Department of Internal Medicine, Justus-Liebig-University Giessen, D-35392 Giessen, Germany
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ABSTRACT |
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Inhalation of aerosolized prostacyclin (PGI2) exerts selective pulmonary vasodilation, but its effect is rapidly lost after termination of nebulization. Amplification of the vasodilatory response to inhaled PGI2 might be achieved by phosphodiesterase (PDE) inhibitors to stabilize its second messenger, cAMP. We established stable pulmonary hypertension in perfused rabbit lungs by continuous infusion of U-46619. Short-term (10-min) aerosolization maneuvers of PGI2 effected a rapid, moderate decrease in pulmonary arterial pressure, with post-PGI2 vasorelaxation being lost within 10-15 min, accompanied by a marginal reduction in shunt flow. Preceding administration of subthreshold doses of the PDE inhibitors theophylline, dipyridamole, and pentoxifylline via the intravascular or inhalational route, which per se did not influence pulmonary hemodynamics, caused more than doubling of the immediate pulmonary arterial pressure drop in response to PGI2 and marked prolongation of the post-PGI2 vasorelaxation to >60 min (all PDE inhibitors via both routes of application). This was accompanied by a reduction in shunt flow in the case of aerosolized theophylline (27.5%), pentoxifylline (30.5%), and dipyridamole (33.4%). Coaerosolization of PGI2 and PDE inhibitors may be considered as a therapeutic strategy in pulmonary hypertension.
gas exchange; multiple inert gas elimination technique; dipyridamole; pentoxifylline; theophylline; shunt flow; U-46619; ventilation-perfusion ratio; ventilation-perfusion mismatch
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INTRODUCTION |
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INHALED VASODILATORS HAVE BEEN SHOWN to achieve selective pulmonary vasorelaxation and supraselective vasodilation in well-ventilated (i.e., inhaled vasodilator-accessible) regions within the lung in experimental and clinical studies. Inhalation of gaseous nitric oxide (NO) (14, 26) and nebulization of prostacyclin (PGI2) (13, 30, 31, 33) were indeed noted to improve ventilation-perfusion matching and to lower pulmonary arterial pressure (Ppa) in patients suffering from acute respiratory distress syndrome and chronic pulmonary hypertension. The prostanoid PGI2 does, however, possess a very short biological half-life (2-3 min) at a physiological pH, and after inhalation of aerosolized PGI2, the pulmonary vasodilatory effect is lost within <30 min both under experimental conditions and when tested in patients (13, 18). Because the vasodilatory effect of the prostanoids is exerted via enhanced cAMP generation, blocking the catabolism of this second messenger might offer amplification of the pulmonary vasodilatory effects of these agents. The hydrolysis of the cyclic nucleotides proceeds via a group of phosphodiesterase (PDE) isoenzymes (25), and the presence of isoenzymes 1 and 3-5 has been demonstrated for the lung parenchyma (15). PDE3 and PDE4 preferentially hydrolyze cAMP, whereas PDE5 possesses a high affinity for cGMP (25). In a recent study in intact rabbits with acute pulmonary hypertension (18), subthreshold intravenous doses of monoselective PDE3, PDE4, and PDE5 inhibitors were noted to augment and prolong the pulmonary vasodilatory response to inhaled PGI2 while limiting the hypotensive effect to the pulmonary circulation. We presently employed clinically approved, mostly nonselective PDE inhibitors in a model of thromboxane-mediated pulmonary hypertension in perfused rabbit lungs. Theophylline, pentoxifylline, and dipyridamole were either admixed to the lung perfusate or administered by aerosolization. Low doses of each agent were chosen, guaranteeing that the PDE inhibitors per se would not affect lung hemodynamics and gas exchange as assessed by the multiple inert gas elimination technique (MIGET). All agents, whether infused or nebulized, strongly enhanced the vasodilatory response to a subsequently performed PGI2 aerosolization maneuver. In addition, coadministration of the PDE inhibitors via the inhalational route resulted in a marked improvement of the gas exchange abnormalities, in particular the increase in shunt flow, accompanying the thromboxane-elicited pulmonary hypertension. We conclude that low-dose PDE inhibitors may offer amplification of the selective pulmonary vasodilatory effects of aerosolized prostanoids and that the inhalational route might be particularly suitable for such an approach.
