroben leistungsfaehigkeit, insbesondere bei trainings- und wettkampfbelastungen
WO1995022335A1 (fr) * 1994-02-21 1995-08-24 Aberdeen University Nitrite acidifie en tant qu'agent antimicrobien

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2047878A1 (en) * 1969-06-13 1971-03-19 Chanteaud Laboratoires Treatment of pheasants using arginine, - ascorbic acid and mineral salts
EP0021984A1 (fr) * 1979-06-19 1981-01-07 Jean-Paul Begouen Médicament vétérinaire pour le traitement des jeunes veaux
US4595591A (en) * 1979-09-27 1986-06-17 Solco Basel Ag Use of dilute nitric acid solutions for treating certain skin lesions
EP0167191A1 (fr) * 1984-06-04 1986-01-08 Jan Willem Bins Préparation thérapeutique contenant le nitrate d'ammonium comme substance active
DD281543A5 (de) * 1988-06-17 1990-08-15 Univ Leipzig Herstellungsverfahren fuer ein mittel zur verbesserung der muskulaeren aeroben leistungsfaehigkeit, insbesondere bei trainings- und wettkampfbelastungen
WO1995022335A1 (fr) * 1994-02-21 1995-08-24 Aberdeen University Nitrite acidifie en tant qu'agent antimicrobien

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ACTA THERAPEUTICA, Volume 16, No. 3, 1990, J.W. BINS et al., "L'acidification des Urines en Pratique Urologique: Interet du Nitrate d'Ammonium", pages 247-252. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001089572A1 (fr) * 1998-06-10 2001-11-29 Nitric Oxide Solutions Systemes et methodes de traitement topique avec de l'oxyde nitrique
AU2001270631B2 (en) * 2000-07-11 2005-07-07 Bayer Aktiengesellschaft Use of strains of the parapox ovis virus for producing antiviral pharmaceuticals and anticancer pharmaceuticals
WO2002017881A2 (fr) * 2000-08-30 2002-03-07 Queen Mary & Westfield College Composition d'administration transdermique d'agent pharmaceutique
WO2002017881A3 (fr) * 2000-08-30 2003-04-17 Queen Mary & Westfield College Composition d'administration transdermique d'agent pharmaceutique
US8114442B2 (en) 2000-08-30 2012-02-14 Queen Mary & Westfield College Transdermal pharmaceutical delivery compositions
US8128964B2 (en) 2000-08-30 2012-03-06 Queen Mary & Westfield College Transdermal pharmaceutical delivery composition

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Publication number Publication date
SE9700617D0 (sv) 1997-02-21
AU6128398A (en) 1998-11-13

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