WO2013186607A1 - Method of using boronic acid teboroxime for pharmacologic myocardial perfusion spect studies with specific compositions, unit dosage forms and kits - Google Patents

Method of using boronic acid teboroxime for pharmacologic myocardial perfusion spect studies with specific compositions, unit dosage forms and kits Download PDF

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WO2013186607A1
WO2013186607A1 PCT/IB2013/000424 IB2013000424W WO2013186607A1 WO 2013186607 A1 WO2013186607 A1 WO 2013186607A1 IB 2013000424 W IB2013000424 W IB 2013000424W WO 2013186607 A1 WO2013186607 A1 WO 2013186607A1
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patient
agent
bato
stressing
adenosine
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French (fr)
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Philippe Gorny
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Adenobio N.V.
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating 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
    • A61K31/395—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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
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    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
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    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid

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Abstract

A method of reducing radiation exposure to a patient undergoing cardiac diagnosis is performed by administering to the patient a single dose of an effective amount of imaging agent comprising a complex of BATO, or a BATO derivative, with a radioisotope, administering to the patient a pharmacological stressing agent, where the amount of the imaging agent administered allows for cardiac imaging during both a rest state and a stressed state and results in reduced radiation exposure to the patient compared to the radiation exposure to a patient when using an ultrafast SPECT method with isotopes not coupled with BATO or BATO derivatives or an existing/conventional method, and acquiring cardiac images of the patient.

