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Journal of Cardiovascular Pharmacology:
doi: 10.1097/FJC.0b013e3181673be0
Original Article

Pharmacology and Safety of Tetradecylthioacetic Acid (TTA): Phase-1 Study

Pettersen, Reidar J MD*; Salem, Mohamed MD, PhD*; Skorve, Jon PhD†‡; Ulvik, Rune J MD, PhD†‡; Berge, Rolf K PhD†‡; Nordrehaug, Jan Erik MD, PhD*

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Author Information

From the *Department of Heart Disease, Haukeland University Hospital, Bergen, Norway; †Institute of medicine, University of Bergen and ‡Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway.

Received for publication December 17, 2007; accepted June 4, 2008.

The authors state that they have no financial interest in the products mentioned within this article.

Reprints: Reidar J. Pettersen, MD, Haukeland University Hospital, Department of Heart Disease N-5021 Bergen, Norway (e-mail: rpet@helse-bergen.no).

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Abstract

This study describes the clinical, hematological, and biochemical safety of tetradecylthioacetic acid (TTA). A total of 18 healthy volunteers were included. Subjects were randomly assigned into 3 groups according to the daily given dose of TTA: group 1 (200 mg), group 2 (600 mg), and group 3 (1000 mg). TTA was given as a single oral dose for 7 consecutive days. Safety was evaluated by following the adverse events, vital signs, and hematological and biochemical parameters in blood and urine samples. Efficacy was estimated through its effects on plasma lipids profile. Few adverse events of mild severity were reported. No clinically significant changes were observed in the hematological or clinical chemical parameters in blood/urine. TTA did not induce significant changes in the blood lipids or free fatty acids, but it did result in an increase in plasma concentration of Δ9 desaturated TTA (TTA: 1n-8). Serum concentration pattern of TTA at day 1 showed a 1.5-hour lag time followed by a rapid absorption and a slower elimination phase. The median peak values were 2.9 mg/L (range, 1.1 to 5.4 mg/L), 11.5 mg/L (range, 4 to 35 mg/L), and 11 mg/L (range, 5 to 25 mg/L), in groups 1, 2, and 3, respectively (P = 0.006). The time to peak levels were 3.5 hours (range, 2.5 to 6.5 hours), 2.5 hours (range, 2.5 to 4.5 hours), and 4.5 hours (range, 2.5 to 12 hours), respectively (P = 0.2). TTA is safe and well tolerated.

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INTRODUCTION

It has been found that structurally modified fatty acids show an enhanced potency in modulating critical steps in lipid metabolism. The substituted fatty acids are saturated fatty acids that are modified by insertion of a sulfur atom at specific positions in the carbon backbone. One such modified fatty acid is the sulfur-containing tetradecylthioacetic acid (TTA), which has been found to beneficially affect disorders in lipid metabolism.1-4 It has structural similarity to the ordinary fatty acids, but it differs by the substitution of a sulfur atom for a methylene group in the 3-position of the fatty acid chain.5 The biological responses to TTA include mitochondrial proliferation, increased catabolism of fatty acids, antiadiposity, improvement in insulin sensitivity, antioxidant properties, reduced proliferation and induction of apoptosis in rapidly proliferating cells, cell differentiation, and antiinflammatory action. These biological responses indicate that TTA changes the plasma profile from atherogenic to cardioprotective.1 Different mechanisms are involved in the hypolipidemic effects of TTA. As a panperoxisome proliferator-activated receptor ligand, TTA regulates the adipose tissue mass and the expression of lipid metabolizing enzymes, particularly those involved in catabolic pathways. TTA reduced the total plasma cholesterol and triacylglycerol levels by 17% by increasing the number of mitochondria and by stimulating the mitochondrial β-oxidation of normal fatty acids.1,6

TTA affects antioxidant status at different levels by having the potential of changing the antioxidant defense system in addition to being an antioxidant itself through its free radical scavenging capacity. It may prevent the oxidative modification of LDL particles in plasma and reduce the generation of lipid peroxides.7 The potent antioxidant and antiproliferative properties of TTA were reported in both in vitro and in vivo studies.7-9 TTA, given as peroral supplements or delivered locally reduced negative remodeling after balloon angioplasty injury in a rabbit iliac model9 and porcine coronary arteries.10 It seems to be well tolerated in mice, rats, and dogs. Studies with administration of a single dose of TTA in mice and rats showed no significant acute toxicity.11 Long-term (3 months) administration to rats had an effect on the lipid levels in liver and blood, but only minor signs of toxicity were observed.12

Dyslipidemia and restenosis after percutaneous coronary interventions could be the targets for TTA therapy in the future. Toxicity, plasma concentration of TTA, and effects on blood biochemistry has not been evaluated in humans. In this study, we aimed to assess clinical safety and efficacy of TTA in terms of hematological and biochemical tolerance to increasing multiple doses of TTA and the short-term effects on blood lipids as well as its pharmacokinetics after single and multiple oral doses.