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METHODS |
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Materials
PGI2 (Epostenol) was supplied by Wellcome (London, UK), and the thromboxane A2 mimetic U-46619 was from Paesel-Lorei (Frankfurt, Germany). Sterile Krebs-Henseleit hydroxyethylamylopectine buffer (KHHB) was obtained from Serag-Wiessner (Naila, Germany). Theophylline (Euphyllin) was supplied by Byk Gulden (Constance, Germany), pentoxifylline (Trental) was from Hoechst Marion Roussel (Bad Soden, Germany), and dipyridamole (Persantin) was from Boehringer (Ingelheim, Germany). The ultrasonic nebulizer Pulmo Sonic 5500 was obtained from DeVilbiss Medizinische Produkte (Langen, Germany). All other chemicals were purchased from Merck (Darmstadt, Germany).Isolated Lung Model
The isolated lung model has been previously described in detail (22). Briefly, rabbits weighing 2.6-2.9 kg were deeply anesthetized with intravenous ketamine-xylazine and anticoagulated with heparin (1,000 U/kg). A tracheostomy was performed, and the animals were ventilated with room air with a Harvard respirator (tidal volume, 9-13 ml/kg; frequency, 10 breaths/min; positive end-expiratory pressure, 1 mmHg). After a midsternal thoracotomy, catheters were placed in the pulmonary artery and left atrium, and perfusion with KHHB was started and slowly increased to a final flow of 115 ml/min. Left atrial pressure was set at 1.2 mmHg in all experiments, and weight gain was recorded. Pressures in the pulmonary artery, left atrium, and trachea were continuously registered (zero referenced at the hilum). Perfusate samples (total perfusate volume, 500 ml) were taken from the arterial and venous parts of the system. Gas samples were taken from the outlet of an expiration gas mixing box.Aerosolization
PGI2 and PDE inhibitors were nebulized with an ultrasonic device (mass median aerodynamic diameter, 4.5 µm; geometric SD, 2.6; Pulmo Sonic 5500). The nebulizer was located between the ventilator and the lung to be passed by the inspiration gas; the nebulization system was previously described in detail (20). For the given ventilator setting (tidal volume, 9-13 ml/kg; frequency, 10 breaths/min; positive end-expiratory pressure, 1 mmHg), this nebulization system resulted in a deposition fraction of 0.25 ± 0.02 as determined by a laser photometric technique (21).Ventilation-Perfusion Ratio Determination in Isolated Lungs by MIGET
The distribution of ventilation and perfusion was determined by the MIGET as described by Wagner et al. (27). Six inert gases (sulfur hexafluoride, ethane, cyclopropane, halothane, diethyl ether, and acetone) were dissolved in KHHB and continuously infused (0.5 ml/min). After an equilibration period of at least 40 min, 10-ml perfusate samples were drawn from the left atrium and pulmonary artery. A corresponding 30-ml gas sample was collected from an expiration gas mixing box. The dissolved gases in the perfusate were extracted by equilibration (40 min) with nitrogen in a shaking water bath. The gas phases and exhaled gases were analyzed by gas chromatography. The ratios of left atrial to venous partial pressures (retention) and of expired to mixed venous partial pressures (excretion) were calculated for each gas. With a computer program, the retention and excretion resulted in a ventilation-perfusion ratio (Determination of cAMP
As previously described (19), cAMP was measured with a radioimmunoassay kit (Immunotech, Marseilles, France). Briefly, duplicate samples of 500 µl of perfusate were collected at 0, 30, 45, 60, 75, 105, and 135 min and incubated with 125I-labeled cAMP in antibody-coated tubes. After incubation, bound radioactivity was counted, and values were calculated with a standard curve. The cAMP level is given as picomoles per milliliter.Experimental Protocols
As previously described (29), a sustained increase in Ppa from 7.2 ± 0.2 to 32.7 ± 1.1 mmHg was achieved by a continuous infusion of 25-55 ng · kg
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Control lungs.
After termination of the steady-state period,
A/
measurements were performed at 30, 45, 60, 75, 105, and 135 min (n = 6 lungs); no interventions
were undertaken.
