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Clinical Applications of Blood-Derived
and Marrow-Derived Stem Cells for
Nonmalignant Diseases
Richard K. Burt, MD
Context Stem cell therapy is rapidly developing and has generated excitement and promise
as well as confusion and at times contradictory results in the lay and scientific literature.
Many types of stem cells show great promise, but clinical application has lagged due toethical concerns or difficulties in harvesting or safely and efficiently expanding sufficient quantities. In contrast, clinical indications for blood-derived (from peripheral or umbilical cord blood) and bone marrow–derived stem cells, which can be easily and safely harvested,are rapidly increasing.
Objective To summarize new, nonmalignant, nonhematologic clinical indications for
use of blood- and bone marrow–derived stem cells.
Evidence Acquisition Search of multiple electronic databases (MEDLINE, EMBASE,
Science Citation Index), US Food and Drug Administration [FDA] Drug Site, and NationalInstitutes of Health Web site to identify studies published from January 1997 to Decem- STEMCELLSAREUNDIFFERENTI- ber2007onuseofhematopoieticstemcells(HSCs)inautoimmune,cardiac,orvascular diseases. The search was augmented by hand searching of reference lists in clinical trials, review articles, proceedings booklets, FDA reports, and contact with study authors and de-vice and pharmaceutical companies.
Evidence Synthesis Of 926 reports identified, 323 were examined for feasibility and
terms, there are 2 types of stem cells, em- toxicity, including those with small numbers of patients, interim or substudy reports, andreports on multiple diseases, treatment of relapse, toxicity, mechanism of action, or stem bryonic stem cells and adult stem cells.
cell mobilization. Another 69 were evaluated for outcomes. For autoimmune diseases, 26 reports representing 854 patients reported treatment-related mortality of less than 1% lated from a 50- to 150-cell, 4- to 5-day- (2/220 patients) for nonmyeloablative, less than 2% (3/197) for dose-reduced myeloablative, and 13% (13/100) for intense myeloablative regimens, ie, those including total body ir- onic stem cells generate every specialized radiation or high-dose busulfan. While all trials performed during the inflammatory stage of autoimmune disease suggested that transplantation of HSCs may have a potent disease- pable of indefinite ex vivo proliferation, remitting effect, remission duration remains unclear, and no randomized trials have been exist only transiently in vivo (during em- published. For reports involving cardiovascular diseases, including 17 reports involving 1002 patients with acute myocardial infarction, 16 involving 493 patients with chronic coronaryartery disease, and 3 meta-analyses, the evidence suggests that stem cell transplantation performed in patients with coronary artery disease may contribute to modest improvement Conclusions Stem cells harvested from blood or marrow, whether administered as
purified HSCs or mesenchymal stem cells or as an unmanipulated or unpurified prod- tionally thought to be restricted in their uct can, under appropriate conditions in select patients, provide disease-ameliorating differentiation to cell lineages of the or- effects in some autoimmune diseases and cardiovascular disorders. Clinical trials are gan system in which they are located.
needed to determine the most appropriate cell type, dose, method, timing of delivery, and adverse effects of adult HSCs for these and other nonmalignant disorders.
with adult stem cells, are currently dif- Author Affiliations are listed at the end of this article.
Corresponding Author: Richard K. Burt, MD, Divi-
sion of Immunotherapy, Department of Medicine,Northwestern University Feinberg School of Medi- cine, 750 N Lake Shore Dr, Room 649, Chicago, IL 2008 American Medical Association. All rights reserved.
(Reprinted) JAMA, February 27, 2008—Vol 299, No. 8 925
BLOOD- AND MARROW-DERIVED STEM CELLS FOR NONMALIGNANT DISEASES fected. In contrast, adult stem cells nor- ing of reference lists in clinical trials, specific differentiation patterns, fulfill- pirate are cultured in plastic flasks, he- aging, or damaged tissues. For these rea- cluded in the search: stem cell transplan- testinal tract, heart, brain), the major- tation, bone marrow transplantation, pe- ripheral blood stem cell transplantation, hematopoietic stem cell transplantation, mal cells and mesenchymal stem cells.