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METHODS

Study Design

Eighteen healthy volunteers were included into an open, single-center, randomized, phase I, multiple-dose study to assess the safety, tolerance, and efficacy of TTA. The Regional Ethics Committee approved the study protocol. The study was assessed and found satisfactory by the Norwegian Medicines Control Authority (NMCA). Informed consent was signed before allocation into the study. The study subjects were randomly assigned into 3 equal groups on the basis of oral dose of TTA: group 1 (200 mg/d TTA), group 2 (600 mg/d TTA), and group 3 (1000 mg/d TTA). Drug administration in groups 2 and 3 was to be started only after review of hematological and biochemical safety data from the previous dose level of the previous dose group. Hematological and biochemical safety data were studied during the 7-day treatment period and up to 1 week after last administration of TTA. Efficacy data were measured by short-term effects of TTA on blood lipid parameters (total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, free fatty acids). Drug concentrations were analyzed during the treatment period and at days 14 and 28. To exclude any unforeseen side effects, this tolerance study was performed by starting with a low dose and increasing the dose level only after evaluation of safety parameters of the previous dose group (Figure 1).

Figure 1
Figure 1
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Study Subjects

Healthy volunteers were recruited among students and staff at Haukeland University Hospital, Bergen, Norway. The following key inclusion criteria were used: age between 18 and 55 years, men or postmenopausal or sterilized women, good general health as determined by medical history, clinical examination, electrocardiogram (ECG), chest x-ray, plasma/urine biochemistry, and hematology.

Subjects were excluded if they had any of the following: any prescribed systemic or topical medication administered within 4 weeks before study start, any systemic or topical nonprescription medication administered within 48 hours before study start, donation of blood in the past 4 months, participation in other clinical trials within 4 weeks before study start, drug allergies, asthma or general history of allergic reactions, smoking more than 5 cigarettes per day, history of alcoholism or drug/chemical abuse, history of mental illness, history of peptic ulceration, severe indigestion or gastrointestinal disorders likely to influence drug absorption, history of hepatic, cardiac or metabolic disorders, clinically important illness within 4 weeks before study start. Subjects could be withdrawn from the trial for general reasons (Helsinki Declaration) or for safety reasons, at the discretion of the investigator. Subjects were also free to withdraw from the study at any time without the need to give any reason(s) and without any consequence for their future relationship to the institution or investigator.

Verbal and written information were applied regarding nature, purpose, possible risks, and benefits of the study.

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Drug Administration

The study drug was hard gelatin capsules containing 200 mg of the active ingredient TTA (Penn Pharmaceutical Ltd. Tafarnaubach Industrial estate, Tredegar Gwent, UK). The drug was supplied in containers individually labeled for each study subject. The containers contained 7, 21, and 35 capsules for groups 1, 2, and 3, respectively. The drug was stored at 2°C to 8°C. On study days 1 and 7, a standard breakfast and lunch were served at the clinic. On the evening before study days 1 and 7, the subjects were to fast overnight for 10 hours. At all other times during the study, the subjects were allowed to eat their normal diet. The subjects were refrained from alcohol during the study period. Administration of TTA for 7 consecutive days was set up for all study groups. The dose levels selected in the study (200, 600, or 1000 mg/d TTA) were anticipated to cover the effective human dose. This estimation was based on effective lipid-lowering doses in animals.

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Assessment of Pharmacokinetics

The short-term effects of TTA on blood lipid parameters (total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and free fatty acids) were assessed. Blood samples were taken at baseline and at days 1, 7, and 14 after study start. To describe the pharmacokinetics of TTA after single and multiple oral doses, drug concentration was measured in serum in 7 consecutive blood samples drawn at day 1, in one sample from each of the days 2, 3, 4, 5, 6, 14, and 28, and in 7 consecutive blood samples taken at day 7. Samples were frozen and stored at -80°C until analysis. Lipids were extracted from the serum, and fatty acids were methylated. TTA was quantified by gas chromatographic analysis and identified by GC/MS analysis. The method for TTA analysis in serum was validated and found to be appropriate for pharmacokinetic investigation.

