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WO1996000076A1 - Use of the enantiomers of oxazophosphorines, e.g. ifosfamide, in anti-tumour therapy, for reducing side-effects - Google Patents

Use of the enantiomers of oxazophosphorines, e.g. ifosfamide, in anti-tumour therapy, for reducing side-effects Download PDF

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Publication number
WO1996000076A1
WO1996000076A1 PCT/GB1995/001475 GB9501475W WO9600076A1 WO 1996000076 A1 WO1996000076 A1 WO 1996000076A1 GB 9501475 W GB9501475 W GB 9501475W WO 9600076 A1 WO9600076 A1 WO 9600076A1
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WO
WIPO (PCT)
Prior art keywords
iff
ifosfamide
substantially free
enantiomers
oxazophosphorine
Prior art date
Application number
PCT/GB1995/001475
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French (fr)
Inventor
Helen Frances Baker
Original Assignee
Chiroscience Limited
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
Priority claimed from PCT/GB1994/002171 external-priority patent/WO1996000075A1/en
Application filed by Chiroscience Limited filed Critical Chiroscience Limited
Priority to EP95922649A priority Critical patent/EP0772444A1/en
Priority to AU27474/95A priority patent/AU2747495A/en
Publication of WO1996000076A1 publication Critical patent/WO1996000076A1/en
Priority to NO965528A priority patent/NO965528L/en
Priority to FI965171A priority patent/FI965171L/en

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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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate

