Zelrix™: A Novel Transdermal Formulation of Sumatriptan


  • Mark Pierce MD, PhD,

    1. From the University of Pennsylvania – Psychiatry, Philadelphia, PA, USA (S. Siegel); NuPathe – Research and Development, Conshohocken, PA, USA (M. Pierce, T. Marbury, C. O'Neill, W. Du, and T. Sebree).
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  • Thomas Marbury MD,

    1. From the University of Pennsylvania – Psychiatry, Philadelphia, PA, USA (S. Siegel); NuPathe – Research and Development, Conshohocken, PA, USA (M. Pierce, T. Marbury, C. O'Neill, W. Du, and T. Sebree).
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  • Carol O'Neill BA,

    1. From the University of Pennsylvania – Psychiatry, Philadelphia, PA, USA (S. Siegel); NuPathe – Research and Development, Conshohocken, PA, USA (M. Pierce, T. Marbury, C. O'Neill, W. Du, and T. Sebree).
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  • Steven Siegel MD, PhD,

    1. From the University of Pennsylvania – Psychiatry, Philadelphia, PA, USA (S. Siegel); NuPathe – Research and Development, Conshohocken, PA, USA (M. Pierce, T. Marbury, C. O'Neill, W. Du, and T. Sebree).
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  • Wei Du PhD,

    1. From the University of Pennsylvania – Psychiatry, Philadelphia, PA, USA (S. Siegel); NuPathe – Research and Development, Conshohocken, PA, USA (M. Pierce, T. Marbury, C. O'Neill, W. Du, and T. Sebree).
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  • Terri Sebree BA

    1. From the University of Pennsylvania – Psychiatry, Philadelphia, PA, USA (S. Siegel); NuPathe – Research and Development, Conshohocken, PA, USA (M. Pierce, T. Marbury, C. O'Neill, W. Du, and T. Sebree).
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  • Financial Support: This work was sponsored by NuPathe Inc.

  • Conflict of Interest: Dr. Pierce, Ms. O'Neill, and Ms. Sebree are employees of NuPathe. Dr. Marbury is an employee of Orlando Clinical Research Center. Drs. Siegel and Du are consultants to NuPathe.

M. Pierce, NuPathe Inc., 227 Washington Street, Suite 200, Conshohocken, PA 19428, USA.


Objective.— This study evaluated the pharmacokinetic and tolerability profiles of Zelrix™ (NuPathe Inc., Conshohocken, PA, USA), the novel formulation of sumatriptan (formerly known as NP101).

Background.— Migraine is an episodic headache disorder characterized by a combination of neurological, gastrointestinal, and autonomic symptoms. Gastrointestinal disturbances, including nausea, vomiting, and gastric stasis are common and can result in significant impact on treatment. Triptans are 5-hydroxytriptanime1B/1D agonists that work on the trigeminal nerve that is activated during migraine. All triptans approved for use in the US are currently available as oral formulations; however, this may not be the ideal route of administration for many migraineurs. Sumatriptan is also available as a nasal spray and subcutaneous (sc) injection. Therefore, the need to develop improved methods for noninvasive parenteral delivery of triptans remains high.

Methods.— This was a Phase I, single-center, open-label, crossover study that assessed the pharmacokinetic properties of a single dose of sumatriptan delivered using an iontophoretic transdermal patch in comparison with oral, injection, and nasal delivery. Subjects were healthy male and female volunteers who received each of 5 treatments: sumatriptan 100 mg oral tablets, sumatriptan 6 mg sc, sumatriptan 20 mg nasal spray, Zelrix I (transdermal patch with 3 g of gel solution delivering 6 mg of sumatriptan transdermally), or Zelrix II (transdermal patch containing 2.6 g of gel solution delivering 6 mg of sumatriptan).

Results.— The Cmax for Zelrix was reduced to 30% and 28% of the sumatriptan sc dose, thereby reducing the risk of triptan-like sensations associated with high peak plasma concentrations. Plasma concentrations for Zelrix I and Zelrix II were intermediate between those for oral and nasal sumatriptan doses tested. Transdermal patch delivery of sumatriptan to the systemic circulation reached plasma concentrations of 10 ng/mL within about 30 minutes. The mean drug delivery of Zelrix I and II was 6.11 mg (confidence intervals [CI] 5.33-6.88) and 6.09 mg (CI 5.52-6.66), respectively. The AUC0-inf was approximately 99% for the Zelrix I patch and 100% for the Zelrix II patch as compared with sumatriptan 6 mg sc dose. Both doses of sumatriptan transdermal patches were well tolerated. Skin reactions at the patch site were mild and erythema resolved in most subjects within 48-72 hours.