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Assessment of Safety

Occurrence of adverse events during treatment period was assessed by review of medical history, physical examination, including vital signs (blood pressure, heart rate), electrocardiography (ECG), and by measurements of the following hematological and chemical parameters in blood/urine samples taken at baseline and days 1, 7, and 14 after study start.

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Blood Biochemistry

Serum tests: electrolytes (sodium, potassium, chloride), fasting glucose, kidney function testes (urea, creatinine), liver function tests (alkaline phosphatase, AST, ALT, total bilirubin, total protein, albumin), serum calcium, uric acid, CRP, fibrinogen, ferritin, creatine kinase (CK), CK-MB, folate, and homocysteine. Plasma fibrinogen was also analyzed.

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Hematology

Erythrocytes, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (with differential counting), erythrocyte sedimentation rate (ESR), platelet count, prothrombin time (Thrombotest/INR), activated partial thromboplastin time (Cephotest), and reticulocytes with fractions.

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Immunology

IgG, IgA, and IgM.

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Endocrinology

Serum tests: Thyroxine (T4), free serum thyroxine (FT4), Triiodothyronine (T3), and thyroid stimulating hormone (TSH).

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Urine Biochemistry and Microscopy

pH, protein, glucose, ketons, erythrocytes, leukocytes, epithelial cells, and cylinders.

The biochemical, immunological and hematological analyses and TTA were analyzed at Laboratory of Clinical Biochemistry, and the thyroid tests were analyzed at the Hormone Laboratory, Haukeland University Hospital, Bergen, Norway.

Adverse events were reported spontaneously by the subject or elicited through open (nonleading) questioning during and at the end of the trial. As far as possible, each event was described by its duration (start and stop date), severity and relationship to treatment, and according to the need of other specific therapy.

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Study Objectives

The primary objectives were to assess the clinical safety and the hematological and biochemical tolerance to increasing multiple doses of TTA. While secondary objectives were to study the short-term effects of TTA on lipid profile and the pharmacokinetics of TTA after single and multiple oral doses.

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Statistical Analysis

Data are presented as mean ± SD for continuous data and as number (%) for categorical data. Paired sample Student t test was used for within groups analysis. One-way analysis of variance (ANOVA) was used for between-groups analysis. Changes over time in lipid profile, TTA levels, hematological and biochemical parameters within and between groups were analyzed by repeated GLM-ANOVA. Data of TTA concentration patterns are presented as median (range) because it was not normally distributed. Kruskal-Wallis Test was used for between-groups differences in TTA concentrations. Two-sided P value of less than 0.05 was considered to indicate statistical significance. Analysis were conducted with SPSS program version 14.

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RESULTS

Baseline Characteristics

A total of 18 healthy volunteers, all men and with a mean age (SD) of 33 ± 11 years, were included in this study, with 6 subjects in each dose group. Seventeen subjects were of European descent, and 1 was of Asian descent. All subjects completed the study. At the beginning of the study, there were no differences among the different groups with respect to weight, age, medical history, clinical characteristics, and lipid profile. None of the subjects received concomitant medications at baseline or during study period. A light viral infection in regress was reported at baseline in one subject, but this was expected to have no influence on the study parameters. Baseline characteristics are summarized in Table 1.

Table 1
Table 1
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Adverse Events and Safety Analysis

Adverse events during the study were reported in 4 subjects, with a total of 5 events. All events were of mild severity and completely resolved during the study period. Four events occurred in group 2 (600 mg/d), and 1 occurred in group 3 (1000 mg/d). Increased acne vulgaris was reported in 2 subjects. The reaction resolved spontaneously during the study time in one subject and shortly after the study end in the other. One subject complained of light diarrhea and dizziness 50 minutes after drug intake. The reaction was self-limiting, and he had no problems later in the study. Serum-free thyroxine (FT4) increased slightly, and TSH decreased from baseline in 1 subject from 16.7 pmol/L to 22.8 pmol/L at day 14 for FT4 and from 0.26 mU/L to 0.17 mU/L at day 14 for TSH. However, the subject was evaluated to be clinically euthyroid. No significant changes in ECG, heart rate, or systemic blood pressure were reported except for 2 episodes of sinus bradycardia in 2 subjects in group 3. Both episodes were not of clinical significance and resolved spontaneously. All adverse events recovered completely without further interventions. Adverse events are shown in Table 2. Repeated measures did not show significant changes over time from baseline in serum electrolytes, fasting blood glucose, liver function parameters, kidney function parameters, or hematological parameters, in any of the groups (Table 3).

