J Clin Pharmacol
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
0091270007309705v1
48/2/184    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (1)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Suzuki, J.
Right arrow Articles by Mizushima, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Suzuki, J.
Right arrow Articles by Mizushima, Y.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

PHARMACOKINETICS

Pharmacokinetics of PC-SOD, a Lecithinized Recombinant Superoxide Dismutase, After Single- and Multiple-Dose Administration to Healthy Japanese and Caucasian Volunteers

Jun Suzuki, PhD, Freerk Broeyer, MD, Adam Cohen, MD, PhD, Masato Takebe, BSc, Jacobus Burggraaf, MD, PhD and Yutaka Mizushima, MD, PhD

From LTT Bio-Pharma Co, Ltd, Atago, Minato-ku, Tokyo 105-6201, Japan (Dr Suzuki and Dr Mizushima); Centre for Human Drug Research, Leiden, The Netherlands (Dr Broeyer, Dr Cohen, Dr Burggraaf); Institute for Drug Development, Inc, Minami-azabu, Minato-ku, Tokyo, Japan (Mr Takebe); and DDS Institute, Jikei University, Nishi-shinbashi, Minato-ku, Tokyo, Japan (Dr Suzuki and Dr Mizushima).

Address for correspondence: Jun Suzuki, PhD, R&D Division, LTT Bio-Pharma Co, Ltd, Tokyo 105-6201, Japan.


   ABSTRACT
TOP
 ABSTRACT
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGEMENTS
 REFERENCES
 
To study the pharmacokinetics of single increasing intravenous doses (40-160 mg) and repeated doses (80 mg for 7 days) of lecithinized superoxide dismutase (PC-SOD) in Japanese volunteers and to compare the pharmacokinetics of PC-SOD between Caucasians and Japanese. The Japanese study consisted of 2 parts: a single-dose, open-label, dose-escalation part and a multiple-dose, single-blind, placebo-controlled part. The pharmacokinetics of PC-SOD were determined using noncompartmental and compartmental methods. Pharmacokinetic data from a study with PC-SOD in Caucasians were reanalyzed using the same methodology. The mean (SD) terminal half-life of PC-SOD in Japanese subjects was 25 (4) hours for the 40-mg and 80-mg doses and 31 (15) hours for the 160-mg dose. There was nonlinearity between dose-normalized Cmax and clearance (P values .002 and .022). After multiple dosing, steady state was reached after 5 days. The observed accumulation ratio was 2.6 (0.5). The pharmacokinetics of the single 80-mg dose were similar for Japanese and Caucasians. The pharmacokinetics of PC-SOD was shown to be nonlinear with dose, which may be attributable to a saturable clearing mechanism. The relatively long half-life of PC-SOD (>24 hours) suggests that it is worthwhile to study the compound as a protective agent in clinical conditions with free radical overload.

Key Words: Pharmacokinetics • superoxide dismutase • free radicals • oxidative stress • PC-SOD

Overproduction of free radicals, such as the superoxide anion, is associated with the pathology of different diseases.1-3 Superoxide dismutase (SOD), which catalyses the dismutation of superoxide to hydrogen peroxide and oxygen, is important in the defense against free radical overload.4 It thus seems logical to develop SOD as a potential treatment modality. However, attempts to achieve this have failed mainly because exogenous SOD has a low affinity for the cell membrane and has unfavorable pharmacokinetics (PK) (eg, a very short half-life).5 These characteristics limit the clinical use of SOD, especially because the intracellular isoforms of SOD play a role in protection against free-radical-induced damage and because exogenous SOD needs to be active for a certain period of time to exert its potential protective effect.5-7

Therefore, a recombinant Cu,Zn SOD, covalently bound to an average of 4 molecules of lecithin (PC-SOD), has been developed. In preclinical experiments, PC-SOD has shown a 4.5 times greater oxygen-radical scavenging effect, which leads to a 100-fold increase in protective effect against O2-induced vascular endothelial cell damage compared with unmodified SOD.8 In addition, a stronger binding to human vascular endothelial cells was demonstrated.9 Furthermore, studies in rats showed that PC-SOD had a prolonged residence time, compared with unmodified SOD, and was effective in various animal models.2,3,10-19 These characteristics make PC-SOD a potentially protective agent in various pathological conditions that involve free radical overproduction.

