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DRUG INTERACTIONS |
From the Department of Clinical Pharmacy, University Medical Centre, Nijmegen, the Netherlands (C. la Porte, C. Verweij-van Wissen, N. van Ewijk, R. Aarnoutse, Y. Hekster, D. Burger); Nijmegen University Centre for Infectious Diseases, Nijmegen, the Netherlands (C. la Porte, R. Aarnoutse, P. Koopmans, Y. Hekster, D. Burger); Department of General Medicine, University Medical Centre, Nijmegen, the Netherlands (P. Koopmans); Department of Infectious Diseases and National AIDS Therapy Evaluation Centre (NATEC), Academic Medical Center, Amsterdam, the Netherlands (P. Reiss); and Merck & Co, Whitehouse Station, New Jersey (M. Stek, Jr).
Address for reprints: Charles J. L. la Porte, PharmD, Department of Clinical Pharmacy, University Medical Centre Nijmegen, PO Box 9101, 533 KF, 6500 HB, Nijmegen, the Netherlands.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Indinavir • ritonavir • didanosine • highly active antiretroviral therapy (HAART) • pharmacokinetics • drug interactions
The protease inhibitor indinavir is approved for 800 mg ter in die.4 However, the combination with ritonavir, another protease inhibitor, allows decreased dosing frequency to twice-a-day (bis in die) dosage due to inhibition of cytochrome P450 3A enzymes by ritonavir, which are responsible for the metabolism of indinavir.5-7 In addition, once-daily indinavir with ritonavir was studied in healthy subjects,8 showing that 1200 mg indinavir with 400 mg ritonavir resulted in pharmacokinetic parameters that were promising for the once-daily treatment of patients. The combination was best taken with food to avoid high peak plasma levels that are associated with nephrotoxicity. The preliminary results of a study investigating this combination in patients showed good virological and immunological response.9
Didanosine, a nucleoside reverse transcriptase inhibitor, has a recommended dose of 400 mg once daily (OD). Didanosine decomposes in an acid environment and therefore is unstable in the acid environment of the stomach.10 To protect didanosine from decomposition, it was previously formulated in tablets with a buffer to increase gastric pH after intake. However, this formulation of didanosine was not well tolerated due to the buffer included in the tablets. A new formulation of didanosine has become available with encapsulated enteric-coated (EC) beads. The EC formulation dissolves once the low gastric pH is neutralized in the gut lumen. The EC capsules are much better tolerated and are approved for intake on an empty stomach, defined as at least 2 hours before or after a meal.10
Combining indinavir/ritonavir with didanosine EC in a once-daily regimen yields problems with regard to food intake. To take full advantage of a once-daily regimen, it is important that all drugs involved can be taken at the same time. This study was undertaken to characterize the pharmacokinetics of both indinavir and didanosine when given together with or without food.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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In preparation for study days, participants had to fast for 8 hours. Beverages containing alcohol were prohibited from 15 hours before the start of each study day. Medication was administered with 420 mL of tap water. After intake of medication, blood and urine samples were collected for 24 hours. On study days, participants received a standardized breakfast (550 kcal; 28% fat) at the clinical research unit. Lunch (4 hours after breakfast) and dinner (9 hours after breakfast) were also standardized and provided at the clinical research unit. For up to 12 hours after administration, participants had to drink 2.5 L of fluid according to a prescribed schedule. The intake of grapefruit (juice) was prohibited throughout the whole study period.
Selection of Subjects
Subjects were eligible for inclusion if they met the following inclusion criteria: aged 18 years or older and healthy (ie, not suffering from an acute or chronic illness and not using medications). Subjects meeting any of the following criteria were excluded: documented hypersensitivity to indinavir, ritonavir, or didanosine; positive HIV test; pregnancy; history of pancreatitis; history of alcohol abuse; or 1 or more prespecified laboratory abnormalities. Written informed consent was obtained from all subjects, and the Regional Ethical Review Board approved the study. The study was conducted at the Department of Clinical Pharmacy of the University Medical Centre St. Radboud, Nijmegen, in collaboration with the Department of General Medicine.
Blood and Urine Sampling Procedures
On study days, 10-mL blood samples were collected in heparinized tubes by an indwelling catheter or venipuncture. The first sample was collected immediately before dosing; the other samples were taken at 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, and 24.0 hours after ingestion. Plasma for the determination of indinavir, ritonavir, and didanosine was transferred to labeled polypropylene tubes and stored at –20°C.
