THE SMALL MOLECULE TERAMEPROCOL (tetra-O-methyl nordihydroguaiaretic acid, also called M4N, EM1421), derived from the plant Larrea tridentata, demonstrates antiviral properties.1–5 Terameprocol specifically blocks the Sp1 transcription factor from binding to the human immunodeficiency virus (HIV) long-terminal repeat, thus inhibiting Tat-driven transactivation of the HIV long-terminal repeat promoter. Terameprocol also inhibits Sp1-regulated production of human papillomavirus (HPV) E6 and E7 proteins (anti-HPV).6 Terameprocol causes inhibition of transcription from the herpes simplex virus type 1 (HSV-1) ICP4 gene promoter and interferes with Sp1 protein binding to cognate sites on the HSV-1 ICP4 gene promoter.7,8 Terameprocol may potentially inhibit replication of 3 major sexually transmitted viruses, HIV, HPV, and HSV, and thus be highly useful as a vaginal microbicide in reducing transmission on sexual exposure to these viruses. The lipophilic properties of terameprocol support potential use as a topical agent in humans (Fig. 1).
Terameprocol as a Vaginal Microbicide in HIV Sexual Transmission
The potential use of terameprocol as a vaginal microbicide effective against HIV, HPV, and HSV is supported by the following: (a) an excellent safety profile in preliminary studies in human volunteers with CIN using topical terameprocol9 (b) wide therapeutic index (high efficacy and low toxicity); (c) a broad therapeutic spectrum against sexually transmitted infections; (d) a two-pronged approach in the prevention of HIV and related sexually transmitted diseases; (e) a potential mechanism to bridge the gaps in vaccine coverage worldwide for HPV vaccine and in the future for HIV and HSV vaccines. The terameprocol ointment has previously been used in a phase I clinical trial conducted in 7 women using a classic 3-dose study in women with HPV-linked cervical intraepithelial neoplasia. This study extensively used colposcopy in safety assessments and an excellent safety profile has been shown.9
HIV is a worldwide epidemic with 4.3 million new acquired infections in adults and children per day.10 Despite the knowledge of successful HIV prevention strategies (i.e., condom use, reduction in the number of sexual partners, diagnosis, and treatment of sexually transmitted infections), HIV continues to spread at an alarming rate, especially among heterosexual women in developing countries. The development and use of a safe, effective, and acceptable microbicide will empower women and present a viable option to protect themselves from HIV and other organisms that cause sexually transmitted infections.
HPV and HSV infections have a high prevalence in reproductive-age women.11,12 The advent of the HPV vaccine has the promise of enhancing global cervical cancer control in the future in combination with HPV screening and treatment.13 In the interim, there are opportunities for the development of terameprocol topical application to decrease genital transmission of HPV. Genital herpes is a common sexually transmitted infection throughout the world. Important implications of having genital herpes include the risk of transmission to sexual partners and the increased risk of acquiring and transmitting HIV. Use of an effective vaginal microbicide is expected to offer benefits to reproductive age women by reducing the likelihood of HIV, HPV, and HSV disease transmission.14
Terameprocol is a host-dependent antiviral agent and, unlike viral factors, host factors are under no selective pressure to mutate and are in general structurally invariable. In comparative studies of mutation insensitivity between terameprocol and acyclovir, there was no increase in the IC50 of terameprocol against HSV-1 following 10 passages of virus, indicating HSV-1 was incapable of developing resistance to terameprocol over the short term. In contrast, the IC50 of acyclovir increased from 7.54 μmol/L in the first passage to 444 μmol/L in the tenth passage of HSV-1.8
Toxicology Studies of Terameprocol
Cottontail rabbit vaginal irritation toxicology studies, which were conducted before phase I/II, used 20 mg of terameprocol vaginal ointment (concentration of 200 mg/mL) applied to the rabbit vagina daily for 14 days. No evidence of vaginal irritation or systemic toxicity was noted. In toxicokinetic studies of terameprocol intravenous administration in dogs, doses up to 90 mg/kg were administered with reversible CNS toxicity at the highest dose. In human clinical studies, doses up to 3300 mg (∼45 mg/kg) have been administered intravenously, with generally good tolerability.9
Our central hypothesis is that terameprocol at a 2% ointment formulation using a daily dosing schedule for 7 days has a low toxicity profile and is thus a viable antiviral candidate for topical use as a vaginal microbicide. Supported by prior animal and human data on terameprocol, we conducted a phase I clinical trial in healthy female volunteers using daily application of topical vaginally applied ointment to study safety, tolerability, and pharmacokinetics and explore the maximum tolerated dose and the toxicity profile.