Conclusions.— The results from this study show that sumatriptan administration using a novel iontophoretic transdermal technology delivers plasma levels within the range for nasal spray, tablet, and injectable sumatriptan. Zelrix I and II were well tolerated and adverse events were mild and transient. Transdermal delivery of sumatriptan using the SmartRelief iontophoretic technology may prove beneficial for a large segment of the migraine population based upon fast, consistent delivery of drug and avoidance of common gastrointestinal disturbances associated with migraine.

Sumatriptan belongs to the class of agents known as 5-hydroxytriptanime1B/1D (5-HT1B/1D) agonists.1 The clinical aim for developing this class of drugs focused on finding a pharmacological agent that had receptor selectivity at the trigeminal 5-HT1B/1D receptors believed to be specifically involved in the pathophysiology of migraine.2 It has been 2 decades since Humphrey and colleagues published the first pharmacology papers assessing the clinical profile of sumatriptan as a new class of drug with prospective therapeutic efficacy for the acute treatment of migraine.3 Pharmacological studies show that sumatriptan binds selectivity to the 5-HT1B/1D receptors believed to be involved in the pathogenesis of migraine.

Given its affinity at the 5-HT1B/1D receptor, like subsequently developed triptans, sumatriptan exerts its clinical effects through 1 or more of 4 different proposed mechanisms.2

  • 1Direct contraction of dilated cranial extracerebral blood vessels.
  • 2Suppression of neuropeptide synthesis and release at the peripheral neurovascular junctions in the dura.
  • 3Inhibition of impulse transmission centrally in the trigeminal nucleus caudalis.
  • 4Presynaptic blocking of synaptic transmission between axon terminals of the peripheral trigeminovascular neurons and cell bodies of their central counterparts.

While these proposed mechanisms of action remain under investigation, their therapeutic efficacy in aborting migraine is well established.2 To date, 7 triptans are available for migraine treatment including almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan. These are available in 3 different delivery forms: subcutaneous injection (sumatriptan sc), nasal spray (sumatriptan, zolmitriptan), and oral delivery (all seven are available as oral tablets; rizatriptan and zolmitriptan are available as orally disintegrating tablets). Despite this diverse group of triptans available via multiple routes of administration, patients continue to experience dissatisfaction with their migraine treatment.4 This may be due in part to the long-lasting, disabling nature of migraine often exacerbated by associated symptoms as well as inconsistent response due to variable drug absorption.

Migraine has been identified as one of the top 20 disabling illnesses worldwide, which may be due to the severe pain, nausea, vomiting, and long duration of attacks if left untreated.5 Migraine is unique from other headache types and is specifically diagnosed as a recurrent headache with associated symptoms of nausea, vomiting, and/or sensitivity to light and sound manifesting in attacks that last between 4 and 72 hours.6,7 In some, a migraine is preceded by aura, which is recognized as fully reversible visual, sensory, or language symptoms that often precede the headache phase of migraine.6,8 These are commonly recognized by the patient as shimmering lights, zigzag lines, or even prickling or tingling sensations characteristic of paresthesia.

Burstein and colleagues demonstrated that some migraineurs develop an incomplete response to triptans when treatment is delayed (eg, pain progresses to severe or there is a >2 hours time delay from onset of pain to treatment).9 These studies suggest that early treatment interventions are critical for achieving complete response to triptan therapy. Therefore, for the majority of patients who experience nausea, their possible hesitation to take an oral medication may have considerable consequences. Clinically, Burstein and colleagues suggest that early intervention with triptans is an important component in successful management.9-11 Early sumatriptan intervention has been shown to block development of central sensitization.9 The task, therefore, lies in achieving sufficient plasma levels of triptan medication quickly following the onset of pain, which can often be problematic due to gastric stasis or delayed administration if the patient is experiencing nausea or vomiting. Additionally, the most common reasons for delay of sufficient plasma levels are that patients wait to take their triptan because they are not sure the headache is a migraine and are not sure it will be severe enough.