Definitions

  • This invention relates to oxazophosphorines and their 5 therapeutic use.
  • Oxazophosphorines are cytotoxic al ylating agents, examples being ifosfamide and cyclophosphamide. Ifosfamide has been shown to be more effective and less toxic than
  • Ifosfamide is licensed for use in refractory testicular cancer in the US, and for tumours of lung, ovary, cervix, breast and testis and soft tissue sarcoma in the UK. It is used as a single agent and in combination
  • Ifosfamide (by way of example only) is a cytotoxic compound and effects other than the antitumour effect are expected. Myelosuppression. alopecia, nausea and vomiting are all unwanted effects of the compound.
  • the compound has other unwanted toxicities, e.g. on the urinary tract, and neurotoxicity, which limit the dosing and make the compound difficult to use.
  • Combination with the uroprotective agent mesna has reduced the incidence of hae orrhagic cystitis, but nephrotoxicity is
  • Ifosfamide is a chiral compound. Its enantiomers dexifosfamide (herein sometimes ••(R)-IFF”) and levoifosfamide (herein sometimes "(S)-IFF”) are known, and may be prepared by classical resolution. Processes for their preparation are described in US Patent No.4,684,742, Polish Patent No. 119,971, and British Patent No. 1,553,984.
  • Ifosfamide requires metabolic activation.
  • One of the two main metabolic pathways produces the active species, the isophosphoramide mustard.
  • the 4-hydroxy-ifosfamide may also be an active species.
  • the second main pathway, N- dechloroethylation produces 2 and 3-dechloro metabolites, with the release of chloroacetaldehyde.
  • S-Ifosfamide produces R-3-dechloroifosfamide (R-3DCE) and S-2- dechloroifosfamide (S-2DCE) .
  • R-ifosfamide produces S-3- dechloroifosfamide (S-3DCE) and R-2-dechloroifosfamide (R- 2DCE) .
  • Metabolism is induced by dividing the dose over several days; the main increase being in the route to the mustard. On a single dose, between 20-40% of the drug is excreted unchanged, and 15-50% of the compound is metabolised through the N- dechloroethylation pathway.
  • FIG. 1 shows the mean plasma concentration ⁇ SEM ( ⁇ m) versus time (hours) profiles of (R)-IFF and (S)-IFF over 24 hours, following a 3 hour infusion of 3 g/m 2 (R,S)-IFF, in 14 cancer patients.
  • the data indicate a significantly greater rate of metabolism of the (S) enantiomer compared with the (R) .
  • Figure 2 shows the mean area ⁇ SEM ( ⁇ M.hr) under the plasma concentration versus time curve (AUC) for ifosfamide and for its dechloroethylated metabolites, following a 3 hour infusion of 3 g/m (R,S)-IFF in 14 cancer patients.
  • the present invention is based on the discovery that the known side-effects can be reduced by the administration of enantiomeric ifosfamide.
  • the discovery should apply to all oxazophosphorines.
  • the desired enantiomer is substantially free of the other enantiomer and is preferably in an enantiomeric excess of at least 60% and more preferably at least 80%, most preferably 90% or more.
  • the drug used in this invention may be formulated in conventional media. It may be administered orally or by intravenous infusion.
  • the formulation may include any suitable carrier. Such administration of the drug may avoid hospitalisation.
  • discrete unit dosage forms may be provided.
  • "blister packs” of such unit dosages may be used, e.g. of tablets, capsules, vials, ampoules and the like.
  • An integral package or “kit” of the dosages may be provided with instructions or coding, to indicate the appropriate order of administration.
  • the enantiomer used in the invention is administered in an amount determined by the nature of the tumour and the skill of the physician, such as 100 to 5000, e.g. 600, mg/m per day/single dose; see also De Kraker, Anticancer Drugs 2:339-341 (1991), the contents of which are incorporated herein by reference.
  • An advantage of the present invention is to allow higher/more frequent dosing, e.g.
  • the invention is based on a comparison of the metabolism of ifosfamide enantiomers with that of the racemic compound and measurement of certain metabolites. By means of the invention, active rather than toxic metabolites are preferentially obtained in vivo.
  • the pharmacokinetics of (R)- IFF and (S)-IFF were examined in 14 cancer patients treated with a 3 hour infusion of (R,S)-IFF. The results are shown in the drawings.
  • the area under the curve (AUC) of (R)-IFF was significantly larger than that of (S)-IFF (2480 ⁇ 200 versus 1960 ⁇ 150 ⁇ m/hour) .
  • the terminal half-lives (7.57 ⁇ 0.99 hours) and mean residence times (11.17 ⁇ 1.10 hours) of (R)-IFF were significantly longer than those of (S)-IFF, 6.03 ⁇ 0.82 hours and 9.37 ⁇ 0.88 hours, respectively.
  • (S)-IFF was metabolised more rapidly than (R)-IFF. As metabolism to the active moiety is required for the therapeutic effect of this product, the administration of an equivalent dose of (S)-IFF alone will result in the more rapid production of effective substance and an enhanced clinical benefit.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A product containing respective enantiomers of an oxazophosphorine, each substantially free of the other, as a combined preparation for separate, simultaneous or sequential use in anti-tumour therapy. The active component may be ifosfamide. Levoifosfamide is preferred for single drug therapy, owing to its more rapid metabolism.