U-46619-treated lungs.
After termination of the steady-state period, U-46619 was continuously
infused over 135 min to provoke an increase in Ppa to 32.7 ± 1.2 mmHg (n = 6 lungs). A/
measurements were performed 30, 45, 60, 75, 105, and 135 min after the
beginning of the U-46619 application.
Dose-effect curve of inhaled and infused PDE
inhibitors.
U-46619 was titrated and then continuously infused as described in
U-46619-treated lungs, establishing a stable
pulmonary hypertension. Increasing doses of the PDE inhibitors were
either bolus injected into the recirculating medium or nebulized within 10-min aerosolization periods (cumulative dose-effect curves; n = 4 lungs/group). The doses were 2, 4, 6, 10, 20, and
30 µg/ml iv and 2, 10, and 20 µg · kg1 · min
1
(nebulization) for theophylline; 0.1, 1, 2, 10, and 100 µg/ml iv and
30, 60, and 300 µg · kg
1 · min
1
(nebulization) for pentoxifylline; and 1, 5, 50, 500, and 2,500 pg/ml
iv and 2, 10, and 20 ng · kg
1 · min
1
(nebulization) for dipyridamole.
PGI2 aerosolization.
U-46619 was administered as described in U-46619-treated
lungs. Forty-five minutes after the U-46619 infusion was started, PGI2 was aerosolized for 10 min at a dose of 10 ng · kg1 · min
1.
A/
measurements were performed after 30, 45, 60, 75, 105, and 135 min (n = 6 lungs).
PGI2 aerosolization combined with
intravenous or inhaled PDE inhibitors.
U-46619 was infused as described in U-46619-treated lungs,
and after 30 min, a subthreshold dose of one of the PDE inhibitors was
either infused or nebulized (n = 6 lungs/group). The
dose was taken from the dose-effect curve established in the preceding experiments. The doses employed in these experiments were 4 µg/ml and
2 µg · kg1 · min
1 for
theophylline, 2 µg/ml and 30 µg · kg
1 · min
1 for
pentoxifylline, and 1 ng/ml and 2 ng · kg
1 · min
1 for
dipyridamole for infusion and nebulization, respectively. Fifteen
minutes after subthreshold PDE administration, PGI2
nebulization was performed as described for the PGI2 group
(10 ng · kg
1 · min
1 over a
10-min period). The times for the measurement of ventilation-perfusion distribution corresponded to the preceding experiments.
Data Analysis
All values are given as means ± SE or coefficients of variation (SD/mean in percent). A one-way analysis of variance for repeated measures was used to evaluate significant differences among conditions, and where significance was found, post hoc analysis was performed with the Student-Newman-Keuls test. Significance was considered to exist at P < 0.05. These analyses were performed with WinSTAT for Windows, version 3.1 (Kalmia, Cambridge, MA). ![]() |
RESULTS |
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Baseline
All lungs displayed Ppa values in the range between 5 and 7 mmHg after termination of the steady-state period.
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Pulmonary Hypertension and Gas Exchange Abnormalities in Response to U-46619
Continuous infusion of U-46619 (mean dose 41.0 ± 13.9 ng · kgDose-Inhibition Curves of PDE Inhibitors Administered in the Absence of PGI2
All PDE inhibitors presently investigated relieved the U-46619-elicited pulmonary hypertension in a dose-dependent manner via both the intravascular and inhalational routes (Fig. 3). The dose-effect curves for dipyridamole ranged at markedly lower quantities for both modes of application compared with those for theophylline and pentoxifylline.
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Effect of Aerosolized PGI2
At the chosen dose of PGI2 nebulization (10 ng · kg
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Combination of PGI2 Nebulization With Subthreshold Administration of PDE Inhibitors
Based on the dose-effect curves of the different PDE inhibitors via either the intravascular or inhalational route, subthreshold doses of all agents were chosen, which per se did not affect the pulmonary hypertension and gas exchange abnormalities elicited by U-46619 infusion. When applied before the PGI2 nebulization maneuver, however, marked amplification of the response to the aerosolized PGI2 was noted.Theophylline.