MacGregor and colleagues show that many patients are dissatisfied with their migraine therapy.4 Reasons for this may include high frequency of adverse events associated with subcutaneous delivery systems, unpleasant taste associated with nasal deliveries, exacerbation of nausea associated with oral deliveries and the need for more rapid, complete, and consistent pain relief without recurrence. Therefore, transdermal delivery systems may prove ideal for migraine and have already been proven effective and well tolerated for a variety of other illnesses (eg, chronic pain, diabetes, hypertension). Indeed, studies report that as many as 30% of patients report that nausea alone interferes with their ability to take an oral triptan.12 Development of a nonoral and noninvasive delivery system to treat migraine could therefore address several limitations to current treatment options.

In an initial Phase I trial, the safety of transdermal iontophoretic delivery of sumatriptan was assessed for the potential acute treatment of migraine.13 The objective of the previous study was to evaluate the pharmacokinetic profile of 4 prototype patches of sumatriptan compared with a sumatriptan 6 mg sc injection and a sumatriptan 50 mg oral tablet. Data from this study showed a linear relationship between electrical current and sumatriptan delivery, supporting the theory that iontophoretic delivery is an effective method of delivering medication. We now report the second study assessing the safety and pharmacokinetic properties of a transdermal iontophoretic delivery of sumatriptan and compare the PK profile with sumatriptan sc, oral, and nasal delivery.


Subjects.— Twenty-five healthy nonsmoking male and female subjects between the ages of 21-57 years were enrolled in a single-center, open-label, single-dose, crossover study to assess the pharmacological profile of a sumatriptan iontophoretic patch for the acute treatment of migraine. Subjects were excluded for the following criteria: clinically significant abnormality, pregnancy, lactation, participation in other clinical study within 90 days, blood donation within 8 weeks, cardiovascular disease, use of concurrent medications (except oral contraceptives), intolerance or sensitivity to triptans, asthma, hypercholesterolemia, and history of drug or alcohol abuse. In accordance with GCP and ICH guidance, a comprehensive informed consent form, written in understandable language, was signed by each subject prior to the investigator entering a given subject into the study.

Treatment Groups.— Subjects received each of 5 different treatments: Zelrix I patch, Zelrix II patch, sumatriptan 100 mg RT® tablet, sumatriptan 6 mg sc injection, and sumatriptan 20 mg nasal spray. The Zelrix I patch contained 3 grams (g) of sumatriptan gel loaded with 120 mg of sumatriptan succinate. The Zelrix II patch contained 2.6 g of gel loaded with 104 mg of sumatriptan succinate. The amount of drug delivered was determined by iontophoretic current. The patch was applied to the upper arm, alternating right and left sides. Subjects fasted overnight prior to, and for 4 hours following, all treatments. A minimum of 3 days was required between treatments.

Patch Technology.— The Zelrix patches were thin disposable, single-use transdermal patches that delivered a low-level electrical current (4 mA for 1 hour followed by 2 mA for 3 hours; 600 mA minutes), which facilitated transport of sumatriptan through the skin (see Fig. 1 for diagram of patch). Each patch was removed after 4 hours.

Figure 1.—.

Illustration of Zelrix. Schematic representation of a Zelrix patch depicting iontophoresis of positively charged sumatriptan from the anode.

Laboratory Assessment and Blood Assays.— During the baseline screening, subjects underwent a general medical exam including collection of vital signs, 12-lead ECG, and standard clinical laboratory blood samples. Blood samples were collected at approximately 0, 15, 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours post dosing for each of the 5 treatment periods. The Zelrix patch and oral conditions had additional samples taken at 16 hours post dosing and the oral treatment arm had samples drawn at 24 hours post dosing as well. Plasma samples were analyzed using a validated HPLC-MS/MS method (PPD, Middleton, VA, USA).13 Standard pharmacokinetic profile for sumatriptan based on actual plasma concentration–time data included calculation of AUC0-24, AUC, Tmax, Cmax, CL, and inline image.