Description

A METHOD OF USING BORONIC ACID TEBOROXIME
FOR PHARMACOLOGIC MYOCARDIAL PERFUSION SPECT STUDIES WITH SPECIFIC COMPOSITIONS, UNIT DOSAGE FORMS AND KITS
BACKGROUND
[0001] Most current tests for exploring myocardial ischemia status are non-invasive nuclear perfusion imaging methodologies using single photon emission computed tomography (SPECT), projecting a three-dimensional image, with thallium and technetium (Tc99m) as the most currently used radio-isotopes, herein also termed radionuclides or radiopharmaceuticals. A class of radionuclide compounds known as BATOs (boronic acid adducts of technetium or technetium species) has been developed for use in myocardial imaging. Tc99m-Boronic acid teboroxime, also referred to as " Tc99m-BATO", has been approved by the FDA, but has not reached the market and is no longer available for clinical use. This is due to its very fast kinetics at the level of the heart and to the fact that current gamma camera detectors are not sensitive enough to detect its signal. However, the arrival of new ultrafast gamma-cameras allows for improved sensitivity. The development of new semiconductors for gamma photon detection, and, in particular, the use of cadmium telluride zinc (CZT), is an important breakthrough. It has given rise to the emergence of stationary gamma ray multi-detectors made of CZT modules and to the creation of cameras that reduce SPECT-MP imaging acquisition time. Other ultrafast camera systems are expected to become commercially available soon. In this new context, the interest in BATO should be revived to the point that it could become the leading radionuclide in cardiology in the near future.
SUMMARY
[0002] Described herein is an exemplary method, dosages, unit dosage forms (UDFs) and kits that allow BATO and BATO derivatives to form Tc99m-BATO or Tc99m-BATO derivatives and to be used in combination with a stressing agent so as to meet the elements defined in the following paragraphs.
[0003] Described herein is an exemplary method of reducing radiation exposure to a patient undergoing cardiac diagnosis using single photon emission computed tomography (SPECT), where the method comprises : (a) administering to a patient in need thereof a single dose of an effective amount of imaging agent comprising a complex of boronic acid teboroxime
(BATO), or a BATO derivative, with a radioisotope, such as technetium 99, wherein the amount of the imaging agent administered results in reduced radiation exposure to the patient compared to the radiation exposure to a patient when using a current SPECT method or an ultrafast SPECT method as described above in paragraph [0001] with a different radiotracer than the combination of Tc99m with BATO or a BATO derivative ; (b) acquiring cardiac images of the patient in a rest state; (c) administering to the patient a dose of at least one pharmacological stressing agent, and (d) acquiring cardiac images of the patient in a stressed state. In an exemplary embodiment, the pharmacological stressing agent is adenosine, dipyridamole, a mixture of adenosine and dipyridamole, an A2A adenosine agonist such as regadenoson, binodenoson, apadenoson, adenosine phosphate or even papaverine and the like.
[0004] Also described herein, are kits comprising BATO, or a BATO derivative, and at least one pharmacological stressor in unit dosage forms (UDFs) that allow a single dose of a complex of BATO, or a BATO derivative, with a radioisotope, such as technetium 99, to be administered to a patient to allow cardiac imaging under both rest and stress conditions. The pharmacological stressors can be adenosine, dipyridamole, a mixture of adenosine and dipyridamole, an A2A adenosine agonist such as regadenoson, binodenoson, apadenoson, adenosine phosphate, papaverine and the like. The kits may further comprise at least one of a connector, a diluent, an extension set and a venous line. An exemplary kit comprises at least one unit dosage form of BATO, or a BATO derivative, allowing for the administration of about 5 mCi to about 15 mCi of Tc99m, preferably about 5 mCi to about 10 mCi of Tc99m, more preferably about 6 mCi to about 9 mCi of Tc99m.
[0005] Currently, the total duration for a MPI-SPECT study, including stress and rest protocols, as a rule, ranges from about 4 to about 24 hours and results in radiation exposure to the patient of about 20 to 30 millisieverts (mSV) and sometimes more. This is considered to be a high dose compared to 8 mSV exposure for a scanner, 2 mSV natural exposure/year for each person, and the total cumulated dose of 100-150 mSV /year, a level at which people are at risk of developing cancer. With ultrafast gamma cameras that help reduce imaging acquisition time, the duration of study protocols and radiation exposure are both roughly cut by 50%. With the method described herein, the duration of full-study protocols can be further reduced, to a maximum time length of about 20 minutes or even less (about 7 minutes) and radiation exposure reduced to less than about 10 mSV and even less than about 5 mSV using a single radionuclide injection for a full rest/stress protocol.
[0006] As a rule, a full stress/rest or rest/stress MPI study with either traditional or new ultrafast gamma-cameras requires, at the minimum, two radionuclide injections, one at each phase, with quite a long interval of time between them. This is due to the kinetic profiles of the radiopharmaceuticals commonly used in clinical practice, Thallium-201 (Tl-201), Tc99M- sestamibi, and Tc99M-Tetrofosmin. Upon injection, they are primarily distributed throughout the myocardium in proportion to coronary blood flow (these radionuclides have a high first pass myocardial extraction of over 65%). They are also captured by other tissues but only in a second stage. To facilitate the procedure and reduce total radiation exposure, the initial isotope injection is often coupled to the acquisition of images under stress conditions first. Indeed if the images are normal under stress conditions they are presumed to remain unchanged at rest, making the rest phase useless. In case of the contrary, the acquisition of images at rest is mandatory and then follows so as to distinguish between a defect due to ischemia (in general not visible at rest) from a defect due to myocardial necrosis (visible on rest state images). However, this requires the radionuclide, after its initial uptake, to be homogenously redistributed throughout the myocardium, which is not always the case. When it is not the case, a delayed session may be needed under rest conditions, with a second isotope injection.