In the presence of inhaled theophylline, the PGI2-induced
maximum Ppa decrease was augmented from 3.5 ± 0.6 to 7.4 ± 0.5 mmHg (P < 0.05), whereas intravascularly applied
theophylline effected only a minor augmentation of the immediate
PGI2-induced Ppa drop. A prolonged pressure decline in the
subsequent perfusion period was, however, observed for both routes of
application; even after 135 min, the preceding U-46619-elicited
pressure plateau was not yet reestablished (Fig. 4). The increase in
weight gain was not significantly influenced (Fig. 2) by both modes of
theophylline administration. There was a significant reduction in shunt
flow in the aerosolized theophylline and PGI2 lungs from
46.7 ± 5.5 to 27.5 ± 3.9% (P < 0.05; Fig.
1) but not in the intravenous theophylline and PGI2 lungs
(decrease in shunt flow to 42.3 ± 14.7%; not significant; Table
1). Broadening of the perfusion dispersion in the midrange A/
areas was somewhat reduced in the
aerosolized theophylline and PGI2 group.
Pentoxifylline.
Subthreshold doses of inhaled and infused pentoxifylline significantly
enhanced the maximum Ppa decrease in response to the subsequent
PGI2 nebulization from 3.7 to 9.2 (intravenous) and 9.9 (aerosolized) mmHg and prolonged the post-PGI2
vasorelaxation to >60 min (Fig. 4). Intrapulmonary shunt flow was
significantly reduced by aerosolization of pentoxifylline (46.7 ± 5.5 to 30.5 ± 6.2%; P < 0.05; Fig. 1) but not
by intravenous application of this agent (41.9 ± 9.3%).
Dispersion of perfusion (log SD) was significantly
reduced (1.03 ± 0.07 vs. 1.49 ± 0.13; P < 0.01) in the lungs with pentoxifylline aerosolization. The percent
increase in initial weight gain was markedly reduced in the lungs
undergoing either intravascular (57 ± 13 vs. 123 ± 17%;
P < 0.01) or transbronchial (77 ± 15 vs.
123 ± 17%; P < 0.01) pentoxifylline application
before PGI2 nebulization compared with the lungs with only
PGI2 aerosolization (Fig. 2).
Dipyridamole.
Administration of dipyridamole significantly prolonged (>60 vs. 15 min) the vasodilatory efficacy of PGI2 nebulization (Fig. 4). Intravenous application failed to reduce the intrapulmonary shunt
flow (49.4 ± 8.1 vs. 46.7 ± 5.5%), whereas this decreased in the aerosolized dipyridamole and PGI2 lungs (33.4 ± 7.3%; P < 0.05; Table 1). The percent increase in
initial weight gain was reduced in both groups (Fig. 2), but a
significant decrease was only noted in the aerosolized dipyridamole and
PGI2 lungs (76 ± 24 vs. 123 ± 17%;
P < 0.05). No significant impact on the broadening of
the perfusion dispersion in the midrange A/
areas was observed in both groups with dipyridamole administration.
Ventilation Pressures
No significant change in peak airway pressure during constant-volume ventilation was noted in any of the experimental groups (data not shown in detail).Measurement of cAMP
As shown in Fig. 5, the cAMP concentration in control experiments with U-46619 infusion increased slowly to 4.7 ± 0.9 pmol/ml. Aerosolization of PGI2 resulted in a significant increase in cAMP to 8.3 ± 1.4 pmol/ml (P < 0.05). The combination of inhaled PGI2 with aerosolized pentoxifylline and aerosolized theophylline significantly enhanced the PGI2-elicited cAMP liberation (from 8.3 ± 1.4 to 14.6 ± 1.2 and 12.3 ± 0.9 pmol/ml, respectively). In the presence of inhaled dipyridamole, a cAMP concentration of 11.0 ± 2.3 pmol/ml was measured (not significant).
