(Circulation. 1995;91:417-425.)
© 1995 American Heart Association, Inc.
Articles |
Photodynamic Therapy of Normal and Balloon-Injured Rat Carotid Arteries Using 5-Amino-Levulinic Acid
From the Department of Surgery (I.N., A.M., S.B.), National Medical Laser Centre, University College London Medical School, The Rayne Institute; the Division of Cardiology (S.A., J.M.), Hatter Institute for Cardiovascular Studies, University College London Hospitals; and UCL Hospitals Vascular Unit (I.N., C.B.), The Middlesex Hospital, Mortimer Street, London, UK.
Correspondence to Isaac Nyamekye, MBChB, FRCS, Department of Surgery, National Medical Laser Centre, University College London Medical School, The Rayne Institute, 5 University St, London WC1E 6JJ, UK.
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Abstract |
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Background Although the management of atherosclerotic disease by the use of balloon angioplasty is widespread, the treatment is limited by restenosis in 30% to 50% of cases. Fibrocellular intimal hyperplasia, the main cause of restenosis, arises from proliferation and migration of medial smooth muscle cells (SMC) into the intimal layer. Factors leading to intimal hyperplasia are incompletely understood, and drugs have universally failed to influence clinical restenosis. Photodynamic therapy (PDT), the light activation of photosensitizing drugs to generate cytotoxic mediators, may have potential as prophylaxis for intimal hyperplasia. 5-Amino-levulinic acid–induced protoporphyrin IX (ALA-PPIX), a naturally occurring porphyrin precursor, and its product, -PPIX, offers a novel method of sensitization for PDT. We have investigated the pharmacokinetics of ALA in arteries and the effects of ALA-PPIX–sensitized PDT on normal and balloon-injured arteries.
Methods and Results ALA (20 to 200 mg/kg) was injected into healthy rats, and PPIX fluorescence was measured in the carotid arteries. In a second group of rats, the exposed carotid artery was laser illuminated (50 J/cm2, 630 nm) 30 to 90 minutes after sensitization. Three and 14 days after PDT, histological sections from treated arteries were analyzed by light microscopy. Subsequently, two new groups of rats underwent PDT (ALA, 100 mg/kg; laser, 50 J/cm2, 630 nm [at 60 to 90 minutes]). The left carotid arteries underwent balloon angioplasty by intraluminal passage of a Fogarty FG2 catheter immediately before irradiation. These rats were killed at 14 and 28 days together with laser-only, ALA-only, and untreated control rats. The arteries were perfusion-fixed in vivo. ALA-PPIX induced arterial media fluorescence in a dose-dependent manner. In the normal arteries, PDT produced a dose-dependent cellular depletion in the treated arterial segment at 3 days, and this was complete with 100 and 200 mg/kg of ALA. At 14 days, the media remained acellular, although the endothelial lining had regenerated. In the balloon-injured arteries, PDT produced complete inhibition of intimal hyperplasia at both 14 and 28 days (0%). This was significantly greater than that produced by any of the control rats (34% to 69% and 37% to 66% at the two times, respectively). Significance was at 99% using ANOVA and Fisher's PLSD test. No hemorrhage, thrombosis, or aneurysm formation was seen.
Conclusions ALA-PPIX–sensitized PDT applied at the time of angioplasty effectively inhibits experimental intimal hyperplasia development in rats. This may offer a new approach to the management of angioplasty restenosis in patients.