[0007] Thallium has a long half-life (73 hrs) and must be administered at very low doses to limit radiation exposure over time. This reduces image quality. However, it is well redistributed into the myocardium allowing for the acquisition of images at rest (following those acquired under stress conditions), but not before 4 to 24 hrs after the initial injection, since Tl-201 redistribution is a very slow phenomenon. Even then a mini dose of thallium is often administered again.
[0008] Tc99M sestamibi and Tc99M tetrosformin both have a very similar profile. They can be administered at higher doses than thallium and produce better image quality. However, the disadvantage of the use of these imaging agents is the lack of redistribution. This lack of redistribution requires a second radiopharmaceutical injection under rest conditions. This second injection can be done with either thallium or Tc99m, but in the latter case at increased dosages.
[0009] These imaging agents have the disadvantages of requiring time-consuming protocols and exposing patients to high radiation levels. Thus, there is a need to reduce the duration of protocols for the studies and the radiation exposure. It should be noted that many countries other than the United States, especially European countries, consider radiation exposure as an important issue and a key limiting factor for extensive use of myocardial perfusion scintigraphy in clinical practice. In the United States, higher levels of radiation exposure have long been accepted, but this is changing.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] Fig. 1 illustrates the steps involved in the study protocol, where a single dose of the imaging agent, such as Tc99m-BATO, is injected under rest conditions and the single dose of the imaging agent allows for cardiac imaging under both rest and stress conditions.
DETAILED DESCRIPTION
[0011] Tc99m-BATO (Technetium 99m or technetium 99 species with boronic acid teboroxime) is close to the ideal myocardial perfusion tracer and potentially the best of all radiopharmaceuticals. Its extraction fraction (capture by the myocardium) is higher than those of Tl-201 or Tc99m. This goes with its excellent correlation to coronary blood flow. Also, image quality is proportionally improved. Tc99m-BATO's myocardial uptake occurs after about only one minute. The tracer is redistributed no more than about one minute after its capture by myocytes and washed-out from the myocardium after about 3 minutes. This rapid uptake and washout, that includes a redistribution phase, allows, in theory, for extremely short stress/rest protocols.
[0012] The recommended dose for Tc99m-BATO, which means the dose referring to the radioactivity of technetium or technetium species combined to boronic acid, at the time it was marketed, was, in a man weighing 70 kilograms of 15 to 30 millicuries (mCi) for a single injection and of about 35 to 50 mCi for a full stress-rest study (two injections). In U.S. Patent Application Publication Number US2010/0140483A1, several methods of use with low doses of Tc99mBATO (<5 mCi) are detailed. These low doses are considered as theoretically usable and effective when the acquisition of images is performed by an ultrafast gamma- camera system such as CZT cameras. However, all the methods described in the '483 patent application and related to full stress-rest or rest-stress MPI-SPECT studies, require the use of at least two radiopharmaceutical injections separated by a substantial interval of time between them with a suggested dose of Tc99m-BATO radioactivity of 8 to 12 mCi for the first injection and a higher dose for the second injection.
[0013] In one embodiment, the method includes administering only a single injection of radiopharmaceutical Tc99m BATO, or a TC99m-BATO derivative, to perform a full rest- stress SPECT-MPI study protocol, independent of the stressing agent used. [0014] In another embodiment, the method starts with the injection of Tc99m-B ATO, or a Tc99m-BATO derivative, at rest followed by the injection of a stressing agent after about 2.5 minutes to about 4 minutes. Under stress conditions and due to the fact that Tc99mBATO does not penetrate myocardial cells but only binds to cell membranes, it is more rapidly washed out in the healthy regions of the myocardium than in the ischemic regions. As a consequence and as opposed to all existing and previously-described SPECT protocols, the imaging of ischemic regions appears with the present method, in positive instead of in negative (defect). This is innovative and preferable in terms of diagnosis since the human eye sees a light in the dark (positive image) better than a shadow in the daylight (defect). Given the capability of ultrafast gamma cameras to capture Tc99m BATO radioactivity at rest, despite its short time of residency in the heart, this method has now become applicable and can greatly contribute to improve both the quality and the accuracy of myocardial images analysis.
[0015] In an exemplary method of reducing radiation exposure and the duration of the protocol to a patient undergoing cardiac diagnosis using a nuclear technique such as single photon emission computed tomography (SPECT), the method comprises administering parenterally to a patient in need thereof an effective but reduced amount of a
radiopharmaceutical called boronic acid teboroxime-Technetium 99 (BATO-Tc99M) acting as a myocardial radio-labeled tracer, wherein the amounts of the tracer result in reduced radiation exposure for the patient.
[0016] In another exemplary method of reducing radiation exposure and the duration of the protocol to a patient undergoing cardiac diagnosis using a nuclear technique such as single photon emission computed tomography (SPECT), the method comprises administering parenterally to a patient in need thereof an effective, but reduced, amount of a BATO derivative combined to Tc99m. The term "BATO derivatives" means the following compounds:
(a) a boron compound of the formula B-R1, wherein R1 is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R2R3N)-alkyl and R2 and R3 are each independently hydrogen, alkyl, or arylalkyl, or R2 and R3 when taken together with the nitrogen atom to which they are attached form a 5 or 6-membered nitrogen containing heterocycle. R4
_ l _