Previous phase I trials in Caucasians demonstrated that PC-SOD was well tolerated in doses up to 80 mg, but the PK in other ethnic groups have not been reported. This may be of particular importance for the clearance of PC-SOD, because apparently most differences caused by ethnic factors occur during drug metabolism.20

Therefore, a PK study with single intravenous doses (up to 160 mg) and repeated intravenous doses (80 mg/d for 7 days) of PC-SOD in healthy Japanese volunteers was performed. Because a previously performed PK study in Caucasians used the same methodology, the PK of the single intravenous 80-mg dose were compared.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
For the study performed in Japan, subjects eligible for participation were male Japanese volunteers who were within 20% of normal body weight range relative to height and frame size. All subjects were screened prior to study participation and considered healthy based on history, physical examination, and laboratory assessment. This study protocol was approved by the Institutional Review Board of The Kitasato Institute, Research Center for Clinical Pharmacology (formerly known as The Kitasato Institute Bio-Iatric Center).

The study in Caucasian subjects was performed as previously described.21 This protocol was approved by the Medical Ethics Committee of Leiden University Medical Center. From both Japanese and Caucasian subjects, written informed consent was obtained before screening.

Study Design
The study in Japanese subjects was done in 3 cohorts of 6 male volunteers who received escalating single doses of PC-SOD (40, 80, and 160 mg) in an open-label fashion and a single cohort of 8 male volunteers who received 7 daily doses of PC-SOD (80 mg) in a placebo-controlled design (6 active treatment, 2 placebo). Dose escalation occurred when no clinically significant safety issues were observed in the previous dose level. The multiple-dose part of the study started after completion of the highest dose of the single-dose study.

The study in Caucasian subjects included 8 healthy subjects (4 female and 4 male) who received single doses of PC-SOD (20, 40, and 80 mg) in a double-blind, placebo-controlled, 4-way crossover study.

Trial Medication
Recombinant human SOD (rhSOD) was produced in Escherichia coli; the exact procedure is described elsewhere.8 One of the cysteine residues of rhSOD was converted to S-(2-hydroxyethyl-thio-) cysteine, and phosphatidylcholine derivatives were then covalently bound to this modified rhSOD to produce PC-SOD. The specific activity of PC-SOD was about 3000 U/mg of protein when assayed with the cytochrome c method using a xanthine-xanthine oxidase-cytochrome c system. Vials for injection containing 30 mg of PC-SOD were produced by a freeze-drying process with purified sucrose as an additive. The test drug was dissolved in xylitol 5% (Japan) or mannitol 5% (Netherlands). Placebo consisted of either xylitol or mannitol.

Study Days (Japanese)
The subjects were admitted to the research unit after an overnight fast. After preparation and baseline measurements, the study drug was administered intravenously over 60 minutes. For the participants of the multiple-dose cohort, the study drug was administered 7 times with an interval of 24 hours in between. During the study days, we frequently measured vital signs, recorded 12-lead electrocardiographs, evaluated adverse events, conducted blood sampling, and collected fractionated urine. The subjects remained in the unit for 48 hours (multiple dose: 72 hours) and returned for follow-up assessments and blood sampling 1 and 2 weeks after (last) dosing. During the study days, subjects had standard meals and abstained from using xanthine-containing drinks or food.

Sampling (Japanese)
PC-SOD serum concentrations were assessed before administration and at 30, 60, and 90 minutes and 2, 3, 5, 9, 13, 25, and 48 hours after dosing (single dose). For the multiple-dose part, serum PC-SOD concentrations were assessed 60 minutes prior to each administration and at 30, 60, and 90 minutes and 2, 3, 5, 9, and 13 hours on days 1 and 4. In addition, PC-SOD concentrations were determined 23, 48, 72, and 168 hours after the last administration.