Table 2
Table 2
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Table 3
Table 3
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Table 3
Table 3
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Effects on Blood Lipids in TTA-treated Humans

Analysis of the fatty acid composition of the plasma (Figure 2) after 7 days of TTA therapy showed that 2 new components appeared. Using GC/MS, one component was identified as TTA itself (Figure 2A) and the second component as Δ9 desaturated TTA (TTA: 1n-8; Figure 2-B). This resulted in a tendency of reduction on serum total cholesterol, serum LDL-cholesterol, and serum triglyceride (Figure 2, C, D, and E). It is noteworthy that these parameters tended to normalize during the 7-day period after TTA treatment had been stopped. The HDL-cholesterol and free fatty acids (Figure 2, F and G) levels were not affected by TTA therapy. The total fatty acid concentration, however, tended to decrease in a dose-dependent manner (Figure 2H). However, no changes in the amount of saturated, monounsaturated, and polyunsaturated fatty acids were detected.

Figure 2
Figure 2
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TTA Pharmacokinetics

Drug concentration patterns are shown in Figures 3, 4, and 5. TTA concentrations measured daily before drug administration were seen to increase from day to day throughout the study period. This was observed in all dose groups and was dose dependent (Figure 3). This can indicate incomplete drug elimination when the next dose is taken, resulting in serum accumulation of TTA. The drug was still present in the serum at day 14, but it disappeared at day 28 (Figure 3). This indicated a washout time longer than 1 week but shorter than 3 weeks.

Figure 3
Figure 3
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Figure 4
Figure 4
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Figure 5
Figure 5
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Analysis of concentration pattern at day 1 showed a lag time of approximately 1.5 hours followed by a rapid absorption and a slower elimination phase (Figure 4). The median peak values were 2.9 mg/L (range, 1.1 to 5.4 mg/L), 11.5 mg/L (range, 4 to 35 mg/L), and 11 mg/L (5 to 25 mg/L) in groups 1, 2, and 3, respectively (P = 0.006). The time to peak levels were 3.5 hours (range, 2.5 to 6.5 hours), 2.5 hours (range, 2.5 to 4.5 hours), and 4.5 hours (range, 2.5 to 12 hours), respectively (P = 0.2). Changes over time in serum levels were significantly different among groups (P = 0.02). Absorption and distribution patterns at day 7 were similar to that at day 1, but the baseline values were higher due to drug accumulation (Figure 5). However, the median peak values were dose-dependent, 4 mg/L (range, 2 to 15 mg/L), 9 mg/L (range, 6 to 29 mg/L), 14 mg/L (range, 6 to 25 mg/L) in groups 1, 2, and 3, respectively (P = 0.05). The median time to peak levels were 4.5 hours (range, 2.5 to 4.5 hours), 3.5 hours (range, 2.5 to 6.5 hours), and 4.5 hours (2.5 to 6.5 hours), respectively (P = 0.8). Changes over time in serum levels were significantly different between groups (P = 0.01). For the different dose groups, the estimated distribution volume ranged from 52.3 to 84.3 L and the clearance from 4.1 to 5.6 L/hour. This makes the half-lives of TTA from 8.9 to 14.0 hours.

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DISCUSSION

The concentration pattern of TTA during and after the study period allowed for analysis of its pharmacokinetics. With the estimated half-lives of about 9 to 14 hours, daily dosing resulted in accumulation of the drug. The large distribution volumes observed (52 to 84 L) and the fatty acid nature of the drug indicate binding of the drug to lipid compartments of the organism. After a 1-week washout period, there was only a small fraction of the drug left; 3 weeks later, TTA could not be detected in any of the dose groups.

We have previously reported that TTA induces antioxidant and antiproliferative effects in in vitro and in in vivo studies.7-9 In experimental models, the inhibitory effects of TTA on the restenosis process after balloon angioplasty, particularly on negative remodeling, were proven.9,10 In this study, clinical, hematological, and biochemical tolerance to increasing multiple oral doses of TTA were tested. The drug was well tolerated when administered at a dose level of 200, 600, and 1000 mg/d for 7 consecutive days. Relatively few adverse events were reported, all of mild severity. Biochemical and hematological parameters did not change significantly throughout the 7-day treatment and 1-week washout periods. In addition, TTA had no clinically significant effect on vital signs. Safety of TTA was reported in prior experimental studies.11,12 Single dose11 as well as 3-month administration12 of TTA in mice and rats showed none or only minor signs of toxicity.