mesenchymal stem cell transplantation, circulating progenitor cell, autoimmune to contribute to the structural matrix of diseases, multiple sclerosis, systemic scle- rosis, systemic lupus erythematosus, poiesis; the latter describes the ability of Crohn’s disease, rheumatoid arthritis, ju- venile idiopathic arthritis, vasculitis, Weg- ner’s, Sjo¨gren’s, Behcet’s, celiac disease, dermatomyositis, polymyositis, relaps- ing polychondritis, chronic inflammatory demyelinating polyneuropathy, myasthe- nia gravis, diabetes, coronary artery dis- ease, myocardial infarction, myocardial is- rify for HSCs, assays for their detection peripheral vascular disease. Animal data, etic stem cell assays may be divided into population assays.1 The gold standard for EVIDENCE SYNTHESIS
HSCs is the ability to repopulate all he- J.A.R.) judged eligibility of studies inde- tialsearchidentified926articles(FIGURE).
ents reconstitutes hematopoiesis with re- sultant normal life spans. Serial in vivo EVIDENCE ACQUISITION
sential functional criteria of HSCs: pro- stem cell collection, or toxicity reports, liferation to replenish the stem cell com- ity are lifelong repopulating stem cells. A 926 JAMA, February 27, 2008—Vol 299, No. 8 (Reprinted)
2008 American Medical Association. All rights reserved.
BLOOD- AND MARROW-DERIVED STEM CELLS FOR NONMALIGNANT DISEASES Figure. Flow of Eligible Studies of Stem Cell Transplantation for Nonmalignant
on autoimmune disorders [Ն4 patients]that reported on a single autoimmune 926 Articles identified in initial search disease and were not subsequently re-ported as part of a later study or analy- patients with acute myocardial infarc-tion, 493 patients with chronic myocar- dial ischemia, and 169 with peripheralvascular disease.
Stem Cells
for Autoimmune Diseases
55 Interim reports11 Multiple diseases in one report (HSCT) for treatment of patients with se- late 1990s. These clinical trials were basedonextensivepreclinicalanimaltransplan- mune diseases are environmentally in-duced by vaccination with self-peptides,adjuvant, or both and may be cured by a 26 Reports (854 patients) on treatment of 43 Reports on treatment of vascular disease of self- or auto-reactive lymphocytes (ie,lymphoablation). Other animal autoim- aAssessed both acute infarction and chronic ischemia; this study is also included in the 3 meta-analyses shown above.
mune disorders occur spontaneouslywithout intentional or obvious environ- row failure if HSCs are not reinfused.
tion, if any, to duration of clinical remis- eases, ie, for lymphoablation without ir- cells. Following a nonmyeloablative regi- rather as changing the natural history of disease. This second point should be con- reported rates of up to 23%.11 Treatment- tion in justifying mortality end points in related mortality, although generally im- myeloablative regimens11,14-37 (TABLE 1).
2008 American Medical Association. All rights reserved.
(Reprinted) JAMA, February 27, 2008—Vol 299, No. 8 927
BLOOD- AND MARROW-DERIVED STEM CELLS FOR NONMALIGNANT DISEASES Table 1. Treatment-Related Mortality Following Autologous Hematopoietic Stem Cell Transplantation for Autoimmune Diseasesa
or Single
Nonmyeloablative Regimenb
Complete remission (n = 3); partial response (n = 1) 50% ACR criteria 50 or greater response at 12 mo Low-Intensity Myeloablative Regimeng
High-Intensity Myeloablative Regimeni
Mixed Myeloablative and Nonmyeloablative Regimens
Complete remission (n = 6); partial response (n = 5) Complete remission or partial response in 92% Abbreviations: ACR, American College of Rheumatology; CIDP, chronic inflammatory demyelinating polyneuropathy; JIA, juvenile idiopathic arthritis; MS, multiple sclerosis; NA, not available; SLE, systemic lupus erythematosus.
a Excludes reports having Ͻ4 patients, reports with multiple autoimmune diseases, and results included in interim or substudy analyses.
b Nonmyeloablative regimens include combinations of cyclophosphamide, fludarabine, or antilymphocyte antibodies.
c R. K. Burt, Y. Loh, B. Cohen, et al., Autologous non-myeloablative hematopoietic stem cell transplantation for relapsing-remitting multiple sclerosis reverses neurologic disability, d R. M. Craig, Y. Oyama, K. Quigley, et al, Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with refractory Crohn disease 2001-2007, unpublished e Progression-, relapse-, and mortality-free survival.