Cumulative urinary PC-SOD concentrations were measured at -12 to 0, 0 to 6, 6 to 12, 12 to 24, and 24 to 48 hours (and 48 to 72 hours for the multiple dose cohort) after the start of administration for the single-dose cohorts and the first day and the last day of the multiple-dose cohort. In addition, during days 2 to 6, cumulative urinary PC-SOD concentration was measured for each 24-hour period.

For all cohorts, safety laboratory assessments were done before each administration and at 24 hours and 1 week after PC-SOD administration. For the multiple-dose cohort, additional safety assessments were done at 48 and 72 hours after the last dose.

The study outline for the Caucasian subjects was comparable to that of the Japanese volunteers.21

Serum and urinary PC-SOD concentrations were measured using an enzyme-linked immunosorbent assay, consisting of an antibody against human Cu,Zn-SOD and a second antibody against human Cu,Zn-SOD conjugated with horseradish peroxidase. The assay has a lower limit of quantification, 0.626 µg/mL. The intra-assay variability and interassay were investigated at PC-SOD concentrations of 0.626, 2.50, and 10.0 µg/mL for serum and 0.626, 5.0, and 20.0 µg/mL for urine (each concentration in triplicate). The coefficients of variation (CVs) for the intraassay variability for the respective concentrations were 5.6%, 3.2%, and 1.0% in serum and 7.3%, 2.3%, and 2.3% in urine. The CVs for the interassay variability in serum and urine were 7.9%, 2.7%, and 1.3% and 4.9%, 8.2%, and 1.2%, respectively. Repeated freezing and thawing had no appreciable effects (CV <10% after 3 freeze/thaw cycles).

Noncompartmental Pharmacokinetic Analyses
The data were analyzed using noncompartmental analysis with estimation of the elimination half-life (ln2/lz) using log-linear regression of the terminal part of the curve, where the number of included points was determined by the software program WinNonlin V5.0 (Pharsight Corp, Mountain View, Calif). Extrapolation of the area under the plasma drug concentration curve (AUC) from time 0 to infinity (AUC0-{infty}) was done using the calculated AUC from time 0 to last point measured (AUC0-last), to which Clast/lz was added. The PK parameters of PC-SOD after single doses (for both the Japanese and Caucasian subjects, only 80-mg data) were analyzed for Cmax (maximum observed plasma drug concentration), AUC0-24 (area under the AUC from time 0 to 24 hours), AUC0-last, AUC0-{infty}, clearance, volume of distribution (Vd), and terminal elimination half-life (t1/2). The degree of accumulation of PC-SOD expected during the multiple-dose regimen was predicted based on the single-dose data. The predicted accumulation ratio (Rpred) was defined as the AUC0-{infty} of the 80-mg single-dose cohort divided by AUC0-24 of the 80-mg single-dose cohort.

After multiple-dose administration, the following parameters were determined from the PC-SOD concentration versus time data: Cmax, AUC0-{infty}, AUC0-24, and t1/2 after the first administration and Cmax, AUCint (AUC over the 24-hour dosing interval during steady state), and t1/2 after the last administration. The observed accumulation ratio (Robs) was defined as AUCint (AUC over the 24-hour dosing interval) on day 7 of the multiple-dose cohort divided by AUC0-24 on day 1. The accumulation of PC-SOD in serum at steady state (Rss, steady-state accumulation ratio) was defined as the AUCint on day 7 of the multiple-dose cohort divided by AUC0-{infty} on day 1.

Compartmental Pharmacokinetic Analyses
Compartmental analysis was performed using the software program WinNonlin V5.0. A 2-compartment model with macroconstants was used. Observations were iteratively reweighed using the square of the predicted concentration corresponding to a constant coefficient of variation residual error model. Using this model, Cmax, clearance, initial half-life (t1/2, initial), terminal half-life (t1/2, terminal), and volume of distribution were determined for both single- and multiple-dose data.