Population and Methods
Clinical Trial Site
The clinical trial was conducted at Pharmaceutical Profiles Ltd., Nottingham, UK. This study was approved by an Independent Ethics Committee recognized by the United Kingdom Ethics Committee Authority for the review of clinical trials of investigational medicinal products. This study was conducted in accordance with the Clinical Protocol (Amendment 01, January 20, 2006), with the International Conference on Harmonization Good Clinical Practice Guideline approved by the Committee for Proprietary Medicinal Products on July 17, 1996, which came into force on January 17, 1997, the Medicines for Human Use (Clinical Trials) Regulations 2004, and according to the ethical principles that originated with the Declaration of Helsinki (2004).15
Subject Information and Consent
Before the commencement of the study (i.e., before screening) all participants underwent informed consent procedures and were given the opportunity to ask questions from study personnel.
Healthy subjects were recruited by the site in Nottingham, UK, and inclusion criteria included women aged 18 years and above, capable of giving informed consent, body mass index between 18 and 35 kg/m2 with (a) regular menstrual cycles; (b) postmenopausal; or (c) taking hormonal methods of contraception with a current negative pregnancy test were recruited. Subjects agreed to refrain from sexual activity from the first application until 72 hours after the last drug application in each study period to prevent exposure of their partners to the study drug. In addition, subjects agreed to use 2 forms of contraception from 72 hours after the last drug application until 1 week after the last drug application, one of which was to be a condom. Postmenopausal women were required to use a condom (to prevent exposure of their partners to the study drug). Exclusion criteria included prior participation in a clinical research study involving investigational drugs or dosage forms within the previous 3 months and women with a current or history of substance abuse. Also excluded were pregnant or breast-feeding women, those with HIV, hepatitis B virus, hepatitis C virus, or at risk for genital infections or HIV, had significant metabolic or other diseases, structural abnormality of the female genital tract, or allergy to the study drug.
A double-blind placebo controlled phase I dose tolerability and pharmacokinetic crossover study of terameprocol vaginal ointment administered daily intravaginally for 7 days to 14 healthy female volunteers was conducted between January 2006 and May 2006. There were 5 postmenopausal women included in this study. The study consisted of 2 study periods for using the terameprocol vaginal cream and the placebo, of approximately 7 days duration each. A minimum of 7 days for washout was included between the 2 study periods and the study periods were scheduled around regular menstrual cycles to ensure continuity of 7-day application of medication or placebo. Subjects attended the clinical unit on days 1 and 7 of each study period and were dosed with terameprocol at the clinic. Medication was administered in the morning to all subjects followed by observation and pharmacokinetic studies were performed at specified times over a period of 6 hours. Subjects were required to self-administer at home on days 2 to 6 of each study period at approximately the same time every morning.
Formulation of the Terameprocol Vaginal Ointment and Administration
Terameprocol was formulated as a 2% w/w ointment in white petrolatum, packaged in 5 mL containers and remained stable at room temperature for 6 months. A total volume of approximately 5 mL was applied to the cervix by self-application by the female participants using a disposable vaginal applicator. Placebo formulation comprised white petrolatum, with no active ingredient, packaged similarly using a 5 mL container and disposable vaginal applicator.
The study entailed a double-blind, randomized daily dose crossover design with a focus on dose tolerability and pharmacokinetics.
- Regimen A: Approximately 90 mg terameprocol (5 mL 2% w/w ointment) in white petrolatum administered intravaginally (via an applicator by the subject) once per day for 7 days followed by a gap of 7 days before Regimen B.
- Regimen B: Placebo ointment with white petrolatum, administered intravaginally (via an applicator by the subject) once per day for 7 days.