Description

USE OF THE ENANTIOMERS OF OXAZOPHOSPHORINES, E.G. IFOSFAMIDE, IN ANTI-TUMOUR THERAPY, FOR REDUCING SIDE-EFFECTS
Field of the Invention
This invention relates to oxazophosphorines and their 5 therapeutic use.
Background of the Invention
Oxazophosphorines are cytotoxic al ylating agents, examples being ifosfamide and cyclophosphamide. Ifosfamide has been shown to be more effective and less toxic than
10 cyclophosphamide when given by pulsed or infusional regimes. Ifosfamide is licensed for use in refractory testicular cancer in the US, and for tumours of lung, ovary, cervix, breast and testis and soft tissue sarcoma in the UK. It is used as a single agent and in combination
15 with radiotherapy, surgery and other cytotoxic agents.
Ifosfamide (by way of example only) is a cytotoxic compound and effects other than the antitumour effect are expected. Myelosuppression. alopecia, nausea and vomiting are all unwanted effects of the compound.
20 The compound has other unwanted toxicities, e.g. on the urinary tract, and neurotoxicity, which limit the dosing and make the compound difficult to use. Combination with the uroprotective agent mesna has reduced the incidence of hae orrhagic cystitis, but nephrotoxicity is
25 a potentially serious side-effect.
Neurotoxic effects range from mild somnolence to severe encephalopathy, hallucinations and coma. In most cases, they are reversible, but in some they are not. They are more prevalent after oral dosing and large single IV
30 doses. It is thought that they are caused by a metabolite, possibly chloroacetaldehyde. This is a significant problem: the drug must be administered in hospital because of the occurrence of these side-effects.
CNS side-effects were a major dose-limiting side-
35 effect when the compound was in development as an oral formulation. The side-effects appeared at a much lower dose than they did during iv administration, and this meant that cytotoxic doses could not be reached. It is known that there is much more metabolism of the compound after oral dosing; in particular, higher levels of chloroacetaldehyde are produced, indicating more N- dechloroethylation.
Ifosfamide is a chiral compound. Its enantiomers dexifosfamide (herein sometimes ••(R)-IFF") and levoifosfamide (herein sometimes "(S)-IFF") are known, and may be prepared by classical resolution. Processes for their preparation are described in US Patent No.4,684,742, Polish Patent No. 119,971, and British Patent No. 1,553,984.
Ifosfamide requires metabolic activation. One of the two main metabolic pathways produces the active species, the isophosphoramide mustard. The 4-hydroxy-ifosfamide may also be an active species. The second main pathway, N- dechloroethylation, produces 2 and 3-dechloro metabolites, with the release of chloroacetaldehyde. S-Ifosfamide produces R-3-dechloroifosfamide (R-3DCE) and S-2- dechloroifosfamide (S-2DCE) . R-ifosfamide produces S-3- dechloroifosfamide (S-3DCE) and R-2-dechloroifosfamide (R- 2DCE) . Other metabolic routes are responsible for a very small amount of the total metabolism. Metabolism is induced by dividing the dose over several days; the main increase being in the route to the mustard. On a single dose, between 20-40% of the drug is excreted unchanged, and 15-50% of the compound is metabolised through the N- dechloroethylation pathway.
Boos et al. Cancer Chemother. Pharmacol. 28.455-460 (1991), investigated the urinary excretion of the enantiomers of ifosfamide, following administration of the racemate. It was concluded that "Theoretically, an advantage in the form of reduced side-chain metabolism could be expected from the use of the S form of ifo in nearly half of our patients and the R form in the other half", and "stereospecific metabolism does not indicate that any clear-cut advantage can be gained from the application of an individual enantiomer."
Masurel et al. Cancer Res. 5fi: 252-255 (1990), studied the efficacy and toxicity of IFF enantiomers in CBA/CaJ mice. The results indicated that there were no statistically significant differences between the efficacies of (R)-IFF, (S)-IFF, and (R,S)-IFF against childhood rhabdo yosarcoma (HxRh28) grown in vivo as a xenograft in immunoincompetent female CBA/CaJ mice. The same was true regarding the acute toxicities of the stereoisomers. No statistically significant differences were found in the plasma pharmacokinetics of (S)-IFF, or in the in vitro N-dechloroethylation.
Wainer et al. Cancer Res. 5.J 393-4397 (1994), report the pharmacokinetics of ifosfamide and its enantiomers in rats. It is concluded that, because (R)-IFF is metabolised to a greater extent than (S)-IFF via the activation pathway, the former "may be an effective way to deliver active cytotoxic drug while limiting the generation of neurotoxic metabolites". Summary of the Invention