f Two patients received a myeloablative regimen.
g Low-intensity myeloablative regimens may include nonmyeloablative agents as well as either BEAM (carmustine, etoposide, cytarabine, melphalan) or melphalan (Յ140 mg/m2).
h Not categorized as secondary or primary progressive.
i High-intensity myeloablative regimens may include nonmyeloablative agents as well as either total body irradiation (Ն8 Gy) or full-dose busulfan.
j Does not include 2 cases of late radiation-induced myelodysplastic syndrome/leukemia.
k One case of late radiation-induced myelodysplastic syndrome/leukemia included in mortality.
l Includes primary and secondary progressive, relapsing progressive, and relapsing-remitting multiple sclerosis.
m Transplant-related mortality lower with less intense regimens.
928 JAMA, February 27, 2008—Vol 299, No. 8 (Reprinted)
2008 American Medical Association. All rights reserved.
BLOOD- AND MARROW-DERIVED STEM CELLS FOR NONMALIGNANT DISEASES of clinical benefit in patients with pro- mation was abrogated, while loss of brain ease, resulted in marked serologic, clini- agents used in the conditioning regimen.
sion for 5 years.19 In comparison, a mul- Learning from these studies, a trial of au- free survival, but treatment-related mor- sion, and two-thirds of patients had sig- after transplantation in patients receiv- flexibility and quality of life, and rever- matopoietic stem cell transplantation for sal of pulmonary alveolitis.15,18 Two stud- relapsing-remitting multiple sclerosis re- men, termed “ rituximab sandwich,” en- tails 1 dose of rituximab given before and of treatment-related mortality,15,18 respec- date, this regimen has been well tolerated.
sclerosis—ie, treat early while the disease tive regimens with low risk of treatment- increased intensity of the transplant regi- eloablative regimen and selecting patients plete loss of insulin-producing islet cells.
tients with secondary progressive and, to sulted in insulin-free remission of type 1 a lesser extent, primary progressive dis- diabetes in 13 of 15 patients, and some pa- ease. In this subset of patients, intense treated with different conditioning regi- cose levels (as determined by levels of gly- other therapy for more than 3 years at last progressive neurologic disability.27,29-31 clear if, at some point in dose intensity, tensity. It is also unclear if any regimen 2008).20,21 For rheumatoid arthritis, the 2008 American Medical Association. All rights reserved.
(Reprinted) JAMA, February 27, 2008—Vol 299, No. 8 929
BLOOD- AND MARROW-DERIVED STEM CELLS FOR NONMALIGNANT DISEASES Table 2. Ongoing Randomized Controlled Trials of Autologous Hematopoietic Stem Cell
URL (Trial Identifier)
Nonmyeloablative Regimen
domized, noncontrolled trials.55,56 In non- Myeloablative Regimen
Stem Cells for Vascular Disease
Abbreviations: ASSIST, American Scleroderma Stem Cell vs Immune Suppression Trial; ASTIL, Autologous Stem Cell Transplantation International Lupus; ASTIMS, Autologous Stem Cell Transplantation International Multiple Sclerosis;ASTIS, Autologous Stem Cell Transplantation International Scleroderma; KISS, Crohns Immune Suppression vs Stem Cells; MIST, Multiple Sclerosis International Stem Cell Transplant; SCOT, Scleroderma Cyclophosphamide Or Trans-plantation; URL, uniform resource locator.
nonhematopoietic organ function afterinjection of unmanipulated marrow, pe-ripheral blood, or umbilical cord blood vascular Behçet disease,16 neurovascular Sjo¨gren syndrome,16 Takyasu arteritis,47 at least 2 years after transplantation42; results are not yet reported, several ran- lative regimens (TABLE 2).
eases.48-52 Because it changes genetic pre- is considered more likely to cure autoim- ease, is not an acceptable risk following tive or low-intensity myeloablative regi- human data48,49,53 suggest that an alloge- retinitis and optic neuritis (Y. Oyama, R.
cal paracrine or cell-help-cell effect.