Statistical Analysis
Pharmacokinetic parameters were summarized using mean, standard deviation (SD), median, minimum, and maximum. Tolerability and safety variables were summarized using descriptive statistics (n, mean, SD, median, minimum, and maximum for continuous variables).

Dose-normalized Cmax and total clearance were used to assess dose linearity using single-factor factorial analysis of variance on log-transformed data (factor dose) to assess dose linearity. Mean differences and 90% confidence intervals (CIs) in Cmax (µg/mL), t1/2 (hours), clearance (mL/h), volume of distribution, and AUC0-{infty} (µg·hr/mL) between Japanese and Caucasian were determined using 2-sample Student t tests on log-transformed data assuming unequal variances.


   RESULTS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGEMENTS
 REFERENCES
 
General
Twenty-six male Japanese volunteers (age 20-32 years, mean body mass index 21.4 kg/m2) were included. In the Caucasian study, 8 subjects participated (4 female/4 male, age 18-27 years, mean body mass index 23.4 kg/m2).

All Japanese subjects completed the study. No adverse events were observed in 40- and 80-mg single-dose groups. The most common adverse event was mild diarrhea (twice in the 160-mg group, once in the 80-mg multiple-dose group, in 1 subject receiving placebo). These events were considered possibly related to the study drug. Other adverse events were headache, muscle pain, fatigue, pain in the right hip, and influenza. These events occurred once and were considered not to be related to the study medication. In 1 subject in the multiple-dose group, antibodies against PC-SOD were detected at the first follow-up. Follow-up at 6 months showed that these antibodies were no longer present.

Safety analysis in Caucasians did not indicate any safety issues; results of the safety analyses are reported elsewhere.21

Noncompartmental Pharmacokinetic Analyses
The mean serum concentrations of PC-SOD versus time curves for the single-dose and the multiple-dose regimens are shown in Figures 1 and 2, respectively. A summary of the PK parameters is given in Table 1 (single dose) and Table 2 (multiple-dose).


Figure 1
Figure 1
View larger version (20K):
[in this window]
[in a new window]

  		Figure 1. Serum lecithinized superoxide dismutase (PC-SOD) concentration (mean ± SD) after single intravenous doses in Japanese (n = 6, open circles 40 mg, closed circles 80 mg, closed triangles 160 mg) and Caucasian (n = 8, open triangles 80 mg) volunteers.

 

Figure 2
View larger version (7K):
[in this window]
[in a new window]

  		Figure 2. Serum lecithinized superoxide dismutase (PC-SOD) concentration (mean) after repeated administration of 80 mg/d intravenously for 7 days in Japanese volunteers.

 

View this table:
[in this window]
[in a new window]

  		Table I Noncompartmental Pharmacokinetic Parameters in Japanese and Caucasian Volunteers

 

View this table:
[in this window]
[in a new window]

  		Table II Comparison of the Pharmacokinetic Parameters of Intravenous Single-Dose and Multiple-Dose Lecithinized Superoxide Dismutase (PC-SOD) Administrations

 

Following single-dose intravenous PC-SOD administration in Japanese volunteers, serum PC-SOD concentrations were elevated above baseline for 24 hours in all doses used. Mean (SD) terminal half-life (t1/2) of PC-SOD was 24.7 (4.3), 24.9 (3.5), and 31.3 (14.6) hours for the 3 ascending doses, respectively. After the 80-mg single dose in Caucasian volunteers, t1/2 was 26.1 (11.2) hours.

Dose-normalized Cmax and clearance (Japanese) were 259.4 (31.4), 254.9 (24.7), and 358.0 (74.1) ng/mL/mg and 167.4 (27.4), 143.9 (18.9), and 119.4 (30.0) mL/hr for 40-, 80-, and 160-mg PC-SOD, respectively. These data indicated that the PK of PC-SOD are dose-dependent (P values .002 and .022).

Urinary PC-SOD concentrations were below the limit of quantification for the 40-mg and 80-mg doses, but after 160 mg of PC-SOD the cumulative urinary excretion at 0 to 48 hours was 2.28 (1.34) mg, which is 1.4 (0.8)% of the administered dose.