Surprisingly, it has been found that individual enantiomers of oxazophosphorines, e.g. levoifosfamide, have improved therapeutic benefit, since one enantiomer may be more rapidly metabolised. This is based on the results of the analysis of the pharmacokinetics of (R)-IFF and (S)-IFF in 14 cancer patients treated with an infusion of (R,S)- IFF. (S)-IFF was found to be more rapidly metabolised than (R)-IFF, a phenomenon that will result in the more rapid production of the active species and therefore improved efficacy. Accordingly, contrary to the conclusion expressed by Wainer et al, supra, the use of levoifosfamide may give improved results, including reduced side-effects.
Another aspect of the invention is based on an appreciation of the relative effects of the enantiomers of oxazophosphorines such as ifosfamide. It has now been appreciated that, especially for longer-term administration of ifosfamide, it is desirable to use a combination therapy, i.e. one enantiomer (dexifosfamide) initially, and the other enantiomer (levoifosfamide) thereafter. Brief Description of the Drawings Figure 1 of the accompanying drawings shows the mean plasma concentration ± SEM (μm) versus time (hours) profiles of (R)-IFF and (S)-IFF over 24 hours, following a 3 hour infusion of 3 g/m2 (R,S)-IFF, in 14 cancer patients. The data indicate a significantly greater rate of metabolism of the (S) enantiomer compared with the (R) .
Figure 2 shows the mean area ± SEM (μM.hr) under the plasma concentration versus time curve (AUC) for ifosfamide and for its dechloroethylated metabolites, following a 3 hour infusion of 3 g/m (R,S)-IFF in 14 cancer patients. These data indicate that the AUC values for all of the DCE metabolites from (S)-IFF were significantly greater than those from (R)-IFF. Description of the Invention
The present invention is based on the discovery that the known side-effects can be reduced by the administration of enantiomeric ifosfamide. The discovery should apply to all oxazophosphorines. The desired enantiomer is substantially free of the other enantiomer and is preferably in an enantiomeric excess of at least 60% and more preferably at least 80%, most preferably 90% or more.
The drug used in this invention may be formulated in conventional media. It may be administered orally or by intravenous infusion. The formulation may include any suitable carrier. Such administration of the drug may avoid hospitalisation.
Especially for the novel combined therapy, discrete unit dosage forms may be provided. For example, "blister packs" of such unit dosages may be used, e.g. of tablets, capsules, vials, ampoules and the like. An integral package or "kit" of the dosages may be provided with instructions or coding, to indicate the appropriate order of administration. The enantiomer used in the invention is administered in an amount determined by the nature of the tumour and the skill of the physician, such as 100 to 5000, e.g. 600, mg/m per day/single dose; see also De Kraker, Anticancer Drugs 2:339-341 (1991), the contents of which are incorporated herein by reference. An advantage of the present invention is to allow higher/more frequent dosing, e.g. by a factor of 1.5, 2 or more. The frequency and duration may be determined by similar consideration. The invention is based on a comparison of the metabolism of ifosfamide enantiomers with that of the racemic compound and measurement of certain metabolites. By means of the invention, active rather than toxic metabolites are preferentially obtained in vivo. In a first investigation, the pharmacokinetics of (R)- IFF and (S)-IFF were examined in 14 cancer patients treated with a 3 hour infusion of (R,S)-IFF. The results are shown in the drawings.
Assessing the concentrations of each enantiomer in plasma and urine, the area under the curve (AUC) of (R)-IFF was significantly larger than that of (S)-IFF (2480 ± 200 versus 1960 ± 150 μm/hour) . The terminal half-lives (7.57 ± 0.99 hours) and mean residence times (11.17 ± 1.10 hours) of (R)-IFF were significantly longer than those of (S)-IFF, 6.03 ± 0.82 hours and 9.37 ± 0.88 hours, respectively. These data indicate that (S)-IFF was metabolised more rapidly than (R)-IFF. As metabolism to the active moiety is required for the therapeutic effect of this product, the administration of an equivalent dose of (S)-IFF alone will result in the more rapid production of effective substance and an enhanced clinical benefit.
In the same study, an examination of the 2- and 3-N- dechloroethylated (DCE) metabolites of ifosfamide revealed that the AUC values for all of the DCE metabolites from (S)-IFF were significantly greater than those from (R)-IFF, with 47% of the measured AUC accounted for by DCE from (S)- IFF compared with only 20% for (R)-IFF. Therefore, the administration of (S)-IFF alone may result in the initial production of greater quantities of unwanted metabolites. This effect may decrease with time, as the desired pathway to the active mustard is induced by the usual mechanisms associated with liver metabolism.
Therefore, optimum clinical benefit may be achieved by initial administration of (R)-IFF for a period of time to induce the metabolic pathway to the active species with minimum production of toxic metabolites, followed by a switch to (S)-IFF to utilise the benefits of increased metabolic rate resulting in more rapid production of active drug.