Safety assessments were performed per protocol on days 1 and 7 of the study are listed in Table 1. All participants were given a daily diary card to record any new symptoms and to report this to clinical trial personnel. Before the first administration, subjects were provided with training on the self-administration of the terameprocol ointment using the applicator. Training was both oral and written and was provided at the screening visit at a specific visit planned for training or on day 1 of the study period. Additionally, when the subjects were at the clinical unit for the first administration, staffs were available to assist or provide further explanation, if required. At the day 1 visit, all subjects received a thorough examination and laboratory tests as outlined in Table 1, including, a test for HIV, hepatitis C virus, hepatitis B virus, test for alcohol and illicit drugs, and an electrocardiogram. (No cardiotoxicity of the terameprocol was observed in preclinical and animal studies of terameprocol. Formal cardiotoxicity and hERG studies had not been completed at the time of the study and therefore we requested additional electrocardiograms for safety evaluation.) An examination of the vagina was done by a clinical research physician on day 1 (predose and postdose), and day 7 (postdose). The purpose of the examinations was to look for any signs of local mucosal irritation resulting from drug application. On day 7, all the patients received adverse events (AE) questioning.
Toxicity Grading and Response Criteria
Systemic Toxicity Grading Scale
Systemic toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (Version 2.0).16
Local Toxicity Grading at Treatment Site
Local toxicity was graded by evaluating the treatment site. After terameprocol administration, each subject self-reported mucosal reactions including erythema, swelling, bleeding/hemorrhage, necrosis, erosion, ulceration, and eschar formation. It was anticipated that subjects would not experience toxicities above grade 1. In addition, clinical vaginal examination included an assessment of vaginal mucosal toxicity.
Mucosal Local Toxicity Grading Scale
- Grade 1: Erythema, injection, mild pain not requiring analgesics, or mild itching not requiring therapy.
- Grade 2 (mild): Patchy mucositis, might develop inflammatory serosanguinous discharge, moderate pain requiring nonnarcotic analgesic.
- Grade 3 (moderate): Confluent fibrinous mucositis, severe pain requiring narcotic.
- Grade 4 (severe): Ulceration, hemorrhage, or necrosis.
- Plan for intervention: Subjects were to have been discontinued from therapy if they had a grade 2 reaction or higher. If such AE occurred (grade 2 or higher), subjects were to have been treated appropriately on a case-by-case basis by, e.g., analgesia, topical antibiotics etc., and would not receive further study medication.
Pharmacokinetic assessments were performed on days 1 and 7 of the study and blood samples were taken at 1, 2, 4, and 6 hours after dosing. The selection of time periods of observation for pharmacokinetics was based on data from the rabbit vaginal irritation study where absorption into the blood was noted to start at 30 minutes and peak at 1 hour followed by a slow decline. Venous blood samples (5 mL) were withdrawn via an intravenous cannula or by venepuncture into nonheparinized blood/serum sampling tubes without serum/clot activators. The total amount of blood taken from each subject for the study, including pre- and poststudy laboratory tests, was 114 mL. The samples were allowed to clot for at least 30 minutes and then centrifuged at approximately 1600g for 10 minutes at 4°C. The serum fraction was split into 2 aliquots and frozen in labeled polypropylene tubes (cryovials) at approximately −20°C until the end of each study period and then at −70°C or below until required for assay at Covance, US. Pharmacokinetic studies were done using sensitive high performance liquid chromatographic assays with mass spectrometric detection.
The lower limit of detection of terameprocol was 1 ng/mL in the serum with precision values ≤5% and accuracy of ≤15% relative error, respectively.
Clinical monitors were responsible for reviewing protocol compliance, monitoring patients’ medical records, assessing drug accountability, and adherence to regulatory requirements throughout the clinical trial and at clinical trial closeout. Protocol deviations were minor.
Data Management and Statistics
Clinical data quality control comprised regular reviews of the clinical study data, within a few days after acquisition, by clinical research associates. Data were reviewed for completeness and a sense check of critical items was made. Any missing or questionable data were flagged for review and completion or correction by trained personnel. Transcribed data were checked against source documents.
No formal statistics were performed. Data listings and summary statistics (N, mean, standard deviation, minimum, maximum) were tabulated, where applicable, by Regimen. Analysis of safety also included tabulation of incidence of AE.
Application of terameprocol vaginal ointment and daily vaginal application was well tolerated and safe. There was no absorption of the terameprocol into the blood.