After multiple-dose administration of PC-SOD 80 mg, Cmax,day7 was 38.1 (2.1) µg/mL. The AUCint was 649.7 (98.3) h·g/mL. Based on the 7 trough serum PC-SOD concentrations, steady state was reached after 5 days. The Robs 2.6 (0.4) was greater than the value calculated from the single-dose data (Rpred: 2.0 [0.2], P = .02).

Urinary PC-SOD concentrations were below limit of quantification during the multiple-dose regimen.

Compartmental Pharmacokinetic Analyses
When data were modeled using a 2-compartmental model, a good fit was obtained. In 2 subjects (in the 80- and 160-mg single-dose cohort), no adequate estimation of half-life could be calculated. The results after compartmental analyses were comparable to those obtained with noncompartmental analyses (Table 3).


View this table:
[in this window]
[in a new window]

  		Table III Compartmental Analyses of Pharmacokinetic Parameters in Japanese Volunteers

 

Comparison of Caucasians and Japanese
The noncompartmental PK of the 80-mg single-dose administrations were compared between Japanese and Caucasians using Cmax, clearance, volume of distribution, t1/2, and AUC0-{infty} (Table 1).


   DISCUSSION
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 ACKNOWLEDGEMENTS
 REFERENCES
 
In this study we evaluated the PK profile of PC-SOD following single doses of 40, 80, and 160 mg and multiple doses (80 mg/d for 7 days) in Japanese volunteers. Additionally, PK of 80-mg single-dose PC-SOD in Japanese and Caucasian subjects were compared.

The mean plasma concentration versus time curve for the 48 hours following a single dose of PC-SOD was characterized by a biexponential decline from peak plasma concentration. Half-lives were more than 24 hours for all investigated doses, which is substantially longer then previous reports in trials with unlecithinized SOD.22,23 The excretion of PC-SOD is predominantly extrarenal, because urinary excretion was less than 2% in the 160-mg cohort. This is in line with findings from a previous study in healthy Caucasians but contradicts results in earlier trials with unlecithinized recombinant SOD, where urinary excretions up to 57% were reported. These data suggest that the diminished urinary excretion, and possibly the prolonged half-life, can be attributed to the addition of lecithin to SOD.22,23 Contradicting earlier studies in Japanese and Caucasians, this study showed dose-dependency of the PK parameters, likely because we studied higher doses. Given that Cmax also showed dose-dependency, this strongly suggests a saturable clearance for PC-SOD.

After multiple dosing, steady state was reached after 5 days. Pharmacokinetics after the multiple dose regimen showed a similar pattern of distribution and elimination as observed during the single-dose cohorts. But some differences were observed. First, t1/2 was longer than during the single-dose regimen (56.8 vs 24.9 hours); second, a slightly higher accumulation ratio than predicted on the single-dose data (Rpred 2.0 vs Robs 2.6) was found.

For the higher than expected accumulation and longer half-life of PC-SOD after multiple dosing, some possible explanations can be given. First, during the multiple-dose regimen, the final part of AUC0-{infty} is better characterized because of longer sampling (48 hours vs 168 hours in the single- and multiple-dose cohort, respectively). It is therefore highly likely that the calculated AUC0-{infty} during the single-dose regimen and following the first dose in the multiple-dose regimen is underestimated because of incomplete characterization of the terminal elimination phase. Second, it may be that higher exposures, as in the multiple-dose part, make the observed nonlinearity in the single-dose cohorts clearer. When the PK profiles were modeled using a 2-compartment model, the estimated PK parameters were comparable to those determined with noncompartmental methods, indicating that we adequately described the PK properties of PC-SOD. Nevertheless, the finding that steady state is reached after approximately 5 days, which is more compatible with a half-life of 24 hrs, may suggest that there is a "deep" compartment containing very little amounts of drug.24 Thus, for practical reasons it seems that the relevant elimination half-life of PC-SOD is on the order of 24 hours.

Our data provide no indication that after an 80-mg single dose of PC-SOD there are differences of clinical significance between Japanese and Caucasian subjects.