Claims

1. A product containing respective enantiomers of an oxazophosphorine, each substantially free of the other, as a combined preparation for separate, simultaneous or sequential use in anti-tumour therapy.
2. A product according to claim 1, which comprises a plurality of unit dosage forms of each of the respective enantiomers of an oxazophosphorine, each substantially free of the other, the dosage forms being discretely packaged as part of an integral package.
3. A product according to claim 1 or claim 2, wherein the oxazophosphorine is ifosfamide.
4. A method for treating a tumour in a human patient, which comprises the administration to said patient of an anti-tumour effective amount of one enantiomer of an oxazophosphorine, substantially free of the other.
5. A method according to claim 4, which comprises the administration of levoifosfamide substantially free of dexifosfamide.
6. Use of one enantiomer of an oxazophosphorine, substantially free of the other, for the manufacture of a medicament for anti-tumour therapy.
7. Use according to claim 6, wherein said one enantiomer is more rapidly metabolised.
8. Use of levoifosfamide, substantially free of dexifosfamide, for the manufacture of a medicament for anti-tumour therapy.
PCT/GB1995/001475 1994-06-23 1995-06-23 Use of the enantiomers of oxazophosphorines, e.g. ifosfamide, in anti-tumour therapy, for reducing side-effects WO1996000076A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP95922649A EP0772444A1 (en) 1994-06-23 1995-06-23 Use of the enantiomers of oxazophosphorines, e.g. ifosfamide, in anti-tumour therapy, for reducing side-effects
AU27474/95A AU2747495A (en) 1994-06-23 1995-06-23 Use of the enantiomers of oxazophosphorines, e.g. ifosfamide, in anti-tumour therapy, for reducing side-effects
NO965528A NO965528L (en) 1994-06-23 1996-12-20 Use of enantiomers of oxazophosphorins such as ifosfamide, in anti-cancer therapy to reduce side effects
FI965171A FI965171L (en) 1994-06-23 1996-12-20 Use of enantiomers of oxazophosphorines, e.g. ifosfamide, in tumor treatment to reduce side effects

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9412618A GB9412618D0 (en) 1994-06-23 1994-06-23 Cytotoxic agent and its use
GB9412618.2 1994-06-23
GBPCT/GB94/02171 1994-10-05
PCT/GB1994/002171 WO1996000075A1 (en) 1994-06-23 1994-10-05 Use of the enantiomers of ifosfamide in antitumor therapy for reducing side effects

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WO1996000076A1 true WO1996000076A1 (en) 1996-01-04

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PCT/GB1995/001475 WO1996000076A1 (en) 1994-06-23 1995-06-23 Use of the enantiomers of oxazophosphorines, e.g. ifosfamide, in anti-tumour therapy, for reducing side-effects

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EP (1) EP0772444A1 (en)
AU (1) AU2747495A (en)
FI (1) FI965171L (en)
GB (1) GB9412618D0 (en)
NO (1) NO965528L (en)
WO (1) WO1996000076A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022614A1 (en) * 1995-12-19 1997-06-26 Darwin Discovery Limited Ifosfamide, analogues thereof and their preparation
US6153150A (en) * 1998-01-12 2000-11-28 Advanced Technology Materials, Inc. Apparatus and method for controlled decomposition oxidation of gaseous pollutants
US6261524B1 (en) 1999-01-12 2001-07-17 Advanced Technology Materials, Inc. Advanced apparatus for abatement of gaseous pollutants