Thirty-two subjects were screened for this study, of which 17 met the entrance criteria. One subject was rejected at admission and 1 subject was eligible but not required for this study due to adequate number of participants. One subject was not dosed on day 7 of study period 1 as she was menstruating, and 14 subjects completed the study. Protocol deviations were minor during the conduct of this clinical trial.
Fifteen healthy females met inclusion criteria and entered the study. Their age range was 23 to 68 years (mean 39.3 years), mean height was 166.2 cm, the mean weight was 68.34 kg and all were within the normal range of weight for height as required by the clinical protocol. None had history or evidence of substance abuse.
Fourteen subjects completed the study. No significant changes were seen in any of the measured laboratory parameters and the vital signs measured.
Terameprocol 90 mg (2% w/w ointment dosing strength) was well tolerated. AE which occurred were sporadic, did not follow a consistent pattern, and were not directly attributable to terameprocol. In addition, none of the AE was considered to be serious.
Observed AE which were not directly attributable to administration of the terameprocol vaginal ointment are listed in Table 2. Headaches were reported in 3 subjects, upper respiratory tract infections in 2, application site irritation in 1 subject, abdominal pain in 1, groin pain in 1, and tooth abscess in 1 subject. It is conceivable that application site irritation is directly linked to the medication and this observation will be studied further in future clinical trials. However, none of the observed effects had a consistent pattern.
There was no detection of terameprocol in pharmacokinetic samples.
This phase I trial explored an innovative application of terameprocol antiviral properties for use as a topical vaginal microbicide. Healthy female subjects were recruited into this phase I clinical trial to explore safety, tolerability, and pharmacokinetics to support the development of terameprocol as a vaginal microbicide. Large doses of terameprocol up to a maximum of 630 mg/wk were used in this daily application study with an excellent safety profile, providing support for further clinical evaluation of terameprocol as a self-administered vaginal microbicide. Terameprocol was found to be both safe and well tolerated.
The duration of contact of the ointment with the cervico-vaginal tissues is anticipated to have been brief, although the subjects were allowed to self-medicate and ambulate shortly after application of the ointment and no devices, such as diaphragms or pessaries, were used to increase the duration of contact of the ointment with the cervico-vaginal tissues. In contemporary research, the use of diaphragms in microbicide delivery is becoming a popular method in clinical studies.17–20. Using a device with a cream increases the patient effort required for the regular use of a vaginal cream to reduce transmission of HIV and prevent other STDs such as HPV and HSV. In microbicide research, cognizance is needed of the fact that vaginal microbicides will only become a daily part of women’s lives if administration is a simple one step procedure with low or nil side effects and high effectiveness.21,22 Thus, it is conceivable that the development of novel drug delivery mechanisms versus devices for the delivery of topical vaginal microbicides will ultimately prevail.
There are several studies in literature that support the development of drug delivery systems which are bioadhesive to human epithelia. One such system has been studied in buccal delivery of nicotine in the oral cavity, where the formulation N2, containing hydroxypropyl methylcellulose and polycarbophil as the bioadhesive polymers, has shown suitable adhesion and an initial burst release of 40% drug in first 15 minutes followed by a total 80% drug release in a characteristic manner until 4 hours.23 The development of a similar vaginal drug delivery systems would greatly enhance the usability and effectiveness of terameprocol as a vaginal topical microbicide.
The dosage and dosing interval of the terameprocol vaginal ointment used in this study was based on prior human and animal studies and used less than 10% of doses administered safely intravenously. We found no toxicity and no significant AE that were directly attributable to the use of 5 mL of terameprocol ointment in the 2% w/w (90 mg) vaginal ointment dosage that was selected. In 1 participant using 2% ointment, application site irritation was noted. The observation of isolated irritation would suggest the need for future vaginal milieu tests specifically to study the impact of selected dosage of terameprocol on the normal vaginal flora including lactobacilli, and on common vaginal candida, bacterial, and trichomonas infections. In addition, effects of vaginal secretions and semen on terameprocol as a vaginal microbicide would be important observations relevant to future clinical trials. Several previous studies have elucidated in vitro and animal models for preclinical tests of candidate microbicides, which will be adapted for use in terameprocol research in the future.24–26 Abdominal pain was observed in 1 subject, and was transient and self-limited and not thought to be directly attributable to the effects of the drug. However, this observation will need further evaluation in future clinical trials. We found that the use of 7 daily doses of vaginally applied terameprocol was very well tolerated and had an excellent safety profile. However, in future phase II studies it is possible that the formulation of the terameprocol into an epithelial bioadhesive gel form and/or use of a device for delivery may be developed to optimize drug delivery. Future dosing schedules will likely be prolonged to allow longer periods of observation. Terameprocol has the additional advantage of dosing schedule, low cost for manufacture, and efficacy in preclinical studies.