Generally, PC-SOD was well tolerated in doses up to 160 mg. The observation that 1 of the Japanese subjects developed antibodies against PC-SOD after multiple doses of PC-SOD requires further investigation, and the development of antibodies should be monitored in future trials.


   CONCLUSIONS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
ACKNOWLEDGEMENTS
 REFERENCES
 
This study demonstrates that PC-SOD concentrations were elevated above baseline for at least 24 hours after single doses of PC-SOD greater than or equal to 40 mg. Dose nonlinearity was demonstrated after single doses, indicating saturable clearance. During the multiple-dose regimen, steady state was reached after 5 days. Accumulation was slightly higher than expected. It was shown that PK after a single intravenous dose of 80 mg of PC-SOD are similar for healthy Japanese and Caucasian subjects. The PK of PC-SOD make it worthwhile to further investigate PC-SOD in patients with diseases characterized by high free radical overload.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGEMENTS
REFERENCES
 
We thank Mr Wolf Ondracek, MA, who skillfully translated the Japanese documents and was indispensable for the communication between the investigators.

Financial disclosure: This study was financially supported by Seikagaku Corporation, Tokyo, Japan, and the data will be used for further development of the compound by LTT Bio-Pharma Co, Tokyo, Japan. J Suzuki and Y Mizushima are employees of LTT Bio-Pharma Co.

DOI: 10.1177/0091270007309705

Dr Suzuki and Dr Broeyer contributed equally to this manuscript.


   REFERENCES
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGEMENTS
 REFERENCES
 

1. Jourd'heuil D, Morise Z, Conner EM, Grisham MB. Oxidants, transcription factors, and intestinal inflammation. J Clin Gastroenterol. 1997;25(suppl 1): S61-S72.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

2. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004;56: 185-229.[Abstract/Free Full Text]

3. Dhalla NS, Elmoselhi AB, Hata T, Makino N. Status of myocardial antioxidants in ischemia-reperfusion injury. Cardiovasc Res. 2000;47: 446-456.[Abstract/Free Full Text]

4. Halliwell B, Gutteridge JM. Oxidative stress: adaptation, damage, repair and death. In: Halliwell B, Gutteridge JM, eds. Free Radicals in Biology and Medicine. Oxford, United Kingdom: Oxford University Press; 1999: 246-350.

5. McCord JM, Edeas MA. SOD, oxidative stress and human pathologies: a brief history and a future vision. Biomed Pharmacother. 2005;59: 139-142.[CrossRef][Medline] [Order article via Infotrieve]

6. Tanaka M, Mokhtari GK, Terry RD, et al. Overexpression of human copper/zinc superoxide dismutase (SOD1) suppresses ischemia-reperfusion injury and subsequent development of graft coronary artery disease in murine cardiac grafts. Circulation. 2004;110(11 suppl 1): II200-II206.[Web of Science][Medline] [Order article via Infotrieve]

7. Yoshida T, Maulik N, Engelman RM, Ho YS, Das DK. Targeted disruption of the mouse Sod I gene makes the hearts vulnerable to ischemic reperfusion injury. Circ Res. 2000;86: 264-269.[Abstract/Free Full Text]

8. Igarashi R, Hoshino J, Takenaga M, et al. Lecithinization of superoxide dismutase potentiates its protective effect against Forssman antiserum-induced elevation in guinea pig airway resistance. J Pharmacol Exp Ther. 1992;262: 1214-1219.[Abstract/Free Full Text]

9. Igarashi R, Hoshino J, Ochiai A, Morizawa Y, Mizushima Y. Lecithinized superoxide dismutase enhances its pharmacologic potency by increasing its cell membrane affinity. J Pharmacol Exp Ther. 1994;271: 1672-1677.[Abstract/Free Full Text]

10. Logue SE, Gustafsson AB, Samali A, Gottlieb RA. Ischemia/reperfusion injury at the intersection with cell death. J Mol Cell Cardiol. 2005;38: 21-33.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