Safety and Tolerability Assessments.— Severity and frequency of adverse events were collected following each treatment, and erythema was rated using a 5-point scale ranging from 0 (no erythema) to 4 (intense erythema with edema and blistering/erosion).13 Examination of the patch site was done at 4 (patch removal), 24, 48, and 72 hours following application. At 72 hours, if erythema scores were higher than 0, subjects were required to return to the clinic on day 10 for further assessment.


Twenty-five subjects were recruited and enrolled in the study and received at least 1 dose of study medication. Sixteen subjects completed all 5 treatment sessions (64%; Fig. 2 and Table 1). Nine subjects did not complete the trial due to: consent withdrawal (n = 4), adverse events (n = 3, none due to the patch delivery system), lost to follow-up (n = 1), and protocol violation (n = 1).

Figure 2.—.

Subject participation flow diagram: The study design and subject flow diagram are depicted.

Table 1.—. Subject Demographics
Mean age36 years
Females12 (48%)
Males13 (52%)
African American8 (32%)
Caucasian14 (56%)
Hispanic2 (8%)
Native American1 (4%)

Plasma concentrations for Zelrix I and Zelrix II were intermediate between those for oral and nasal sumatriptan doses tested. Specifically, both treatments for Zelrix fell between the plasma concentration–time profiles of sumatriptan 20 mg nasal spray and sumatriptan 100 mg tablets (Fig. 3). Cmax was 24.8 ng/mL for Zelrix I, 23.1 ng/mL for Zelrix II, 82.2 ng/mL for sumatriptan 6 mg sc, 12.5 ng/mL for sumatriptan 20 mg nasal spray, and 51.6 ng/mL for sumatriptan 100 mg RT tablet (Table 2). The Cmax was about 30% and 28% of the subcutaneous injection levels for Zelrix I and Zelrix II, respectively (Fig. 3). The coefficient of variation, which measures the degree of variability, was qualitatively lower for the sc injections and Zelrix than either the oral or nasal medications (Table 2).

Figure 3.—.

Sumatriptan plasma concentrations: The plasma concentrations over time are represented for each formulation. Note that Zelrix patches provide Cmax, which is intermediate between the higher values for subcutaneous and oral formulations and lower level of the nasal preparation. The sumatriptan serum concentration from Zelrix was maintained at a level of approximately 20 ng/mL until cessation of iontophoretic delivery at 4 hours, after which the concentration declined in a manner comparable with other routes of administration. sc – subcutaneous.

Table 2.—. Pharmacological Parameters for Sumatriptan From Each Route of Administration
Treatment groupAUC0-infCmaxTmaxT1/2AUC0-infCmax
SumatriptanHour*ng/mLng/mLHourHourCV (%)CV (%)
sc 6 mg (n = 23)113.682.
Nasal spray 20 mg (n = 23)50.312.
Oral 100 mg (n = 23)
Zelrix I (n = 17)113.524.81.72.924.726.4
Zelrix II (n = 17)112.923.12.52.918.021.6
Dose deliveredMeanCV (%)
  1. Zelrix delivers AUC comparable with that of the sc formulation with lower Cmax. Also, Zelrix and sc routes of administration have lower coefficient of variation relative to oral and nasal formulations, suggesting greater predictability in achieving target drug levels.

  2. CV, coefficient of variation.

Zelrix I6.11 mg24.70
Zelrix II6.09 mg18.20

Sumatriptan was detected in plasma as early as 15 minutes following administration with both Zelrix I and Zelrix II, which was similar to the oral and nasal delivery systems of sumatriptan (Fig. 3). Tmax was shortest for sumatriptan 6 mg sc (0.3 hour) and longest for sumatriptan 100 mg RT (2.2 hours) and Zelrix II (2.5 hours). Of note, Tmax for Zelrix patches describes the highest point during a period of constant release rather than a peak, rendering Tmax as a less meaningful indicant of the pharmacokinetic profile. This may also contribute to the apparent difference in Tmax between Zelrix I and II. The half-life (T1/2) was longest for sumatriptan 100 mg RT (4.8 hours) and shortest for sumatriptan 6 mg sc (2.2 hours; Table 2).