K. Burt, C. Thirkill, E. Hanna, K. Merril, eloablative hematopoietic stem cell trans- disease,22 polyarteritis nodosa,32 neuro- 930 JAMA, February 27, 2008—Vol 299, No. 8 (Reprinted)
2008 American Medical Association. All rights reserved.
BLOOD- AND MARROW-DERIVED STEM CELLS FOR NONMALIGNANT DISEASES express endothelial characteristics. This mixture of cells, whether unselected, en- riched for a stem cell marker, or manipu- lated in culture and from diverse sources, can be used in intracoronary or intramyo- Acute Myocardial Infarction. In pa-
tricular contractility in the cell treat- of the infarct-related artery with or with- out stent placement plus anticoagulation, later by repeat percutaneous coronary in- stem cells57-73 (TABLE 3). The infused stem
tracoronary transplantation.60 In contrast provements in infarct size, left ventricu- studies, the BOOST trial reported that the lating progenitor cells (CPCs), which are peripheral blood cells cultured ex vivo to Table 3. Clinical Trials of Stem Cell Therapy for Acute Myocardial Infarction With Ն30 Patients
LVEF Outcome,
Days After
Stem Cell
increased infarct-relatedartery restenosis Abbreviations: ASTAMI, Autologous Stem Cell Transplantation in Acute Myocardial Infarction; BOOST, Bone Marrow Transfer to Enhance ST Elevation Infarct Regeneration Trial; CPC, circulating progenitor cell; G-CSF, granulocyte colony–stimulating factor; LVEF, left ventricular ejection fraction; MAGIC, Myocardial Regeneration and Angiogenesis in MyocardialInfarction With G-CSF and Intracoronary Stem Cell Infusion; MAGIC Cell-3-DES, MAGIC-3-Drug Eluting Stents; MI, myocardial infarction; NA, not available; NS, not significant; REPAIR-AMI,Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction; TOPCARE-AMI, Transplantation of Progenitor Cells and Regeneration Enhancement inAcute Myocardial Infarction.
a Study assessed both acute and old MI.
c Randomized to high-dose, low-dose, or no cells.
2008 American Medical Association. All rights reserved.
(Reprinted) JAMA, February 27, 2008—Vol 299, No. 8 931
BLOOD- AND MARROW-DERIVED STEM CELLS FOR NONMALIGNANT DISEASES farction) trial found no significant ben- eficial effects from intracoronary trans- Chronic Coronary Artery Disease.
In chronic ischemic cardiac disease or old sponse to hypoxic stress that halts the en- tion, and global LVEF, and to relieve an- group.64,79 Left ventricular ejection frac- Peripheral Vascular Disease. Tis-
there was an increase in restenosis in pa- tion. Several reports have suggested that pass graft surgery84-99 (TABLE 4). Erbs et
al84 treated chronic (Ͼ30-day) total coro- derived stem cells into the affected limb intracoronary CPC infusion or no cells.
nary Artery Disease) trial, Strauer et al85 needle into multiple sites 1 to 3 cm apart dure has generally been performed safely, 932 JAMA, February 27, 2008—Vol 299, No. 8 (Reprinted)
2008 American Medical Association. All rights reserved.
BLOOD- AND MARROW-DERIVED STEM CELLS FOR NONMALIGNANT DISEASES obtained by intra-arterial injection of cells tration (ie, puncturing the tibia) to al- a “cure,” appears to be a potentially useful clinical approach available to ame- injection of progenitor cells remains un- blative regimens are used, indicating the tients with thromboangiitis obliterans re- sponded to therapy.103,104 In contrast, de- prove to be the elusive “cure” for some au- esis, or release factors such as nitric ox- ide that augment local endothelial cell at- patients with bilateral (n=22) or unilat- graft, and whether an allogeneic graft-vs- therapy have been used to facilitate tis- sue repair following ischemic injury.
est benefit with little toxicity from stem Table 4. Clinical Trials of Stem Cell Therapy for Chronic Myocardial Ischemia and/or Heart Failure With Ն20 Patients
No. of Follow-
Stem Cell
Stem Cell
Trial Type/Name
Patients up, mo
LVEF Outcome; Comment
Improved mortality in high-order CFUs injected Improved LVEF and left ventricular volumes Improved LVEF, CCS angina score, perfusion Abbreviations: CABG, coronary artery bypass graft; CCS, Canadian Cardiovascular Society; CFU, colony-forming unit; CHF, congestive heart failure; CPC, circulating progenitor cell; IACT, Intracoronary Autologous Bone Marrow Cell Transplantation in Chronic Coronary Artery Disease; LVEF, left ventricular ejection fraction; NS, not significant; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; TOPCARE-CHD, Transplantation of Progenitor Cells and Recovery of Left Ventricular Function in Patients With ChronicIschemic Heart Disease.
a Control group refused treatment with bone marrow-derived cells.