Recent research found that frequent use of N-9 by sex workers increased the risk of HIV transmission, compared with placebo, possibly by increasing mucosal irritation, inflammatory response and epithelial disruption.27–31 In addition, use of N-9 is known to increase the susceptibility of mice genital epithelium to infection with HPV and carageenan has been shown to reduce susceptibility to HPV.32 Terameprocol studies of the local vaginal milieu and local cervical inflammatory cytokines may need to be conducted in an in vitro model before progression to future human trials of efficacy.24,26,33 Thus, it is conceivable that the use of terameprocol may be as an independent formulation versus its formulation with other complementary medications for optimal microbicide effects to enhance drug delivery. Carefully conducted vaginal milieu tests could study the impact of the terameprocol on the local vaginal flora and the effects of vaginal secretions and sperm on the terameprocol. Also conceivable is the use of terameprocol as a microbicide in women with HIV in the future. Consideration should be given to a future study of women with HIV with and without HAART to study the shedding of HIV in women using vaginal terameprocol.34 Terameprocol used systemically has been shown to have anticancer effects and in the future, the vaginal ointment needs a similar series of studies to elucidate the anticancer effects.35
Terameprocol vaginal cream formulated in white petroleum used daily has shown promising in vitro results and has been shown to have an excellent safety profile in the study outlined here. These results support the progression of terameprocol in further efficacy studies to support its application as a vaginal microbicide.
1. Gnabre JN, Brady JN, Clanton DJ, et al. Inhibition of human immunodeficiency virus type I transcription and replication by DNA sequence-selective lignans. Proc Natl Acad Sci U S A 1995; 92:11239–11243.
2. Hwu JR, Tseng WN, Gnabre J, et al. Antiviral activity of methylated nordihydroguaiaretic acid (I) synthesis, structural identification and inhibition of Tat regulated HIV transactivation. J Med Chem 1998; 41:2994–3000.
3. Dohm JA, Hsu MH, Hwu JR, et al. Influence of ions hydration and the transcriptional inhibitor P4
N on conformations of the Sp1 binding site. J Mol Biol 2005; 349:731–744.
4. Heller JD, Kuo J, Wu TC, et al. Tetra-O
-methyl nordihydroguaiaretic acid induces G2 arrest in mammalian cells and exhibits tumoricidal activity in vivo. Cancer Res 2110; 61:5499–5504.
5. Lambert JD, Meyers RO, Timmermann BN, et al. Tetra-O
-methyl nordihydroguaiaretic acid inhibits melanoma in vivo. Cancer Lett 2001; 171:47–56.
6. Craigo J, Callahan M, Huang RC, et al. Inhibition of human papillomavirus 16 gene expression by nordihydroguaiaretic acid plant lignan derivatives. Antiviral Res 2000; 47:19–28.
7. Park R, Giza PE, Mold DE, et al. Inhibition of HSV-1 replication and reactivation by the mutation-insensitive transcription inhibitor tetra-O
-glycyl-Nordihydro-guaiaretic acid. Antiviral Res 2003; 58:35–45.
8. Chen HS, Teng L, Li JN, et al. Antiviral activities of methylated nordihydroguaiaretic acid. 2. Targeting herpes simplex virus replication by the mutation insensitive transcription inhibitor tetra-O
-methyl-NDGA. J Med Chem 1998; 41:3001–3007.
9. Khanna N, Dalby R, Tan M, et al. Phase I/II clinical safety studies of terameprocol vaginal ointment. Gynecol Oncol 2007; 107:554–562.
11. Dunne EF, Unger ER, Sternberg M, et al. Prevalence of HPV infection among females in the United States. JAMA 2007; 297:813–819.
13. Agosti JM, Goldie SJ. Introducing HPV vaccine in developing countries-key challenges and issues. N Engl J Med 2007; 356:1908–1910.
14. Roberts C. Genital herpes in young adults: Changing sexual behaviours, epidemiology and management. Herpes 2005; 12:10–14.