For total exposure to sumatriptan, the Zelrix formulations were lower than sumatriptan 100 mg RT tablets but higher than that of the 20 mg nasal formulation and approximately equal to the sumatriptan 6 mg sc (Table 2). The AUC0-inf was approximately 99% for Zelrix I and 100% for Zelrix II of the sc injection. There were no significant differences between male and female subjects in PK parameters for Zelrix. No significant differences in AUC and Cmax were observed between sex subgroups after oral, nasal, or subcutaneous treatments.

Safety and Tolerability.— There were no serious adverse events reported in this study. The tolerability profiles of the 3 sumatriptan control groups reflect the recognized adverse events associated with the respective deliveries of sumatriptan, including the increase in events noted with sumatriptan 6 mg sc. Zelrix was well tolerated and there were no unexpected adverse events or significant increases in the frequency of reported adverse events in subjects receiving Zelrix I or Zelrix II treatments. Adverse events associated with Zelrix were generally mild and most resolved without further treatment (Table 3).

Table 3.—. Adverse Events of Different Formulations of Sumatriptan (Adverse Events Reported in More Than One Person Across the 5 Treatment Groups)
Preferred termSubcutaneous sumatriptan (n = 23)Oral sumatriptan (n = 23)Nasal spray (n = 23)Zelrix I (n = 17)Zelrix II (n = 17)
  • There were no unexpected adverse events or a significant increase in the frequency of commonly reported adverse events in subjects receiving the Zelrix patch treatments compared with oral, nasal, and subcutaneous injection formulations of sumatriptan. Adverse events were also categorized into 2 special groupings: (1) atypical sensations (ie, sensation of warmth/cold, paresthesias) and (2) pain and pressure sensations. Atypical sensations, and pain and pressure sensations, which are commonly reported for the subcutaneous injection and for the oral tablet of sumatriptan, were not reported following Zelrix patch applications. All adverse events that occurred in more than 1 patient are included.

  • Atypical sensation includes burning sensation mucosal, ear discomfort, facial pain, feeling hot, flushing, head discomfort, hot flush, sensation of heaviness, and sensation of pressure.

  • Pain and pressure includes sensation of heaviness and sensation of pressure.

Headache8 (35%)3 (13%)3 (13%)2 (12%)
Flushing6 (26%)
Nausea3 (13%)
Burning sensation mucosal3 (13%)
Hot flush3 (13%)
Throat irritation2 (9%)
Feeling hot2 (9%)
Sensation of pressure2 (9%)
Sensation of heaviness2 (9%)
Dizziness2 (9%)
Dysphagia3 (13%)
Application site pruritus7 (41%)4 (24%)
Neck pain2 (9%)
Atypical sensation14 (61%)2 (9%)
Pain and pressure sensation2 (9%)4 (17%)

The most common adverse events were noted with sumatriptan 6 mg sc treatment included atypical sensations of warmth/cold and paresthesias (61%) and flushing (26%), which may have been associated with the higher Cmax of the sc injection, and to a lesser extent, oral administration. No atypical sensations were observed with either patch delivery. Headache occurred for all types of administration, while dysphagia was only seen among the oral group. The most common adverse event associated with the Zelrix patch delivery was application site pruritus. Immediately upon removal of Zelrix patches, skin irritation scores were measured with most (>75%) of subjects experiencing minimal or no skin erythema upon patch removal (Fig. 4). After 48 hours, all subjects had minimal or no erythema. There were no subjects reporting skin irritation score of 3 or 4 at any time during this study. No subject withdrew from the study due to skin irritation.

Figure 4.—.

Skin erythema scores: The mean skin erythema score for Zelrix I and Zelrix II are shown at 4 hours (patch removal), 24 hours, 48 hours, and 72 hours post administration.


The results from this second pharmacokinetic study show that approximately 6.1 mg of sumatriptan is delivered to the systemic circulation following Zelrix I application. The Cmax following treatment with Zelrix falls between those plasma concentrations of 20 mg nasal spray (12.5 ng/mL) and sumatriptan 100 mg RT oral tablets (51.6 ng/mL) demonstrating similar plasma concentrations to those found with other noninvasive deliveries of sumatriptan (oral and nasal spray).