2008 American Medical Association. All rights reserved.
(Reprinted) JAMA, February 27, 2008—Vol 299, No. 8 933
BLOOD- AND MARROW-DERIVED STEM CELLS FOR NONMALIGNANT DISEASES criteria for defining multipotent mesenchymal stro- 25. Capello E, Saccardi R, Murialdo A, et al; Italian
mal cells: the International Society for Cellular Therapy GITMO-Neuro Intergroup on ASCT for Multiple position statement. Cytotherapy. 2006;8(4):315- Sclerosis. Intense immunosuppression followed by nisms of this effect remain undefined and autologous stem cell transplantation in severe mul- 9. Pittenger MF, Mackay AM, Beck SC, et al. Multi-
tiple sclerosis. Neurol Sci. 2005;26(suppl 4):S200- lineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143-147.
26. Carreras E, Saiz A, Marı´n P, et al. CD34ϩ se-
tor cell–derived vasculogenesis and lo- 10. Gratwohl A, Passweg J, Bocelli-Tyndall C, et al;
lected autologous peripheral blood stem cell trans- Autoimmune Diseases Working Party of the Euro- plantation for multiple sclerosis: report of toxicity and cal paracrine effects. Clinical trials are pean Group for Blood and Marrow Transplantation treatment results at one year of follow-up in 15 (EBMT). Autologous hematopoietic stem cell trans- patients. Haematologica. 2003;88(3):306-314.
plantation for autoimmune diseases. Bone Marrow 27. Fassas A, Passweg JR, Anagnostopoulos A, et al;
Transplant. 2005;35(9):869-879.
Autoimmune Disease Working Party of the EBMT (Eu- of delivery for use of HSCs in cardiovas- 11. Nash RA, McSweeney PA, Crofford LJ, et al. High-
ropean Group for Blood and Marrow Transplantation).
cular disease. Similar trials are also being dose immunosuppressive therapy and autologous he- Hematopoietic stem cell transplantation for multiple scle- matopoietic cell transplantation for severe systemic scle- rosis: a retrospective multicenter study [published cor- rosis: long-term follow-up of the US multicenter pilot rection appears in J Neurol. 2002;249(11)1619].
ated in liver disease,109-111 cerebrovascu- study. Blood. 2007;110(4):1388-1396.
J Neurol. 2002;249(8):1088-1097.
12. Burt RK, Marmont A, Oyama Y, et al. Random-
28. Koza´k T, Havrdova´ E, Pit’ha J, et al. High-dose
lar disease, and spinal cord injury.
ized controlled trials of autologous hematopoietic stem immunosuppressive therapy with PBPC support in the Author Affiliations: Divisions of Immunotherapy (Drs
cell transplantation for autoimmune diseases: the evo- treatment of poor risk multiple sclerosis. Bone Mar- Burt, Craig, and Wen), Cardiology (Drs Beohar and lution from myeloablative to lymphoablative trans- row Transplant. 2000;25(5):525-531.
Rapp), Rheumatology (Dr Barr), and Gastroenterol- plant regimens. Arthritis Rheum. 2006;54(12):3750- 29. Burt RK, Cohen BA, Russell E, et al. Hematopoi-
ogy (Dr Craig), Department of Medicine; Division of etic stem cell transplantation for progressive multiple Vascular Surgery, Department of Surgery (Dr Pearce); 13. Statkute L, Verda L, Oyama Y, et al. Mobiliza-
sclerosis: failure of a total body irradiation-based con- and Department of Neurology (Dr Kessler), North- tion, harvesting and selection of peripheral blood stem ditioning regimen to prevent disease progression in western University Feinberg School of Medicine, Chi- cells in patients with autoimmune diseases undergo- patients with high disability scores. Blood. 2003; cago, Illinois; and Department of Hematology, Sin- ing autologous hematopoietic stem cell transplantation.
gapore General Hospital, Singapore (Dr Loh).