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
B. TESTA ET AL.: "Racemates Versus Enantiomers in Drug Development: Dogmatism or Pragmatism?", CHIRALITY, vol. 2, 1990, pages 129 - 133 *
BLASCHKE, G. ET AL: "Preparative isolation and pharmacological-toxicological studies of the enantiomers of ifosfamide", ARZNEIM.-FORSCH., 1986, VOL. 36, PAGE(S) 1493-5 *
G. BLASCHKE ET AL.: "Metabolismus der Enantiomere des Zytostatikums Ifosfamid", ARZNEIM.-FORSCH., vol. 39, no. 2, 1989, pages 223 - 226 *
KLEINROK, ZDZISLAW ET AL: "Pharmacological evaluation of ifosfamide and its enantiomers in laboratory animals", ARCH. IMMUNOL. THER. EXP., 1986, VOL. 34, PAGE(S) 293-304 *
KUSNIERCZYK, H. ET AL: "Antitumor activity of optical isomers of cyclophosphamide, ifosfamide and trofosfamide as compared to clinically used racemates", J. IMMUNOPHARMACOL., 1986, VOL. 8, PAGE(S) 455-80 *
M. PAPROCKA ET AL.: "Comparative studies on biological activity of (+)R and (-)S enantiomers of cyclophosphamide and ifosfamide", ARCH. IMMUNOL. THER. EXP., vol. 34, no. 3, 1986, pages 275 - 284 *
M. PAPROCKA ET AL.: "Comparative studies on biological activity of (+)R and (-)S enantiomers of cyclophosphamide and ifosfamide", ARCH. IMMUNOL. THER. EXP., vol. 34, no. 3, 1986, pages 285 - 291 *
MASUREL, DOMINIQUE ET AL: "Efficacy, toxicity, pharmacokinetics, and in vitro metabolism of the enantiomers of ifosfamide in mice", CANCER RES., 1990, VOL. 50, PAGE(S) 252-5 *
WAINER, I. W. ET AL: "Efficacy and toxicity of ifosfamide stereoisomers in an in vivo rat mammary carcinoma model", CANCER RES., 1994, VOL. 54, PAGE(S) 4393-7 *
Z. KLEINROK ET AL.: "Comparison of pharmacological properties of cyclophosphamide and its enantiomers", ARCH . IMMUNOL. THER. EXP., vol. 34, no. 3, 1986, pages 263 - 273 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022614A1 (en) * 1995-12-19 1997-06-26 Darwin Discovery Limited Ifosfamide, analogues thereof and their preparation
US6153150A (en) * 1998-01-12 2000-11-28 Advanced Technology Materials, Inc. Apparatus and method for controlled decomposition oxidation of gaseous pollutants
US6464944B1 (en) 1998-01-12 2002-10-15 Advanced Technology Materials, Inc. Apparatus and method for controlled decomposition oxidation of gaseous pollutants
US6511641B2 (en) 1998-01-12 2003-01-28 Advanced Technology Materials, Inc. Method for abatement of gaseous pollutants
US7138096B2 (en) 1998-01-12 2006-11-21 Applied Materials, Inc. Method for decomposition oxidation of gaseous pollutants
US7790120B2 (en) 1998-01-12 2010-09-07 Applied Materials, Inc. Apparatus and method for controlled decomposition oxidation of gaseous pollutants
US6261524B1 (en) 1999-01-12 2001-07-17 Advanced Technology Materials, Inc. Advanced apparatus for abatement of gaseous pollutants

Also Published As

Publication number Publication date
FI965171A0 (en) 1996-12-20
NO965528L (en) 1997-02-19
EP0772444A1 (en) 1997-05-14
NO965528D0 (en) 1996-12-20
FI965171L (en) 1996-12-20
AU2747495A (en) 1996-01-19
GB9412618D0 (en) 1994-08-10

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