Relative to sumatriptan 6 mg sc, the Cmax for Zelrix was approximately 30% for Zelrix. The lower peak plasma level for Zelrix may be a positive clinical attribute based on the noted lack of triptan-associated adverse events with the Zelrix patch. This is likely to be due to the lower peak plasma concentration (Cmax) relative to both sc and oral formulations. Duration of action is another potentially clinically relevant difference between sc sumatriptan and the Zelrix patch. Sumatriptan 6 mg sc is rapidly cleared from the blood, and by 2 hours plasma concentrations fall below the Zelrix levels. Plasma sumatriptan levels delivered using the Zelrix device are sustained through 5 hours following treatment due to the controlled, infusion-like profile, which may have beneficial therapeutic implications.

The results of this pharmacological study show that the Zelrix delivery may offer an effective nonoral, noninvasive alternative for migraineurs needing acute triptan treatment. The migraine patients that may find this delivery system particularly helpful are those with gastrointestinal symptoms (eg, nausea, vomiting) frequently associated with their migraine attacks. Transdermal delivery of sumatriptan may prove particularly helpful for migraineurs with gastric stasis, a phenomenon identified in migraineurs and thought to alter gastrointestinal absorption of oral medications.14 Because nausea may cause sufferers to delay taking oral medication, transdermal administration of sumatriptan may increase the willingness of patients with nausea to treat early. In a study by Silberstein and colleagues, the presence of nausea interfered with the patient's ability and willingness to take an oral medication in 30% of migraine sufferers and 42% of those who experience vomiting.12 Treatment options that provide nonoral and noninvasive delivery of effective medication may help reduce the pain and burden associated with acute migraine episodes. However, the 6-mg sumatriptan sc injection may be associated with adverse events either at the injection site or from high circulating plasma concentrations. A 4-mg sumatriptan injection is also available and is associated with less injection site reactions and other side effects, possibly due to a lower peak serum level.

Another advantage of transdermal delivery is the benefit of drugs bypassing first-pass metabolism. Oral medications are absorbed through the gastric mucosa prior to first-pass hepatic metabolism. Similarly, with nasal delivery some of the nasal dose of sumatriptan or zolmitriptan is swallowed, and therefore enters the systemic circulation through gastric absorption in addition to modest nasopharyngeal absorption.15 Additionally, interindividual variation in cytochrome P450 enzymes and concomitant drugs that lead to induction or inhibition of liver enzymes can reduce the consistency of circulating plasma concentrations with oral medications. As highlighted in Table 2, Zelrix had lower coefficients of variation than oral or nasal routes of administration, supporting the hypothesis that parenteral administration leads to more consistent and predictable serum concentrations.

This study shows that the pharmacokinetic profile of Zelrix is similar to other clinically effective deliveries of sumatriptan, including oral, nasal, and sc treatments. One limitation to the current study is the relatively small sample size and high dropout rate. Furthermore, the development of new technologies requires a significant amount of education and training in order to get healthcare professionals and patients familiar and comfortable with new approaches to treatment. However, transdermal medications are being used successfully to treat a number of other conditions such as nicotine dependence, attention deficit hyperactivity disorder, Parkinson's disease, and chronic pain syndromes, all of which suggest that transdermal delivery may be applied to migraine as well.

This is the second study to show that transdermal iontophoretic delivery of sumatriptan may offer an improved way of consistently delivering medication through noninvasive and nonoral routes that bypass known gastrointestinal issues associated with migraine. While larger clinical trials are necessary to fully assess the efficacy, safety, and tolerability profile of Zelrix, these data suggest transdermal delivery of sumatriptan with Zelrix may provide fast, effective relief of acute migraine and may reduce the risk of classic triptan-related adverse effects.


Acknowledgment: The authors wish to thank Starr H. Pearlman, PhD, for her editorial assistance.


Category 1

  • (a)Conception and DesignCarol O'Neill; Terri Sebree; Mark Pierce; Steven Siegel
  • (b)Acquisition of DataThomas Marbury
  • (c)Analysis and Interpretation of DataWei Du

Category 2

  • (a)Drafting the ArticleSteven Siegel
  • (b)Revising It for Intellectual ContentSteven Siegel; Mark Pierce; Terri Sebree; Carol O'Neill

Category 3

  • (a)Final Approval of the Completed ArticleSteven Siegel; Mark Pierce; Terri Sebree