17. Williams DL, Newman DR, Ballagh SA, et al. Phase I safety trial of two vaginal microbicide gels (acidform or buffergel) used with a diaphragm compared to KY jelly used with a diaphragm. Sex Transm Dis 2007; 34:977–984.
18. Guest G, Johnson L, Burke H, et al. Changes in sexual behavior during a safety and feasibility trial of a microbicide/diaphragm combination: An integrated qualitative and quantitative analysis. AIDS Educ Prev 2007; 19:310–320.
19. Barnhart KT, Rosenberg MJ, MacKay HT, et al. Contraceptive efficacy of a novel spermicidal microbicide used with a diaphragm: A randomized controlled trial. Obstet Gynecol 2007; 110:577–586.
20. Hardy E, Hebling EM, Sousa MH, et al. Delivery of microbicides to the vagina: Difficulties reported with the use of three devices, adherence to use and preferences. Contraception 2007; 76:126–131.
21. Joglekar N, Joshi S, Kakde M, et al.; HIV Prevention Trial Network 047 Protocol Team. Acceptability of PRO2000 vaginal gel among HIV un-infected women in Pune, India. AIDS Care 2007; 19:817–821.
22. Doh AS, Ngoh N, Roddy R, et al. Safety and acceptability of 6% cellulose sulfate vaginal gel applied four times per day for 14 days. Contraception 2007; 76:245–249.
23. Garg S, Kumar G. Development and evaluation of a buccal bioadhesive system for smoking cessation therapy. Pharmazie 2007; 62:266–272.
24. Galen BT, Martin AP, Hazrati E, et al. A comprehensive murine model to evaluate topical vaginal microbicides: Mucosal inflammation and susceptibility to genital herpes as surrogate markers of safety. J Infect Dis 2007; 195:1332–1339.
25. Patton DL, Sweeney YT, Balkus JE, et al. Preclinical safety assessments of UC781 anti-human immunodeficiency virus topical microbicide formulations. Antimicrob Agents Chemother 2007; 51:1608–1615.
26. Cummins JE Jr., Guarner J, Flowers L, et al. Preclinical testing of candidate topical microbicides for anti-human immunodeficiency virus type 1 activity and tissue toxicity in a human cervical explant culture. Antimicrob Agents Chemother 2007; 51:1770–1779.
27. Van Damme L, Niruthisard S, Atissok R, et al. Safety evaluation of nonoxynol-9 gel in women at low risk of HIV infection. AIDS 1998; 12:433–437.
28. Van Damme L, Chandeying V, Ramjee G, et al. Safety of multiple daily applications of COL-1492, a nonoxynal-9 vaginal gel among female sex workers. AIDS 2000; 14:85–88.
29. Van Damme L, Ramjee G, Vuvlsieke B, et al. Effectiveness of COL-1492, a nonoyxnol-9 vaginal gel, on HIV-1 transmission in female sex workers: A randomized trial. Lancet 2002; 360:971–977.
30. Marais D, Carrara H, Kay P, et al. The impact of the use of COL-1492, a nonoxynol-9 vaginal gel, on the presence of cervical human papillomavirus in female sex workers. Virus Res 2006; 121:220–222.
31. Hillier SL, Moench T, Shattock R, et al. In vitro and in vivo: The story of nonoxynol 9. J Acquir Immune Defic Syndr 2005; 39:1–8.
32. Jeffrey N, Roberts JN, Buck CB, et al. Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan. Nat Med 2007; 13:857–861.
33. Trifonova RT, Pasicznyk JM, Fichorova RN. Biocompatibility of solid-dosage forms of anti-human immunodeficiency virus type 1 microbicides with the human cervicovaginal mucosa modeled ex vivo. Antimicrob Agents Chemother 2006; 50:4005–4010.
34. Graham SM, Holte SE, Peshu NM, et al. Initiation of antiretroviral therapy leads to a rapid decline in cervical and vaginal HIV-1 shedding. AIDS 2007; 21:501–507.
35. Lopez RA, Goodman AB, Rhodes M, et al. The anticancer activity of the transcription inhibitor terameprocol (meso-tetra-O-methyl nordihydroguaiaretic acid) formulated for systemic administration. Anticancer Drugs 2007; 18:933–939.