Administration of TTA did not cause a marked change in the total fatty acid composition of plasma lipids. The increase in Δ9 desaturated by TTA therapy may reflect attenuated Δ9 desaturase activity, and that TTA is a good substitute for this enzyme. However, no correlation was found between the level of TTA:1n-8 and the amount of oleic acid (18:1n-9). Fredriksen et al report that TTA in combination with dietary intervention reduces total cholesterol, LDL-cholesterol, and triglyceride in HIV-infected patients on PI-based HAART.13 TTA has previously been found to have hypolipidaemic effects in rats and dogs.5 The hypolipidemic effect of TTA seems to involve activation of peroxisome proliferator-activated receptor (PPAR) α in the liver, and it has recently been shown that TTA is a ligand for all PPAR subtypes.1 In addition, TTA may upregulate the scavenger and LDL-receptor expression.13

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Study Limits

Limitations of this phase-1 study are the lack of a randomized control group and the small sample size.

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CONCLUSION

This study has demonstrated that TTA was safe and well tolerated when given once daily for 7 consecutive days at doses up to 1000 mg. No major changes were observed in hematological or biochemical parameters. Further studies in humans are needed to determine optimal dose, dose intervals, and long-term safety and efficacy.

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REFERENCES

1. Berge RK, Skorve J, Tronstad K, et al. Metabolic effects of thia fatty acids. Curr Opin Lipidol. 2002;13:295-304.

2. Willumsen N, Vaagenes H, Rustan AC, et al. Enhanced hepatic fatty acid oxidation and upregulated carnitine palmitoyltransferase II gene expression by methyl 3-thiaoctadeca-6,9,12,15-tetraenoate in rats. J Lipid Mediat Cell Signal. 1997;17:115-134.

3. Taylor M, Wallhaus TR, Degrado TR, et al. An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro-6-thia-heptadecanoic acid and [18F]FDG in patients with congestive heart failure. J Nucl Med. 2001;42:55-62.

4. Berge RK, Aarsland A, Kryvi H, et al. Alkylthio acetic acids (3-thia fatty acids)-a new group of non-beta-oxidizable peroxisome-inducing fatty acid analogues: II. Dose-response studies on hepatic peroxisomal and mitochondrial changes and long-chain fatty acid metabolizing enzymes in rats. Biochem Pharmacol. 1989;38:3969-3979.

5. Asiedu DK, al-Shurbaji A, Rustan AC, et al. Hepatic fatty acid metabolism as a determinant of plasma and liver triacylglycerol levels. Studies on tetradecylthioacetic and tetradecylthiopropionic acids. Eur J Biochem. 1995;227:715-722.

6. Froyland L, Madsen L, Vaagenes H, et al. Mitochondrion is the principal target for nutritional and pharmacological control of triglyceride metabolism. J Lipid Res. 1997;38:1851-1858.

7. Muna ZA, Bolann BJ, Chen X, et al. Tetradecylthioacetic acid and tetradecylselenoacetic acid inhibit lipid peroxidation and interact with superoxide radical. Free Radic Biol Med. 2000;28:1068-1078.

8. Muna ZA, Gudbrandsen OA, Wergedahl H, et al. Inhibition of rat lipoprotein oxidation after tetradecylthioacetic acid feeding. Biochem Pharmacol. 2002;63:1127-1135.

9. Kuiper KKJ, Muna ZA, Erga KS, et al. Tetradecylthioacetic acid reduces stenosis development after balloon angioplasty injury of rabbit iliac arteries. Atherosclerosis. 2001;158:269-275.

10. Pettersen RJ, Muna ZA, Kuiper KKJ, et al. Sustained retention of tetradecylthioacetic acid after local delivery reduces angioplasty-induced coronary stenosis in the minipig. Cardiovasc Res. 2001;52:306-313.

11. Denton S. Single-dose Oral Toxicity Study in the Mouse (Approximation of the Minimum Lethal Dose Level). Covance report no.1382/003-1032, March 1998.

12. Demoz A, Asiedu DK, Lie Ø, et al. Modulation of plasma and hepatic oxidative status and changes in plasma lipid profile by n-3(EPA and DHA), n-6(corn oil) and a 3-thia fatty acid in rats. Biochimica et Biophysica Acta. 1994;1199:238-244.

13. Fredriksen T, Ueland E, Dyrøy B, et al. Lipid-lowering and anti-inflammatory effects of tetradecylthioacetic acid in HIV-infected patients on highly active antiretroviral therapy. Eur J Clin Invest. 2004;34:709-715.

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Keywords:

modified fatty acids; dyslipidemia; pharmacokinetics

© 2008 Lippincott Williams & Wilkins, Inc.

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