Key Words: photodynamic therapy • angioplasty • stenoses
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Introduction |
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Atheromatous occlusive disease of the arteries may be treated with percutaneous angioplasty or surgery. Angioplasty allows restoration of arterial patency in selected stenoses and occlusions without the need to perform major surgical reconstruction and may have the potential to offer safer and more cost-effective patient management. Angioplasty is limited, however, by the recurrence or worsening of symptoms (restenosis) in 30% to 50% of patients within the first year.1 2
Clinical restenosis arises from complex mechanisms, including plaque collapse, acute vasoconstriction, thrombosis, chronic remodeling, and a major contribution from fibrocellular intimal hyperplasia. Experimental, clinical, and postmortem studies have shown the important role played by the migration and proliferation of medial vascular smooth muscle cells (SMC) in intimal hyperplasia.3 4 5 6 This appears to be a relatively nonspecific response of the artery to many different types of injury.7 8 9 The mechanism of restenosis is complex, and many different cytokines have been implicated in the stimulation of SMC proliferation.9 11 No drugs have been clinically effective in preventing or reducing intimal hyperplasia after angioplasty, and this is the subject of intense research.12 13
Photodynamic therapy (PDT) involves the local activation of a preadministered photosensitizer drug by light of specific wavelength that is matched to the absorption characteristic of the particular sensitizer.14 The sensitizer, which is given systemically, is widely distributed in the various body tissues. On activation by the local application of an appropriate light dose and in the presence of tissue oxygen, the photosensitizer stimulates the formation of cytotoxic oxidizers such as singlet oxygen. The cell death is localized to the illuminated area because the highly reactive oxidizers have a very short diffusion distance, and thus spatial selectivity is retained. PDT is being investigated as a possible treatment for intimal hyperplasia, and recent reports of its effectiveness in preventing or reducing experimental intimal hyperplasia have been encouraging.
5-Amino-levulinic acid (ALA) offers a new approach to sensitization and PDT of arteries by acting as a precursor for the sensitizer protoporphyrin IX (PPIX). This may be appropriate for early patient trials as it causes only transient skin hypersensitivity lasting 1 to 2 days in ambient light.15 16 17
The aim of the present study was to investigate the pharmacokinetics and PDT effects of ALA-PPIX on the medial cells in the normal rat carotid artery. Fluorescence is an inherent photoproperty of sensitizers, and we use its detection to quantify the photoactivity of ALA-PPIX. The effectiveness of ALA-PPIX in causing media SMC depletion is assessed, and the lowest dose of ALA that effectively produced media SMC depletion in normal vessels was used for PDT in balloon-injured vessels. In this well-established model of intimal hyperplasia, balloon injury produces transient medial edema, followed by progressive intimal thickening from 4 days on.18 PDT was given at the time of angioplasty injury, and its effectiveness in preventing intimal hyperplasia was assessed 2 and 4 weeks after injury.
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Methods |
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Photosensitizer
ALA was obtained as a hydrochloride in 98% pure powder from Sigma Chemical Company. It was dissolved in phosphate-buffered saline for administration. The concentration of ALA was adjusted to maintain the volume of injection between 0.3 and 0.6 mL.
Animals
All studies were performed on mature adult male
Wistar rats
(University College London) with weights ranging from 300 to 350 g.
Injections of ALA into the tail vein were made 5 to 10 minutes after
sedation with Hypnorm (fentanyl and fluanisone, 0.1 mL). PDT was
performed during exposure of the left carotid artery, with the animal
under anesthesia with intraperitoneal Hypnorm (0.3 mL) and diazepam
(0.3 mL).
Distribution of PPIX in Normal Rat Artery
Four groups of rats
were sensitized with doses of
20, 50, 100, and 200 mg/kg of ALA. The rats were killed by increasing
the concentration of carbon dioxide at intervals from 5 minutes to 24
hours after the administration of ALA, and the carotid arteries were
resected and immediately frozen by submersion in a bath of isopentane
(2-methyl-butane) prechilled in liquid nitrogen. The frozen arteries
were stored in liquid nitrogen until sectioning. Five-millimeter blocks
of artery were mounted on OCT medium (Tissue Tek 11 embedding compound,
BDH), and 3- to 10-µm sections were placed onto slides using a
Cryocut E microtome (Reichert-Jung). These were stored in a
freezer at -20°C. The slides were thawed just before fluorescence
microscopy using an inverted microscope with epifluorescence and
phase-contrast attachments.19 The PPIX fluorescence was
excited using an 8-mW helium-neon laser (632.8 nm) delivered by a
liquid light guide and through a 10-nm bandpass filter centered at 633
nm to remove extraneous light, onto the dichroic mirror (Omega Optical
Inc) for epifluorescence study. Fluorescence was detected between 665
and 700 nm using a combination of bandpass (Omega Optical Inc) and
long-pass (Schott RG665) filters. The fluorescence signal was detected
by a highly sensitive cryogenically cooled CCD (charge-coupled device)
camera (Wright Instruments, model 1; resolution 400x600 pixels) fitted
to the microscope. This signal was processed by a personal computer
into a falsely color-coded microscopic image of the section depicting
the counts per pixel in arbitrary units. Quantitative analysis was
performed by calculating the mean fluorescence count within the intima,
media, and adventitia on the fluorescence image. Six readings were
taken from each layer of artery wall in each section, and three
sections from each of the three rats killed at each dose time point
were studied. Conventional light microscopy of the same specimens fixed
in formalin and stained with hematoxylin and eosin were used for
comparative light microscopy.
PDT of Normal Rat Artery
Groups of 10 rats sensitized with
20, 50, 100, and 200
mg/kg of ALA were used for PDT of normal carotid artery. PDT was
performed using external beam irradiation of a pulsed (12 kHz) copper
vapor pumped dye laser (Oxford Lasers) peaked at 630 nm with a laser
tip power of 100 to 180 mW adjusted to deliver an energy density of 50
J/cm2 at the surface of the irradiated artery. After
sensitization, the artery was exposed through a midline neck incision,
and laser light was applied at the time of peak media PPIX fluorescence
for each dose of ALA. A field 1 cm in diameter was irradiated and this
was centered on the region of isolated left common carotid artery
immediately caudal to the origin of the external carotid artery. The
remaining neck structures were excluded from the laser beam by placing
a shield deep to the isolated artery and superficial to all other
structures. After surgery, the rats were maintained on standard rat
chow and water with a 12-hour light/dark cycle. Groups of 5 rats
(untreated, laser only, and ALA only) were used as controls. Five rats
at each ALA dose were killed at 3 days and five were killed at 14 days
by a lethal dose of anesthetic. The irradiated arterial segments were
excised, fixed in 2% paraformaldehyde and 1% gluteraldehyde, and
embedded in paraffin. Then, we cut 10-µm-thick cross sections and
stained them with hematoxylin and eosin. Morphometric evaluation of
cross sections was performed by counting the number of cells in a
high-power field (HPF) using a high-power light microscope (Olympus
IMT-2). Six representative counts were taken from sections obtained
from the middle of the treated segment of each artery. The medial SMC
counts per HPF are expressed as median and interquartile range (IQR)
values, with 30 counts (six counts in each of 5 rats) at each dose.
Statistical analysis was made with ANOVA, with comparison of
different treatment groups by Fisher's PLSD test.
PDT of Balloon-Injured Rat Artery
Twenty rats were sensitized
with 100 mg/kg of ALA, and an
additional 20 rats were sham-sensitized with 0.4 mL of
phosphate-buffered saline. In all rats, the left carotid artery and its
bifurcation were exposed, and a 2FG Fogarty arterial embolectomy
catheter was introduced via a transverse arteriotomy in the external
carotid artery and passed into the thoracic aorta. The balloon was
inflated with 0.2 mL of saline and withdrawn to the carotid bifurcation
with a rotating motion to produce endothelial denudation and medial
stretching in the common carotid artery. After three passages, the
catheter was removed, and the external carotid was ligated. This model
of balloon injury in the rat is the most established of animal models
of intimal hyperplasia.20 Ten rats in each group of 20
underwent subsequent laser irradiation (energy, 50 J/cm2)
of the common carotid artery. The artery was irradiated 60 to 90
minutes after ALA injection. This corresponded to the time at which
peak PPIX fluorescence was measured. The 10 rats remaining in each
group were not exposed to laser light. This gave the following
treatment groups of 10 rats each: balloon only; balloon and sensitizer;
balloon and laser; and balloon, laser, and sensitizer (PDT).
At 14 and
28 days after the injury and treatment, the 5 rats per
group were again anesthetized. To maintain physiological
dimensions, the experimental arterial segments were fixed in
vivo by intra-aortic infusion of 2% paraformaldehyde and 1%
gluteraldehyde at 120 mm Hg for 10 minutes. The fixed segments of the
left common carotid artery were excised and placed in fresh fixative
for 16 hours. The treated segments of artery were carefully separated
from the untreated segments, and three separate cross sections were
taken from the midportion of each treated segment. Paraffin sections of
the treated arteries were mounted on a glass slide, stained with
hematoxylin and eosin, and examined under a light microscope.
Planimetric measurements were made directly from the slide in a blinded
manner using an interactive computerized image-analysis system
(Colourmorph, Perceptive Instruments). The ratio of the area of
intimal hyperplasia (IH) to the total area enclosed by the
internal elastic lamina (IEL) was calculated (IH/IEL) and expressed as
a percentage to represent the portion of the lumen occupied by the
hyperplastic change (Fig 1
).21
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Three sections from each rat were analyzed (15 sections per treatment group). As for the normal artery groups, descriptors used are median and IQR values, and statistical analysis was made with ANOVA and Fisher's PLSD test.
All animal care was in accordance with the Animal (Scientific Procedures) Act 1986 and Guidance on the Operation of the Animals (Scientific Procedures) Act 1986 (HMSO Publications, UK 1990: HC 182).
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Results |
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Photosensitizer Distribution in Normal Rat Artery
After intravenous injection of ALA, the induced fluorescence intensity of PPIX rises in areas corresponding to the three layers of the arterial wall as judged from the hematoxylin and eosin slides (Fig 2
). The fluorescence intensities were highest within the
arterial media with lower intensities in the intima and adventitia (Fig
3A). We measured medial and intimal peak fluorescence at
30 minutes for the 50-mg/kg dose and at 60 minutes for the 100-mg/kg
and 200-mg/kg doses, after which the levels dropped to near-background
levels by 6 hours. The magnitude of the peak intensities of the
fluorescence was dose dependent, with the 200-mg/kg dose producing the
highest intensity (Fig 3B). ALA (20 mg/kg) produced no
additional fluorescence above the background levels.
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PDT in Normal Rat Artery
The effectiveness of ALA for PDT was
assessed by its cytotoxicity
on the medial SMC in normal arteries after light exposure (Fig
4).
Vessels harvested 3 days after PDT 100 and 200 mg/kg of ALA showed a
complete depletion of cells in the treated artery to leave the
connective tissue layers of the artery only. The cell counts differed
significantly from those of the remaining groups. The 20- and 50-mg/kg
doses produced a partial depletion of cells. Vessels that were
irradiated but not sensitized also produced a lesser degree of cell
depletion (Fig 5A and 5B). Here, the cell
depletion was more pronounced in the area of the circumference closest
to the source of the laser beam. The effect of the 50-mg/kg dose
differed significantly from the 20-mg/kg dose and laser alone; however,
these latter two did not differ significantly from each other. Vessels
that underwent PDT showed loss of the endothelial layer. Quantitative
assessment at 3 days showed no significant difference between the
medial cell counts after ALA alone and normal arteries, and there was
no endothelial cell loss. All significances were at 99% by Fisher's
PLSD. Vessels harvested 14 days after treatment showed a pattern of
cell distribution that was similar to that found at 3 days, although
there was regeneration of cells in the endothelial layer, and these
were confirmed as endothelial cells by specific staining with isolectin
B4 (Vector Laboratories Ltd) specific for rat endothelium.
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Results of PDT of Balloon-Injured Rat Artery
Vessels treated
with PDT at the time of balloon angioplasty and
harvested at both 14 and 28 days were free of intimal hyperplasia
formation in all cases. At both times, arteries treated with laser
alone also showed reduction in the levels of intimal hyperplasia when
compared with sensitizer alone, and untreated but injured vessels (Fig
6A to 6C). The arteries injured and treated with
sensitizer alone and those injured but not treated showed a similar and
marked development of intimal hyperplasia. At 14 and 28 days, the
levels of intimal hyperplasia after balloon injury alone expressed as
median IH-to-IEL ratios were 69 (IQR, 64 to 75) and 66 (77 to 47),
respectively. These did not differ significantly from sensitizer alone,
which had median values of 63 (52 to 74) and 54 (69 to 42),
respectively. Laser alone gave partial reduction of the intimal
hyperplasia, with median values of 34 (23 to 45) and 37 (41 to 24),
respectively, which differed significantly from the untreated arteries.
PDT-treated vessels showed no intimal hyperplasia (median IH-to-IEL
ratio, 0 to 0) at both times; this differed significantly from the
laser-only group (Fig 7). Significance is reported at
99% by Fisher's PLSD test. Sections taken from injured areas proximal
to the field of irradiation in PDT-treated rats showed marked formation
of intimal hyperplasia. No rats died prematurely during the period of
study, although some rats died after being anesthetized and before
surgery or laser irradiation. No hemorrhage, thrombosis, or aneurysm
formation was seen in any treated segments.
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Discussion |
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The fluorescence studies showed that after intravenous ALA injection, PPIX preferentially accumulated in the media of the vessel wall (compared with the endothelium and adventitia) in a dose-dependent manner. The unsensitized arteries showed some degree of autofluorescence, and 20 mg/kg of ALA did not produce any further increase in fluorescence intensity above the background levels. ALA (50 mg/kg) produced only a marginal rise in fluorescence above the background autofluorescence; 100 and 200 mg/kg of ALA produced distinct peaks, with the latter having almost double the intensity of the 100-mg/kg dose, once the background autofluorescence had been accounted for. The time of peak fluorescence also varied in a dose-dependent manner, with the 50-mg/kg dose peaking at 30 minutes and the 100- to 200-mg/kg dose peaking closer to 1 hour. These findings were in accord with those of Loh et al,17 who studied the distribution of PPIX in the rat stomach and found an earlier peak for the lower doses of ALA. The peak fluorescence times in the arterial media were used as the time for laser illumination in the PDT experiments.
The studies of PDT on normal arteries showed a dose-dependent depletion of medial SMC. Under the experimental conditions used, the lowest dose of ALA that caused total medial cell destruction in the whole vessel circumference was 100 mg/kg, and this was used to treat the balloon-injured vessels. It is interesting to note that some cell depletion was seen in vessels treated by laser in the absence of ALA. This was most pronounced in the region of highest light intensity. The possibility that these cells underwent thermal destruction is unlikely because the laser fiber was not hot to touch and there was no obvious inflammation. The difference in the histology of these vessels and those treated by ALA and light was quantitative rather than qualitative. These are probably PDT effects mediated by intermediates in the heme pathway, which act as naturally occurring sensitizers. The dose-dependent PDT destruction of the medial cells in normal arteries allowed the selection of the dose to be used in the balloon-injury experiments. Normal arteries in rats treated by PDT and killed after 3 and 6 months showed an endothelial cell lining with persistent media cell depletion. The arteries retained their strength and showed no degeneration or aneurysm formation. One of 5 rats at 3 months and 2 of 5 rats at 6 months showed a patchy distribution of a minor intimal lesion within the treated segment, which was one or two cells thick and this may be considered a limitation of any ablative therapy. Nevertheless, no exuberant intimal hyperplasia was seen in these late sections (I.N., unpublished observations). PDT given at the time of balloon angioplasty prevented intimal hyperplasia formation in all cases 14 and 28 days after the combined treatment. This was highly significant compared with the control vessels.
Intimal hyperplasia arising from the migration and proliferation of SMC appears to be a nonspecific response of the artery to angioplasty. The mechanism of formation of intimal hyperplasia is complex, and many different cytokines have been implicated in the stimulation of SMC proliferation, migration, and secretion.9 10 11 It is the complexity of these controlling factors that may have undermined the effectiveness of drug monotherapy to prevent or reduce clinical intimal hyperplasia following angioplasty, despite intense research efforts. The rationale for using PDT treatment is to nonspecifically target the SMC, the final common pathway in the development of intimal hyperplasia.
The uptake of sensitizers into atheroma, first reported by Spears et al22 using dihematoporphyrin ester and ether (DHE/E), was followed by the demonstration of the uptake in arteries of healthy animals, experimental atheromatous lesions in hyperlipidemic animals, and in vitro human plaques.23 24 25 26 27 28 Most of these early studies explored the effectiveness of sensitizer localization in atheromatous plaque as an aid to plaque detection or as a guide to improve safety in ablative laser therapy. None of these techniques have really become established. Early reports of arterial PDT involved unconvincing attempts at treating experimental atheroma in swine and rabbits using DHE/E.23 26
In 1990, Dartsch et al29 demonstrated the inhibition of cultured SMC proliferation by PDT (DHE/E and UV light, 30 to 1200 mJ/cm2) and suggested the suitability of PDT for the treatment of restenotic lesions. Subsequent reports of PDT on experimental balloon-injured arteries by Eton et al,21 Ortu et al,30 and LaMuraglia et al31 have demonstrated the effective use of this treatment. Eton et al applied PDT using DHE/E (Photofrin, 5 mg/kg) and extraluminal application of laser light (630 nm at 7.6 J/cm2) 9 days after balloon injury to rabbit carotid arteries. They found inhibition of intimal hyperplasia relative to the untreated control arteries when the vessels were assessed 5 weeks after treatment; however, there was no significant difference relative to control vessels treated with sensitizer only and with laser only because all three treatments reduced the levels of intimal hyperplasia. DHE/E sensitizers cause a marked skin hypersensitivity in sunlight that may persist for 6 weeks or longer. During this prolonged period, the patient must stay out of direct sunlight. This side effect may have a prohibitive effect on the use of PDT in restenosis trials. Ortu et al used phthalocyanine-sensitized PDT (chloroaluminum sulfonated phthalocyanine; 5 mg/kg) with extraluminal laser light (675 nm at 100 J/cm2) to treat rat carotid arteries 2 or 7 days after balloon injury and showed complete inhibition of balloon catheter–induced intimal hyperplasia at 14 days. The long-term results of similar experiments have recently been reported by LaMuraglia et al from the same group. Similar studies to be reported from this laboratory using aluminum disulfonated phthalocyanine in a prophylactic role support this finding. These second-generation phthalocyanine sensitizers, unlike the porphyrins, show reduced and shorter-lasting skin hypersensitivity in ambient light32 ; however, they are not yet available for clinical study. Other phototherapeutic approaches to the prevention of intimal hyperplasia are being researched. Low-dose light of 594 to 600 nm produced selective inhibition of migration of bovine SMC in vivo in the absence of any changes in the cell proliferation.33 An alternative method of photochemotherapy with a similar approach to PDT is 8-methoxypsoralen activation by UVA irradiation (PUVA). PUVA inhibits bovine SMC proliferation in vitro34 and in vivo after balloon injury of rabbit and pig arteries.35 36 Demonstration of its inhibition of intimal hyperplasia is reported only in abstract form,35 where PUVA significantly lowered the neointimal cellularity 5 days after balloon injury in atherosclerotic rabbits. The survival of PUVA-treated SMC is believed to be advantageous compared with cytotoxic treatments like PDT; however, the long-term effects of DNA damage and the possibility of genetic transformation in these surviving cells are not known.
ALA is a promising sensitizer precursor for PDT of both visceral and skin neoplasms.16 37 38 The method of sensitization with ALA differs from other methods because the ALA acts as a "prodrug," ie, a precursor for the actual sensitizer. ALA is a natural porphyrin precursor whose synthesis by living cells is the rate-determining step in the synthetic pathway for heme. Exogenous administration of large quantities of ALA overloads the synthetic pathway and leads to the accumulation of porphyrin intermediates, particularly the potent sensitizer PPIX, which is optimally activated by 630 nm light.15 PPIX is lost by conversion to heme, and its skin photosensitivity lasts for only 24 to 48 hours. It is currently undergoing preliminary clinical trials in tumor therapy. These advantages of ALA and the fact that it may be applied clinically led to its choice as the sensitizer for this study.
Depletion of the media cells by PDT may raise concern over the integrity of the arterial wall after PDT. However, PDT appears to strengthen the connective tissue. Studies on the magnitude of intraluminal pressure required to burst PDT-treated arteries and normal arteries showed that the treated vessel required a higher pressure before bursting (Grant W.E., S.B., unpublished observations). PDT may act by cross-linking collagen fibers within the vessel wall.39 Similar observations have been made in other organs after PDT treatment. The acellular arterial wall remaining after PDT resembles a more substantial form of the adventitial remains after endarterectomy, which is well able to maintain the structural integrity of the vessel.
The results reported here show that it is not necessary to delay PDT after balloon injury to prevent intimal hyperplasia. These experiments show that PDT given at the time of angioplasty completely abolishes the expected intimal hyperplasia response at 14 and 28 days. We envisage that PDT given for prophylaxis of intimal hyperplasia in patients will be with an intraluminal light source at the time and site of angioplasty. A fiber-optic angioplasty balloon catheter developed for simultaneous balloon inflation and radial intra-arterial irradiation could serve this purpose. The results of these preliminary experiments suggest that intraluminal PDT could be a successful treatment strategy for angioplasty restenosis.
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Acknowledgments |
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This study was funded by the British Heart Foundation (BHF project grant PG/93083). Dr Anglin is supported by BHF grant PG/93044, and the Sir Jules Thorn Charitable Trust supports Dr Nyamekye (91-34A).
Received April 27, 1994; accepted August 19, 1994.
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