(b) a boron compound of the formula Rs° B 0R5 , or a pharmaceutically acceptable salt thereof, wherein R4 is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, alkoxy- alkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl, or R6R7N-alkyl and R$ and R7 are each independently hydrogen, alkyl, or arylalkyl, or R4 and R5 when taken together with nitrogen atom to which they are attached form a 5 or 6-membered nitrogen containing heterocycle, and R5 is hydrogen, alkyl or aryl;
[0017] The term "about" means approximately or in the region of. The values encompassed by the number are related to the significant digits in the number. When used in the context of the amount of radiation administered in an imaging agent, such as "about 10 mCi," the amount of radiation could range from 9.5 mCi to 10.5 mCi. When used in the context of the quantity of time, such as "about 45 seconds," the time could range from 42.5 seconds to 47.5 seconds. When the time period is under 10 seconds, the range is ± 2 second.
[0018] The use of the terms "from" and "between" in the description of values of ranges include the upper and lower limits. The term "a" means one or more.
[0019] In one embodiment , the preferred radioactivity dose for Tc-99m-BATO (or a BATO derivative combined to technetium) is about 9 mCi (3 mSv radiation exposure) to about 12 mCi (4 mSv exposure). In some cases, the dose can be as low as about 6 mCi to about 8 mCi.
[0020] In another embodiment , a unit dosage form comprising an amount of boronic acid teboroxime (BATO) or a derivative allowing for the administration of about 5 millicuries to about 15 millicuries of Tc-99m is provided. Useful unit dosage forms can allow for the administration of about 5 mCi to about 15 mCi, of about 5mCi to 10 mCi or even about 6 mCi to about 12 mCi.
[0021] In another embodiment , the stressing agent used after the administration of Tc99m- BATO at rest can be adenosine, dipyridamole, a combination of adenosine and dipyridamole, an adenosine A2 agonist (e.g. regadenoson, binodenoson, apadenoson), adenosine phosphate, or any other useful coronary vasodilator (e.g., papaverine etc). Preferred stressors are those with a short duration of action allowing for the best imaging sensitivity, the best imaging contrast during Tc99m-BATO' clearance from the heart, and the shortest full protocol (rest and stress) duration. [0022] Best stressing agents for the method described herein are those with a short onset of action, a short duration of action and a rapid return to baseline. Among existing stressors dipyridamodole is the least suitable since it requires a 4 minute infusion, produces its maximal effect after only 7 or 8 minutes, and has a prolonged return to base line. The same remark applies to Lexiscan® (regadenoson) that maintains hyperaemia for 2 to 3 minutes and is followed by a slow return to baseline with a sustained vasodilating effect persisting until about 7 to about 10 minutes post-injection. Being more A2a specific than regadenoson and thus profiled with a longer duration of action other A2a agonists, such as binodenoson and apadenoson, are applicable but even less suitable than regadenoson. Standard adenosine infused at its recommended dose of 140 μg/kg/min, can also be applicable, especially if administered for no more than 2 minutes and no less than one minute. Due to its very short kinetics the preferred stressor, called Adenofast, is the combination of about 1 mg to 4 mg adenosine with about 9 mg to 14 mg dipyridamole, more preferably, 2 mg to about 2.6 mg adenosine with 12 mg to about 12.6 mg dipyridamole administered intravenously as an about 30 second bolus.
[0023] In another embodiment, kits comprising a unit dosage form of non radioactive BATO or BATO derivative (before its combination to technetium), possibly similar to those described above, with one or several unit dosage forms of a stressing agent are provided. They can also be co-packaged.
[0024] In an exemplary method of reducing radiation exposure and total study time to a patient undergoing cardiac diagnosis using a nuclear technique such as single photon emission computed tomography (SPECT), the method comprises administering to a patient in need thereof an amount of Tc99m-BATO allowing for the administration of no more than about 5 to about 15 millicuries (mCi) of Tc99m while the patient is under rest conditions, acquiring images of the patient for a period of up to about 2.5 minutes to about 4 minutes, then administering a stressing agent after about 2.5 minutes to about 4 minutes, and acquiring images of the patient (Tc99m-BATO's clearance) for a period of up to about 2 minutes to about 15 minutes after administration of the stressing agent (preferably no more than about 4 minutes) depending on the duration of action of said stressing agent.
[0025] All publications, patents, patent applications and other documents cited in this application are hereby incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent, patent application or other document were individually indicated to be incorporated by reference for all purposes.
[0026] While various specific embodiments have been illustrated and described, it will be appreciated that various changes can be made without departing from the spirit and scope of the claims.
EXAMPLE
[0027] Steps of an exemplary method:
1. Injection of Tc99m-BATO under rest conditions.
2. Continuous acquisition of rest images starting about 40 to about 60 seconds after injection of Tc99m-BATO and continuing for about 3 to about 4 minutes.
3. Injection of the stressor, such as Adenofast, after about 3 to about 4 minutes without any additional injection of Tc99m-BATO and continuous acquisition of stress images for about 2 to about 20 minutes depending on the stressing agent used.
[0028] In this protocol, ischemic regions appear in positive instead of in negative (=defect) as opposed to usual protocols. This is innovative and takes into account that the human eye sees a light in the dark (positive image) better than a shadow in the daylight (defect).
[0029] This study mode, which is totally new, is optimally performed with a stressing agent having a very short duration of action such as the one described in U.S. provisional application No. 61/594,744 (Feb 3, 2012) This is because a rapid coronary hyperemia kinetic enhances contrasts between healthy and non-healthy zones after the uptake of Tc99m-BATO by the myocardium. However it can also be performed, although less convenient and less sensitive in terms of diagnosis with other stressing agents.