11. Chan PH. Role of oxidants in ischemic brain damage. Stroke. 1996;27: 1124-1129.[Abstract/Free Full Text]

12. Yunoki M, Kawauchi M, Ukita N, Sugiura T, Ohmoto T. Effects of lecithinized superoxide dismutase on neuronal cell loss in CA3 hippocampus after traumatic brain injury in rats. Surg Neurol. 2003;59: 156-160.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

13. Nakagawa K, Koo DD, Davies DR, et al. Lecithinized superoxide dismutase reduces cold ischemia-induced chronic allograft dysfunction. Kidney Int. 2002;61: 1160-1169.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

14. Nakajima H, Hangaishi M, Ishizaka N, et al. Lecithinized copper, zinc-superoxide dismutase ameliorates ischemia-induced myocardial damage. Life Sci. 2001;69: 935-944.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

15. Hangaishi M, Nakajima H, Taguchi J, et al. Lecithinized Cu, Zn-superoxide dismutase limits the infarct size following ischemia-reperfusion injury in rat hearts in vivo. Biochem Biophys Res Commun. 2001;285: 1220-1225.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

16. Chikawa T, Ikata T, Katoh S, et al. Preventive effects of lecithinized superoxide dismutase and methylprednisolone on spinal cord injury in rats: transcriptional regulation of inflammatory and neurotrophic genes. J Neurotrauma. 2001;18: 93-103.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

17. Nakajima H, Ishizaka N, Hangaishi M, et al. Lecithinized copper, zinc-superoxide dismutase ameliorates prolonged hypoxia-induced injury of cardiomyocytes. Free Radic Biol Med. 2000;29: 34-41.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

18. Shimmura S, Igarashi R, Yaguchi H, et al. Lecithin-bound superoxide dismutase in the treatment of noninfectious corneal ulcers. Am J Ophthalmol. 2003;135: 613-619.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

19. Tsubokawa T, Jadhav V, Solaroglu I, et al. Lecithinized superoxide dismutase improves outcomes and attenuates focal cerebral ischemic injury via antiapoptotic mechanisms in rats. Stroke. 2007;38: 1057-1062.[Abstract/Free Full Text]

20. Kim K, Johnson JA, Derendorf H. Differences in drug pharmacokinetics between East Asians and Caucasians and the role of genetic polymorphisms. J Clin Pharmacol. 2004;44: 1083-1105.[Abstract/Free Full Text]

21. Broeyer FJF, van Aken BE, Suzuki J, et al. The pharmacokinetics and effects of a long-acting preparation of superoxide dismutase (PC-SOD) in man. Br J Clin Pharmacol. In press.

22. Uematsu T, Nagashima S, Umemura K, Kanamaru M, Nakashima M. Pharmacokinetics and safety of intravenous recombinant human superoxide dismutase (NK341) in healthy subjects. Int J Clin Pharmacol Ther. 1994;32: 638-641.[Web of Science][Medline] [Order article via Infotrieve]

23. Tsao C, Greene P, Odlind B, Brater DC. Pharmacokinetics of recombinant human superoxide dismutase in healthy volunteers. Clin Pharmacol Ther. 1991;50: 713-720.[Web of Science][Medline] [Order article via Infotrieve]

24. Darwish M, Kirby M, Robertson P Jr, Hellriegel E, Jiang JG. Single-dose and steady-state pharmacokinetics of fentanyl buccal tablet in healthy volunteers. J Clin Pharmacol. 2007;47: 56-63.[Abstract/Free Full Text]
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
T. Ishihara, K.-I. Tanaka, Y. Tasaka, T. Namba, J. Suzuki, T. Ishihara, S. Okamoto, T. Hibi, M. Takenaga, R. Igarashi, et al.
Therapeutic Effect of Lecithinized Superoxide Dismutase against Colitis
J. Pharmacol. Exp. Ther., January 1, 2009; 328(1): 152 - 164.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
0091270007309705v1
48/2/184    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (1)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Suzuki, J.
Right arrow Articles by Mizushima, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Suzuki, J.
Right arrow Articles by Mizushima, Y.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS