Orthostatic stability with intravenous levodopa

Shan H. Siddiqi, M.D. (1), Mary L. Creech, R.N., M.S.W., L.C.S.W. (2), Kevin J. Black, M.D. (1-4)* ORCID 0000-0002-6921-9567

Departments of (1) Psychiatry, (2) Neurology, (3) Radiology, and (4) Anatomy & Neurobiology, Washington University School of Medicine, St. Louis, Missouri, USA

* Address correspondence to Dr. Black at Campus Box 8134, 660 S. Euclid Ave., St. Louis, Missouri, USA or kevin@WUSTL.edu

#Publication notice
This is a preprint of an article whose final published version is now freely available at https://peerj.com/articles/1198/. Preferred citation:

Siddiqi SH, Creech ML, Black KJ. Orthostatic stability with intravenous levodopa. PeerJ 3:e1198, 2015. doi: 10.7717/peerj.1198. PubMed PMID: 26336641.

Abstract

Intravenous levodopa has been used in a multitude of research studies due to its more predictable pharmacokinetics compared to the oral form, which is used frequently as a treatment for Parkinson’s disease (PD). Levodopa is the precursor for dopamine, and intravenous dopamine would strongly affect vascular tone, but peripheral decarboxylase inhibitors are intended to block such effects. Pulse and blood pressure, with orthostatic changes, were recorded before and after intravenous levodopa or placebo—after oral carbidopa—in 13 adults with a chronic tic disorder and 16 tic-free adult control subjects. Levodopa caused no statistically or clinically significant changes in blood pressure or pulse. These data add to previous data that support the safety of i.v. levodopa when given with adequate peripheral inhibition of DOPA decarboxylase.

Keywords

levodopa, intravenous, carbidopa, randomized controlled trial, blood pressure, heart rate, Tourette syndrome

Introduction

The first therapeutic use of levodopa for Parkinson disease (PD) was by the intravenous route (Birkmayer et al., 1961; Birkmayer et al., 1998; Hornykiewicz, 2010). Oral administration is preferred clinically due to ease of use, although intravenous (i.v.) levodopa infusion has been favored in certain clinical circumstances (Chase et al., 1994; Abramsky et al., 1974; Horai et al., 2002; Mizuno et al., 2009).

The i.v. route has advantages for some research purposes as well (Black et al., 2004; Black et al., 2010; Black et al., 2015). However, levodopa is approved by the U.S. Food and Drug Administration for treatment of PD and other parkinsonian conditions only in a tablet formulation. In the U.S., giving an approved drug by another route for research purposes may require an investigational new drug (IND) application if changing the route of administration “significantly increases the risks (or decreases the acceptability of the risks)” (§21 CFR 312.2(b)(iii)). Some have assumed that this might hold for i.v. compared to oral levodopa.

In fact, however, numerous studies have reported on brief (\(<\)24 hr) infusions or large single-dose i.v. boluses, and i.v. levodopa has been tolerated approximately as well as oral levodopa (Abraham et al., 2015; Siddiqi et al., 2015). One study even deliberately attempted to induce hallucinations by giving high-dose i.v. levodopa to patients at high risk, but produced no hallucinations (Goetz et al., 1998). However, data on hemodynamic effects of i.v. levodopa have been limited over the past 20 years, and such results have not yet been quantitatively reported in the presence of a peripheral decarboxylase inhibitor (Abraham et al., 2015; Siddiqi et al., 2015).

Here we provide quantitative data, from a double-blind, random-allocation crossover study, on orthostatic blood pressure and pulse responses to i.v. levodopa in the presence of adequate carbidopa pretreatment.

Methods

Subjects

44 generally healthy adults (23 with Tourette syndrome or chronic motor tic disorder [TS] and 21 tic-free healthy control [HC] subjects) enrolled in a study investigating dopaminergic effects on cortical function during a working memory task as measured by functional magnetic resonance imaging (ClinicalTrials.gov identifier NCT00634556). The study was approved by the Human Research Protection Office (IRB) of Washington University in St. Louis (project #05–0832, #201105100), and all subjects provided written documentation of informed consent prior to participation. This study was performed under FDA IND #69,745, Kevin J. Black, Sponsor-Investigator. After the first 10 subjects had been enrolled, the FDA asked us to record orthostatic blood pressure and pulse before and during the infusions. No subjects took any dopaminergic or antidopaminergic medications at baseline, including levodopa, dopamine agonists, or antipsychotics. Six subjects dropped out or were withdrawn from the imaging study (claustrophobia 1, abnormal structural MRI 1, scheduling problems 2, vomiting 2). Complete vital signs were still available for one of the two subjects who were excluded from the imaging study due to vomiting, so these data were included. Therefore, 15 of the 44 subjects were not included in vital signs analysis (10 subjects enrolled before initiation of vital sign collection, 5 subjects dropped out before full range of vital signs could be collected), leaving 29 subjects for analysis.

Medications

No subjects were taking dopaminergic or antidopaminergic medications at baseline. All subjects avoided caffeine, nicotine, and proteins starting at midnight before the morning of the study. Water, juice, and other non-protein food items were allowed prior to study initiation, but subjects had no oral intake during the study period. At least 1 hour after taking 200mg carbidopa by mouth, levodopa was given intravenously in a 2 mg/mL solution according to the “final protocol” described in Black et al. (2003). Specifically, a loading dose of 0.6426 mg/kg was given i.v. over 10 minutes followed by a maintenance infusion at 2.882 \(\times\) 10\(-\)5 mg/kg/min \(\times\) (140 yr \(-\) age)/yr for an additional 90 min. A 35-year-old patient weighing 70 kg would receive a total dose of 64 mg (in 32 mL of normal saline); an oral dose of 150-200 mg would provide the same total absorbed dose, though over a slower time scale (Sasahara et al., 1980; Robertson et al., 1989; Kompoliti et al., 2002). The mean peak levodopa plasma concentration (\(C_p\)) with this method was \(\sim\)2350ng/ml, and the steady-state \(C_p\) was \(\sim\)600ng/ml (Black et al., 2003). On a separate day at least 1 week later, each patient received a placebo infusion after carbidopa. The order of the levodopa and placebo infusions was balanced. Both placebo and levodopa infusions were initiated between 8:00 AM and 10:00 AM on the study day. Study staff were blinded to the order of infusions, so both infusions occurred at approximately the same time of day.

Measurements

Vital signs were measured for each patient before and after the infusion on each day. Each vital sign measurement included heart rate, systolic blood pressure, and diastolic blood pressure (P, SBP, DBP) measured when the subject had lain supine for at least 3 minutes, and repeated after at least 1 minute standing, a protocol that was approved by the FDA reviewer. The method of blood pressure measurement was consistent between pre-infusion and post-infusion measurements: most measurements were taken electronically, but measurements by manual sphygmomanometry were conducted on a minority of study days. At the end of the study, these measurements were available on both infusion days for 29 patients. Subjects and staff measuring vital signs were blind to infusion order.

After each infusion, subjects completed the Pittsburgh Side Effects Rating Scale (Pelham, 1993), a self-rated checklist of common psychotropic side effects in which scores range between 0 and 57. Before and after each infusion, subjects completed a visual analog scale (on a scale of 1-100) to rate light-headedness–dizziness, nausea–vomiting, sleepiness, and overall health.

Statistical analysis

Means for each vital sign parameter were compared between levodopa treatment days and placebo treatment days by paired t tests. For each parameter, within-subjects confidence intervals were computed based on patients for whom the parameter was available for both placebo and levodopa days (Morey, 2008). Pittsburgh Side Effects Rating Scale scores and change in visual analog scale scores for adverse effects were compared similarly.

Results

14 patients received placebo infusion on the first study day and levodopa on the second day, while 15 received the converse. All data were collected as intended with the exception of a standing pulse for one subject and post-infusion standing blood pressure for one patient after levodopa infusion and for one patient after placebo infusion. Baseline clinical characteristics are summarized in Table 1.

Baseline clinical characteristics of subjects. *Of the 3 patients taking antihypertensives, only 1 was for hypertension; the other two were taking alpha-2 agonists for treatment of Tourette’s syndrome.
Age (years) 32.7 ± 11.2
Weight (kg) 79.1 ± 12.4
Sex 21 M, 8 F
Concurrent antihypertensives 10.3% *
Concurrent dopaminergic medications 0%


No significant difference was found between vital sign parameters during levodopa versus placebo infusions (table 2, figure 1). Standing increased P and DBP, and the magnitude of this change increased somewhat from earlier to later in the day, but none of these changes differed between levodopa and placebo. The largest absolute orthostatic increases in P, both of which were found on the post-infusion measurements, were 11.7 bpm on the placebo day and 12.3 bpm on the levodopa day. The largest absolute orthostatic increases in DBP, also found on the post-infusion measurements, were 7.4 mmHg in the placebo group and 2.0 mmHg in the levodopa group (p = 0.20). For the differences between levodopa and placebo for all vital sign parameters (supine P/SBP/DBP, standing P/SBP/DBP, orthostatic change in P/SBP/DBP), paired p values ranged between 0.16 (for supine SBP) and 0.92 (for standing SBP). Additionally, no significant difference was found for adverse effect scales (table 3).

Mean and 95% confidence intervals for individual vital sign parameters after levodopa and placebo infusions. No significant levodopa-placebo difference was found in any parameter. BP is given in mm Hg and P is given in beats per minute.
Condition Number of pairs Levodopa (95% CI) Placebo (95% CI) p
SBP (supine) 29 118 (115, 122) 121 (118, 125) 0.16
SBP (standing) 27 117 (112, 122) 120 (115, 125) 0.19
SBP (orthostatic change) 27 \(-\)1 (\(-\)6, 4) \(-\)1 (\(-\)6, 4) 0.91
DBP (supine) 29 75 (72, 78) 74 (71, 77) 0.86
DBP (standing) 27 77 (72, 82) 82 (77, 87) 0.18
DBP (orthostatic change) 27 2 (\(-\)2, 7) 7 (2, 12) 0.20
P (supine) 29 62 (61, 64) 61 (59, 63) 0.34
P (standing) 28 75 (72, 78) 73 (70, 76) 0.35
P (orthostatic change) 28 13 (10, 16) 12 (9, 15) 0.65


Mean and 95% confidence intervals for self-reported side effects with each infusion
Parameter Placebo (95% CI) Levodopa (95% CI) p
Pittsburgh Side Effects Rating Scale 2.0 (1.2, 2.9) 3.0 (1.4, 3.8) 0.25
Change in VAS (light-headedeness) 0.0 (\(-\)2.1, 2.1) 3.0 (\(-\)1.1, 7.1) 0.26
Change in VAS (nausea) 0.7 (\(-\)0.8, 2.3) \(-\)0.2 (\(-\)3.7, 3.4) 0.67
Change in VAS (sleepiness) 2.8 (\(-\)3.1, 8.6) 4.9 (\(-\)0.9, 10.7) 0.88
Change in VAS (overall health) \(-\)1.8 (\(-\)6.2, 2.6) \(-\)1.7 (\(-\)8.6, 5.2) 0.88


Figure 1 Orthostatic vital signs before and after levodopa infusion. No significant changes were observed in (a) heart rate, (b) systolic blood pressure, or (c) diastolic blood pressure between IV levodopa or placebo.

Discussion

These data in generally healthy young adults further support more comprehensive data from previous studies suggesting that i.v. levodopa, at a dose that produces biologically meaningful effects on parkinsonism, does not meaningfully affect orthostatic vital signs when it is given after adequate inhibition of DOPA decarboxylase. Previous studies supporting this conclusion are reviewed elsewhere (Abraham et al., 2015; Siddiqi et al., 2015), but here we summarize the key data.

Even before the advent of peripheral decarboxylase inhibitors, large doses of i.v. levodopa were observed to have minimal effects on blood pressure. Moorthy et al. (1972) gave 100-200mg levodopa i.v. over 10 minutes to 8 cardiac patients ages 40-77, and reported slight increase in heart rate, aortic and pulmonary arterial pressures, cardiac output, oxygen consumption, heart rate, and systolic and diastolic aortic and pulmonary arterial pressure, along with a slight decrease in systemic arterial resistance; however, specific data and statistical significances were not reported and there was no placebo group. Of note, all of these parameters recovered 30 minutes after infusion and no subjective symptoms were reported, so the authors concluded that intravenous levodopa was safe even in PD patients with advanced cardiovascular disease (Moorthy et al., 1972). Bruno and Brigida (1965) and Baldy-Moulinier et al. (1977) monitored pulse and BP at frequent intervals after i.v. infusions of 2mg/kg (140mg) over 5 minutes and 125mg in 15 min respectively, but provided no quantitative data; the authors simply state that there was no change in arterial BP (Baldy-Moulinier et al., 1977, p. 184) or that there were no significant clinical problems with the infusion (Bruno et al., 1965).

The non-neurological side effects of levodopa are further prevented or ameliorated by carbidopa, a peripheral decarboxylase inhibitor whose purpose is to prevent levodopa from being converted to dopamine in the peripheral circulation (Barbeau et al., 1976; Cotzias et al., 1969). Peripheral decarboxylase inhibitors revolutionized the treatment of PD 45 years ago (Papavasiliou et al., 1972) by reducing autonomic and gastrointestinal effects of oral levodopa, most commonly dose-related nausea, dizziness or orthostatic hypotension. Smaller doses of peripheral decarboxylase inhibitors (25-50mg of carbidopa) have minimal impact on the autonomic effects of intravenous levodopa (Irwin et al., 1992), but the same occurs with oral levodopa after 50mg of benserazide (Noack et al., 2014), suggesting that the route of administration of leovodopa is not the key difference.

By contrast, here a larger dose of carbidopa (200mg), given early enough that adequate absorption could occur before levodopa administration, effectively prevented any autonomic effects. One might posit that these favorable results are due to the younger sample without Parkinson disease, because hypotension has been observed with levodopa (without PDIs) in several PD studies (Whitsett et al., 1972; Calne et al., 1970; Sénard et al., 1995; Haapaniemi et al., 2000; Bouhaddi et al., 2004; Wolf et al., 2006). However, hypotension with levodopa in PD is also suppressed by larger doses of PDIs (Mehagnoul-Schipper et al., 2001); similarly, with carbidopa dosed as in the present study oral levodopa produced no mean change in cerebral blood flow (Hershey et al., 1998). Finally, a different brain imaging study in PD that dosed carbidopa similarly found no significant differences in BP or P after vs. before i.v. levodopa (Black et al., 2010, and unpublished data). Thus we ascribe the positive results in the present study to the larger and earlier dosing of carbidopa.

Sedation is the most common central side effect of levodopa, and patients with advanced PD also may experience dyskinesias, hallucinations, or confusion. More recently, attention has been also given to gambling, paraphilias, and other disinhibited behavior that emerges in a substantial minority of patients treated with dopamimetics (Black et al., 2006), but these complications are more common with synthetic dopamine agonists and have been reported only after chronic treatment (Weintraub et al., 2010; Poletti et al., 2013). We are unaware of any evidence that central side effects are more common with intravenous levodopa than with oral levodopa.

Overall, these data further elucidate the safety profile of intravenous levodopa and reaffirm that it causes no meaningful change in orthostatic vital signs when combined with oral carbidopa at the dose and schedule used in the present study. This adds to prior data showing an overall safety profile comparable to that of oral levodopa, and may help alleviate some of the regulatory concerns regarding the use of intravenous levodopa in research.

Acknowledgments

Funded by the U.S. National Institutes of Health (R01 MH073856, K24 MH087913, M01 RR000036, P30 NS057105, C06 RR020092, UL1 RR024992). The Tourette Syndrome Association and its Greater Missouri chapter helped with recruitment. Tamara Hershey, Meghan C. Campbell, Elda Shipley, Jonathan Koller, Samantha Ranck, Kathryn Vehe, and Gary Queensen contributed to the overall study from which the data reported here were drawn.

Author contributions

Study design: KJB
Data collection: KJB, MLC
Data analysis: SHS, KJB
Literature review: SHS, KJB
Writing: SHS, KJB
Review and approve final draft: all authors.

Competing Interests

No competing interests were disclosed.

References

  1. W Birkmayer, O Hornykiewicz. Der l-3,4-Dioxyphenylalanin (=DOPA)-Effekt bei der Parkinson-Akinese. Wien Klin Wochenschr 73, 787–788 (1961).

  2. W Birkmayer, O Hornykiewicz. The effect of l-3,4-dihydroxyphenylalanine (=DOPA) on akinesia in parkinsonism [reprinted, originally 1961]. Parkinsonism Relat Disord 4, 59-60 (1998).

  3. O Hornykiewicz. A brief history of levodopa.. J Neurol 257, S249-52 (2010).

  4. TN Chase, TM Engber, MM Mouradian. Palliative and prophylactic benefits of continuously administered dopaminomimetics in Parkinson’s disease. Neurology 44, S15-8 (1994).

  5. O Abramsky, Z Goldschmidt. Treatment and prevention of acute hepatic encephalopathy by intravenous levodopa. Surgery 75, 188-91 (1974).

  6. T Horai, T Nishiyama, H Yamamoto, K Hanaoka. [High dose L-DOPA infusion during general anesthesia for gastrectomy in a patient with parkinsonism]. Masui 51, 42-5 (2002).

  7. J Mizuno, S Kato, M Watada, S Morita. [Perioperative management of a patient with Parkinson’s disease with intravenous infusion of levodopa]. Masui 58, 1286-9 (2009).

  8. Kevin J. Black, Tamara Hershey, Johanna M. Hartlein, Juanita L. Carl, Joel S. Perlmutter. Levodopa challenge neuroimaging of levodopa-related mood fluctuations in Parkinson’s disease. Neuropsychopharmacology 30, 590–601 Nature Publishing Group, 2004. Link

  9. K. J. Black, J. M. Koller, M. C. Campbell, D. A. Gusnard, S. I. Bandak. Quantification of Indirect Pathway Inhibition by the Adenosine A2a Antagonist SYN115 in Parkinson Disease. Journal of Neuroscience 30, 16284–16292 Society for Neuroscience, 2010. Link

  10. Kevin J. Black, Marilyn L. Piccirillo, Jonathan M. Koller, Tiffany Hseih, Lei Wang, Mark A. Mintun. Levodopa effects on [11C]raclopride binding in the resting human brain [v1; ref status: indexed, http://f1000r.es/4oe]. F1000Research 4, 23 F1000 Research Ltd., 2015. Link

  11. N Abraham, M Karimi, C Devine, KJ Black. The human experience with intravenous levodopa. F1000Posters 6, 268 F1000 Research Ltd., 2015. Link

  12. S. H. Siddiqi, C. Geiger, N. K. Abraham, M. Karimi, C. Devine, K. J. Black. The human experience with intravenous levodopa. Manuscript submitted for publication (2015).

  13. CG Goetz, EJ Pappert, LM Blasucci, GT Stebbins, ZD Ling, MV Nora, PM Carvey. Intravenous levodopa in hallucinating Parkinson’s disease patients: high-dose challenge does not precipitate hallucinations. Neurology 50, 515-7 (1998).

  14. Kevin J. Black, Juanita L. Carl, Johanna M. Hartlein, Stacie L. Warren, Tamara Hershey, Joel S. Perlmutter. Rapid intravenous loading of levodopa for human research: clinical results. Journal of Neuroscience Methods 127, 19–29 Elsevier BV, 2003. Link

  15. K Sasahara, T Nitanai, T Habara, T Morioka, E Nakajima. Dosage form design for improvement of bioavailability of levodopa II: Bioavailability of marketed levodopa preparations in dogs and parkinsonian patients. J Pharm Sci 69, 261-5 (1980).

  16. DR Robertson, ND Wood, H Everest, K Monks, DG Waller, AG Renwick, CF George. The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa. Br J Clin Pharmacol 28, 61-9 (1989).

  17. K Kompoliti, CH Adler, R Raman, JH Pincus, MT Leibowitz, JJ Ferry, L Blasucci, JN Caviness, S Leurgans, WM Chase, LC Yones, E Tan, P Carvey, CG Goetz. Gender and pramipexole effects on levodopa pharmacokinetics and pharmacodynamics. Neurology 58, 1418-22 (2002).

  18. W Pelham. Pharmacotherapy for children with attention deficit hyperactivity disorder. School Psychology Review 22, 199-207 (1993).

  19. Richard D Morey. Confidence intervals from normalized data: A correction to Cousineau (2005). Reason 4, 61–64 (2008).

  20. S Moorthy, H Grendahl, A Andersen, C Müller. The haemodynamic effect of intravenous injection of levodopa. Acta Med Scand 191, 451-4 (1972).

  21. A Bruno, E Brigida. [Action of L-DOPA on the extrapyramidal symptomatology of haloperidol]. Riv Neurobiol 11, 646-54 (1965).

  22. M Baldy-Moulinier, P Bories, H Michel, P Passouant. [Hepatic encephalopathies; hemodynamic and metabolic study of the influence of ammonia and levodopa]. Rev Neurol (Paris) 133, 175-89 (1977).

  23. A Barbeau, M Roy. Six-year results of treatment with levodopa plus benzerazide in Parkinson’s disease. Neurology 26, 399-404 (1976).

  24. George C. Cotzias, Paul S. Papavasiliou, Rosemary Gellene. Modification of parkinsonism—Chronic treatment with l–DOPA. New England Journal of Medicine 280, 337–345 New England Journal of Medicine (NEJM/MMS), 1969. Link

  25. PS Papavasiliou, GC Cotzias, SE Düby, AJ Steck, C Fehling, MA Bell. Levodopa in Parkinsonism: potentiation of central effects with a peripheral inhibitor. N Engl J Med 286, 8-14 (1972).

  26. RP Irwin, JG Nutt, WR Woodward, ST Gancher. Pharmacodynamics of the hypotensive effect of levodopa in parkinsonian patients.. Clin Neuropharmacol 15, 365-74 (1992).

  27. C Noack, C Schroeder, K Heusser, A Lipp. Cardiovascular effects of levodopa in Parkinson’s disease.. Parkinsonism Relat Disord 20, 815-8 (2014).

  28. TL Whitsett, LI Goldberg. Effects of levodopa on systolic preejection period, blood pressure, and heart rate during acute and chronic treatment of Parkinson’s disease.. Circulation 45, 97-106 (1972).

  29. DB Calne, J Brennan, AS Spiers, GM Stern. Hypotension caused by L-dopa.. Br Med J 1, 474-5 (1970).

  30. JM Sénard, P Verwaerde, O Rascol, JL Montastruc. Effects of acute levodopa administration on blood pressure and heart variability in never treated parkinsonians.. Hypertens Res 18 Suppl 1, S175-7 (1995).

  31. TH Haapaniemi, MA Kallio, JT Korpelainen, K Suominen, U Tolonen, KA Sotaniemi, VV Myllylä. Levodopa, bromocriptine and selegiline modify cardiovascular responses in Parkinson’s disease.. J Neurol 247, 868-74 (2000).

  32. M Bouhaddi, F Vuillier, JO Fortrat, S Cappelle, MT Henriet, L Rumbach, J Regnard. Impaired cardiovascular autonomic control in newly and long-term-treated patients with Parkinson’s disease: involvement of L-dopa therapy.. Auton Neurosci 116, 30-8 (2004).

  33. JP Wolf, M Bouhaddi, F Louisy, A Mikehiev, L Mourot, S Cappelle, F Vuillier, P Andre, L Rumbach, J Regnard. Side-effects of L-dopa on venous tone in Parkinson’s disease: a leg-weighing assessment.. Clin Sci (Lond) 110, 369-77 (2006).

  34. DJ Mehagnoul-Schipper, RH Boerman, WH Hoefnagels, RW Jansen. Effect of levodopa on orthostatic and postprandial hypotension in elderly Parkinsonian patients.. J Gerontol A Biol Sci Med Sci 56, M749-55 (2001).

  35. T Hershey, KJ Black, MK Stambuk, JL Carl, LA McGee-Minnich, JS Perlmutter. Altered thalamic response to levodopa in Parkinson’s patients with dopa-induced dyskinesias.. Proc Natl Acad Sci U S A 95, 12016-21 (1998).

  36. K. J. Black, J. H. Friedman. Repetitive and impulsive behaviors in treated Parkinson disease. Neurology 67, 1118-9 (2006).

  37. D Weintraub, J Koester, MN Potenza, AD Siderowf, M Stacy, V Voon, J Whetteckey, GR Wunderlich, AE Lang. Impulse control disorders in Parkinson disease: A cross-sectional study of 3090 patients. Arch Neurol 67, 589-95 (2010).

  38. M Poletti, C Logi, C Lucetti, Dotto P Del, F Baldacci, A Vergallo, M Ulivi, Sarto S Del, G Rossi, R Ceravolo, U Bonuccelli. A single-center, cross-sectional prevalence study of impulse control disorders in Parkinson disease: association with dopaminergic drugs. J Clin Psychopharmacol 33, 691–694 (2013).

[Someone else is editing this]

You are editing this file