Claims

CLAIMS WHAT IS CLAIMED IS:
1. A method of reducing radiation exposure to a patient undergoing cardiac diagnosis, the method comprising administering to a patient in need thereof a single dose of an effective amount of imaging agent comprising a complex of B ATO, or a B ATO derivative, with a radioisotope, such as Technetium 99, administering to said patient a pharmacological stressing agent, wherein the amount of the imaging agent administered allows for cardiac imaging during both a rest state and a stressed state and results in reduced radiation exposure to the patient compared to the radiation exposure to a patient when using an ultrafast SPECT method with isotopes not coupled with BATO or BATO derivatives or an existing conventional SPECT method, and acquiring cardiac images of said patient.
2. The method of claim 1, wherein the imaging agent is Tc99m-BATO (boronic acid teboroxime-Tc99m).
3. The method of claim 2, wherein the amount of imaging agent administered comprises from about 5 millicuries to about 15 millicuries of Tc-99m, preferably about 5 millicuries to about 10 millicuries of Tc-99m, or about 6 to about 12 millicuries of Tc-99m.
4. The method of claim 1, where the pharmacological stressing agent is selected from the group consisting of adenosine, dipyridamole, a combination of adenosine and dipyridamole, and an adenosine agonist.
The method of claim 4, where the adenosine agonist is regadenoson, binodenoson, enoson or adenosine phosphate.
6. The method of claim 4, wherein stressing agent is the combination of a fixed dose of about 1 mg to about 4 mg adenosine with a fixed dose of about 9 mg to about 14 mg dipyridamole administered as a slow bolus injection over a period of about 20 seconds to about 45 seconds, preferably about 30 seconds.
7. The method of claim 6, wherein stressing agent is administered as a slow bolus injection over a period of about 20 seconds to about 45 seconds, preferably about 30 seconds.
8. The method of claim 1, wherein said imaging agent is administered to said patient before the administration of said pharmacological stressing agent, and the administration of said pharmacological stressing agent is made about 2.5 minutes to about 4 minutes after the administration of said imaging agent, said method further comprising acquiring images of said patient: (a) after administration of said imaging agent and before administration of said pharmacological stressing agent, and (b) after administration of said pharmacological stressing agent.
9. The method of claim 1 , wherein at least one dose of the imaging agent and at least one dose of the stressing agent are co-packaged or provided in the form of a kit.
PCT/IB2013/000424 2012-06-11 2013-03-02 Method of using boronic acid teboroxime for pharmacologic myocardial perfusion spect studies with specific compositions, unit dosage forms and kits WO2013186607A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
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Publication number Priority date Publication date Assignee Title
WO2001007089A2 (en) * 1999-07-28 2001-02-01 Bracco Diagnostics Inc. Technetium tc99m teboroxime myokardial-perfusion mittel
WO2007010534A2 (en) * 2005-07-19 2007-01-25 Spectrum Dynamics Llc Imaging protocols
WO2008003479A1 (en) * 2006-07-05 2008-01-10 Adenobio N.V. Methods, compositions, unit dosage forms, and kits for pharmacologic stress testing with reduced side effects
US20100140483A1 (en) 2006-11-13 2010-06-10 Benny Rousso Radioimaging applications of and novel formulations of teboroxime

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Title
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GEMIGNANI A. S. AND ABBOT, B. G.: "The emerging role of the selective A2A agonist in pharmacologic stress testing", JOURNAL OF NUCLEAR CARDIOLOGY, vol. 17, no. 3, 5 May 2010 (2010-05-05), pages 494 - 497, XP002712169 *
MAHMARIAN J J ET AL: "Myocardial perfusion imaging during pharmacologic stress testing", CARDIOLOGY CLINICS, W.B. SAUNDERS COMPANY, PHILADELPHIA, US, vol. 12, no. 2, 1 January 1994 (1994-01-01), pages 223 - 245, XP009090182, ISSN: 0733-8651 *

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