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DISCUSSION |
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When continuously infused, the thromboxane mimetic U-46619 is
suitable for establishing stable pulmonary hypertension in isolated rabbit lungs, and this model has repeatedly been employed for analyzing
the pulmonary vasodilatory effect of various agents (10, 16, 19,
29). When dose-effect curves for the pulmonary vasodilatory
effect of the presently employed PDE inhibitors in this model were
established, largely comparable efficacy was noted for theophylline and
pentoxifylline, with dipyridamole being effective in a three orders of
magnitude lower concentration range. This is in line with available
pharmacological data characterizing the methylxanthines theophylline
and pentoxifylline as nonselective PDE1-5 inhibitors, with
IC50 values ranging between 50 and 200 µM (2,
12), whereas dipyridamole inhibits PDE5, -6, -8, and -10, with
IC50 values ranging between 1 and 5 µM (1, 17, 24). The relief of pulmonary hypertension by various PDE
inhibitors, when applied in sufficiently high doses, has previously
been demonstrated in several animal models (3, 5, 7, 18);
however, under clinical conditions, such an approach is hampered by the
severe side effects caused by these agents at higher concentration
ranges. Notably, when the total amount of substance either admixed to the perfusion fluid or offered via inhalation was calculated, corresponding vasodilatory effects were caused by lower quantities of
all three PDE inhibitors in the case of the inhalational application. This is even more impressive when considering the fact that, at best,
30% of the total nebulized material is definitely deposited in the
alveolar space (20, 29). Thus the predominant mode of
action of the aerosolized PDE inhibitors appears to be "regional" vasodilation rather than "systemic" vasodilation, which might occur
after transit of the agent from the alveolar space into the
recirculating perfusate contained in the vascular compartment.
Aerosolized PGI2 was previously demonstrated to be a potent pulmonary vasodilator in the model of U-46619-elicited pulmonary hypertension (29). Predominant relief of precapillary and a moderate reduction of postcapillary vascular resistance were shown to underlie this prostanoid effect. In the present investigation, the dose and duration of PGI2 nebulization were limited to establish a moderate Ppa decrease response to the prostanoid (3.5 ± 0.6 mmHg), which was rapidly reversible after cessation of the aerosolization maneuver. A prominent finding of the present study is the fact that the preceding administration of subthreshold doses of the methylxanthines theophylline and pentoxifylline, whether undertaken via the intravascular or inhalational route, resulted in a marked amplification of the pulmonary vasodilatory effect of nebulized PGI2, with post-PGI2 vasorelaxation being prolonged to >60 min. These data are in line with recent studies (18, 19) in intact rabbits or perfused rabbit lungs with U-46619-induced pulmonary hypertension, in which an enhanced vasodilatory response to nebulized PGI2 occurred after the preceding administration of monoselective or dual-selective PDE3 or -4 inhibitors. Increased cAMP accumulation in response to the prostanoid was demonstrated in these studies, and stabilization of PGI2-induced cAMP due to inhibition of cAMP-hydrolyzing PDEs by the nonselective PDE inhibitors theophylline and pentoxifylline indeed offers a most plausible explanation for the efficacy of subthreshold doses of these agents. cAMP via activation of protein kinase A results in phosphorylation of the myosin light chain kinase, thereby effecting vascular smooth muscle relaxation.
When coadministration of dipyridamole and PGI2 was tested in a corresponding fashion, this PDE inhibitor was also noted to markedly prolong the post-PGI2 vasorelaxation, although the overall efficacy in amplifying the PGI2 response was somewhat less prominent than that of the methylxanthines. In preceding investigations addressing pulmonary hypertension (9, 32), dipyridamole has been noted to amplify pulmonary vasodilation induced by NO in the ovine fetus and to attenuate the rebound pulmonary hypertension occurring on withdrawal of NO under conditions of cardiac surgery, which may be easily attributed to the stabilization of cGMP arising due to NO-related stimulation of guanylate cyclase. These data corroborate the study by Ichinose et al. (8), who investigated the effect of inhaled NO in the presence of the PDE5 inhibitor zaprinast. They found amplification and prolongation of the NO-induced vasodilation by zaprinast via increased transpulmonary cGMP levels. The intracellular cGMP content is mainly controlled by PDE5, with the role of the recently described cGMP-hydrolyzing PDE9 (23) not yet being fully settled. The present finding of enhanced efficacy of the PGI2-cAMP axis in the presence of dipyridamole does, however, suggest close interaction between cAMP- and cGMP-mediated vasodilatory pathways. Inhibition of the cGMP-sensitive PDE3 by increased cGMP levels arising in the presence of dipyridamole is one well-known mechanism of this type of interaction as similarly suggested from a study (6) in isolated vascular strips.