Bone Marrow Transplant. 2007;39(6):317-329.
30. Nash RA, Bowen JD, McSweeney PA, et al. High-
Author Contributions: Dr Burt had full access to all of
14. Samijn JP, te Boekhorst PA, Mondria T, et al. In-
dose immunosuppressive therapy and autologous pe- the data in the study and takes responsibility for the in- tense T cell depletion followed by autologous bone ripheral blood stem cell transplantation for severe mul- tegrity of the data and the accuracy of the data analysis.
marrow transplantation for severe multiple sclerosis.
tiple sclerosis. Blood. 2003;102(7):2364-2372.
Study concept and design: Burt, Beohar.
J Neurol Neurosurg Psychiatry. 2006;77(1):46-50.
31. Openshaw H, Lund BT, Kashyap A, et al. Periph-
Acquisition of data: Burt, Loh, Barr, Wen, Rapp.
15. Oyama Y, Barr WG, Statkute L, et al. Autolo-
eral blood stem cell transplantation in multiple scle- Analysis and interpretation of data: Burt, Pearce, gous non-myeloablative hematopoietic stem cell trans- rosis with busulfan and cyclophosphamide condition- plantation in patients with systemic sclerosis. Bone Mar- ing: report of toxicity and immunological monitoring.
Drafting of the manuscript: Burt, Beohar.
row Transplant. 2007;40(6):549-555.
Biol Blood Marrow Transplant. 2000;6(5A):563- Critical revision of the manuscript for important in- 16. Statkute L, Oyama Y, Barr WG, et al. Autolo-
tellectual content: Burt, Loh, Pearce, Beohar, Barr, gous non-myeloablative hematopoietic stem cell trans- 32. Daikeler T, Ko¨tter I, Bocelli Tyndall C, et al; EBMT
plantation for refractory systemic vasculitis [pub- Autoimmune Diseases Working Party. Haematopoi- Administrative, technical, or material support: Burt, lished online ahead of print October 18, 2007]. Ann etic stem cell transplantation for vasculitis including Rheum Dis. doi:10.1136/ard.2007.070227.
Behcet’s disease and polychondritis: a retrospective Financial Disclosures: None reported.
17. Voltarelli JC, Couri CE, Stracieri AB, et al. Autolo-
analysis of patients recorded in the European Bone Mar- Additional Contributions: We thank Donald Orlic, PhD
gous nonmyeloablative hematopoietic stem cell trans- row Transplantation and European League Against (National Heart, Lung, and Blood Institute, National In- plantation in newly diagnosed type 1 diabetes mellitus.
Rheumatism databases and a review of the literature.
stitutes of Health, Bethesda, Maryland), and Douglas JAMA. 2007;297(14):1568-1576.
Ann Rheum Dis. 2007;66(2):202-207.
Losordo, MD (Feinberg Cardiovascular Research Insti- 18. Vonk MC, Marjanovic Z, van den Hoogen FH, et al.
33. Saccardi R, Kozak T, Bocelli-Tyndall C, et al; Au-
tute, Northwestern University, Chicago, Illinois), for criti- Long-term follow-up results after autologous haema- toimmune Diseases Working Party of EBMT. Autolo- cal review of the manuscript. Neither of these individu- topoietic stem cell transplantation for severe sys- gous stem cell transplantation for progressive mul- als received extra compensation for their contributions.
temic sclerosis [published online ahead of print May tiple sclerosis: update of the European Group for Blood 25, 2007]. Ann Rheum Dis. 2008;67(1):98-104.
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2008 American Medical Association. All rights reserved.


ORDENANZA SOBRE MANIPULACIÓN Y USO DE ARTIFICIOS PIROTÉCNICOS Y DE LA REALIZACIÓN DE ESPECTÁCULOS PÚBLICOS DE FUEGOS ARTIFICIALES La regulación de los productos pirotécnicos se encuentra contenida en elReglamento de Explosivos aprobado por Real Decreto 230/1998, de 16 de febreroque considera, en su art. 22, artificios pirotécnicos los ingenios o artefactoscargados de material o

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