When employing the MIGET for detailed analysis of gas exchange
conditions, physiological ventilation-perfusion matching in the absence
of any significant shunt flow was encountered in control lungs as
previously described (29). In parallel with the pulmonary hypertensive response, severe gas exchange abnormalities, characterized by a prominent increase in shunt flow to >50%, were encountered in
lungs undergoing the U-46619 challenge. The maneuver of limited-dose and short-term PGI2 aerosolization caused a moderate
reduction in shunt flow that was not significantly different from the
nontreated lungs. Interestingly, transbronchial administration of
subthreshold doses of the methylxanthines and, to some minor extent, of
dipyridamole before PGI2 nebulization resulted in a marked
reduction in shunt formation, with corresponding maintenance of normal
A/
areas. Such an efficacy was, however,
missing on intravascular administration of the PDE inhibitors.
Three mechanisms may underlie the impressive beneficial effect of the
inhaled PDE inhibitors on the U-46619-elicited gas exchange disturbances. 1) The inhaled PDE inhibitors might be
effective by limiting lung edema formation. Significantly lower lung
weight as assessed at the end of the experiments was indeed noted in lungs with coaerosolization of PGI2 and pentoxifylline or
dipyridamole, with the effects of pentoxifylline greater than those of
dipyridamole. This observation is in line with previous reports
on the inhibitory effects of pentoxifylline on microvascular leakage in
models of acute lung injury (4, 11). 2)
Coaerosolization of the PDE inhibitors might possess a higher overall
vasodilatory potency than intravascular administration of these agents.
A previous study (29) of the gas exchange abnormalities in
the present model demonstrated that the strength of the pulmonary
hypertensive response is correlated with the severity of
A/
mismatch and, in particular, the extent of
shunt flow even before onset of marked lung edema formation. This
finding suggests that the increased Ppa forces perfusate flow through
poorly or nonventilated lung areas, existing even in nonedematous
lungs, or perfusion of some type of "preformed shunt vessels" that
are excluded from perfusion under conditions of normal intravascular
pressure. 3) Coaerosolization of the PDE inhibitors might
improve ventilation-perfusion matching via selective pulmonary
vasodilation in well-ventilated lung areas. This interpretation
suggests that combining aerosol-driven distribution of both the
directly vasorelaxant PGI2 and the PDE inhibitor for second
messenger stabilization is the most efficient approach to restrict the
vasodilatory response to aerosol-accessible, i.e., well-ventilated,
lung areas, with preferred distribution of flow to these lung regions.
In conclusion, the pulmonary vasodilatory effect of aerosolized PGI2 is significantly amplified by coadministration of the clinically approved PDE inhibitors theophylline, pentoxifylline, and dipyridamole at doses that per se do not exert any hemodynamic effect. Both the intravascular and inhalational routes of PDE inhibitor administration may be employed for this purpose, with the methylxanthines being somewhat more potent than dipyridamole via both routes. Prolongation of the half-life of the second messenger cAMP by the subthreshold doses of the PDE inhibitors is suggested as the underlying mode of action. Relief of pulmonary hypertension by PGI2 nebulization and coaerosolization but not by coinfusion with the methylxanthines causes a marked improvement in ventilation-perfusion matching, with a reduction in shunt flow, suggesting that use of the inhalational route of application for both PGI2 and the PDE inhibitor is most effective in targeting the vasorelaxant properties to well-ventilated lung regions for maintenance of gas exchange.
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ACKNOWLEDGEMENTS |
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Our gratitude goes to Prof. P. D. Wagner for supplying the computer program.
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FOOTNOTES |
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This work was supported by Deutsche Forschungsgemeinschaft SFB 547.
Address for reprint requests and other correspondence: R. T. Schermuly, Zentrum für Innere Medizin, Justus-Liebig-Universität Giessen, Klinikstrasse 36, D-35392 Giessen, Germany (E-mail: ralph.schermuly{at}innere.med.uni-giessen.de).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 23 March 2000; accepted in final form 1 August 2001.
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