Urine samples were collected predose and during intervals from 2.0, 4.0, 6.0, 8.0, 10.0, 12.0, and 24.0 hours after administration of medication. Total urine volume was measured for each interval. Urine samples (5.0 mL) for the determination of indinavir and ritonavir were transferred to labeled polypropylene tubes and stored at –20°C. Urine samples (1.00 mL) for the determination of didanosine were transferred to labeled polypropylene tubes containing 2.00 mL phosphate buffer (0.2 M) (pH 8.0) and stored at –20°C.
Bioanalysis
Indinavir and ritonavir were analyzed in plasma using a previously described high-performance liquid chromatography (HPLC) method.11 For indinavir, accuracy ranged from 104% to 108%, depending on the concentration level, and intraday and interday precision ranged from 2.1% to 7.5% and 0.4% to 3.5%, respectively. For ritonavir, accuracy ranged from 102% to 108%, and intraday and interday precision ranged from 2.0% to 8.1% and 0.4% to 3.5%, respectively.
For the analysis of indinavir urine levels, a modification of the method used for plasma was used, as described elsewhere.12 For this method, the accuracy ranged from 92% to 101%, and intraday and interday precision ranged from 0.3% to 1.1% and 0.5% to 4.4%, respectively.
Didanosine plasma levels were measured using solid-phase extraction followed by reversed-phase HPLC with ultraviolet detection. Solid-phase extraction was performed with Waters Oasis MAX columns (Waters, Etten-Leur, the Netherlands). The columns were washed with 500 µL of methanol followed by 250 µL of water. Then, 500 µL of the plasma sample was loaded on the column together with 500 µL of HPLC-analyzed water (Baker, Deventer, the Netherlands). After loading the sample, the column was flushed twice with 150 µL of HPLC-analyzed water (Baker, Deventer, the Netherlands) and was vacuumed to dryness. Elution was performed by adding 0.5 mL of a mixture of methanol and water (80/20 vol/vol). The eluate was vaporized under a gentle stream of nitrogen at 37°C and was reconstituted in 0.2 mL 95/5 vol/vol water/acetonitrile. Then, 50 µL of this solution was injected into the HPLC system. Chromatographic analysis was performed at ambient temperature on a Symmetry Shield RP18 3.5-µm analytical column (150 x 4.6 mm ID; Waters, Etten-Leur, the Netherlands), protected by a Symmetry Shield RP18 3.5-µm column (3.9 x 20 mm ID; Waters, Etten-Leur, the Netherlands). Mobile phase was a mixture of 0.020 M acetate buffer (pH 4.6) (94%) and acetonitrile (6%) vol/vol. From 10 to 24 minutes, the composition of the mobile phase gradually changed to 74% acetate buffer with 26% acetonitrile. The gradient was back to the original values by 26 minutes. The flow rate was set at 1 mL/min, and the wave-length for ultraviolet detection was 260 nm. Didanosine retention time was 6 minutes. The didanosine calibration curve was linear over a range of 0.017 mg/L to 5.58 mg/L. Recovery after extraction from plasma was 97%. Accuracy ranged from 100% to 102%, and intraday and interday precision ranged from 1.8% to 2.1% and 1.5% to 2.4%, respectively.
Didanosine urine levels were measured using solid-phase extraction followed by reversed-phase HPLC with ultraviolet detection. Solid-phase extraction was performed with Waters Oasis MAX columns (Waters, Etten-Leur, the Netherlands), which were pretreated with 100 µL of methanol followed by 100 µL of water. Then, 1 mL ammonium hydroxide of (0.1 M) was loaded on the column together with 200 µL of the urine sample. After loading the sample to the column, it was flushed with 1 mL of ammonium hydroxide (0.02 M) and 1 mL of methanol and was vacuumed to dryness. Elution was performed with 0.5 mL 2% acetic acid in methanol in 15-mL glass tubes. The eluate was vaporized under nitrogen at 37°C and resolved in 0.5 mL of disodium monohydrogen phosphate (0.2 M) (pH 8.0), and 20 µL of this solution was used for injection to the HPLC system. Chromatographic analysis was performed on a Platinum EPS C18 300 A 5-µ analytical column (150 x 4.6 mm ID; Alltech, Breda, the Netherlands), protected by a Platinum EPS C18 300 A 5-µ All-Guard column (7.5 x 4.6 mm ID; Alltech, Breda, the Netherlands). Mobile phase was a mixture of 0.025 M potassium dihydrogenphosphate (97%) and acetonitrile (3%) vol/vol. The flow rate was 1 mL/min, and the wavelength for ultraviolet detection was 250 nm. Didanosine retention time was 10.5 minutes. The didanosine calibration curve was linear over a range of 1.56 mg/L to 467 mg/L. Recovery after extraction from urine was 100.3%. Accuracy ranged from 101% to 105%, and intraday and interday precision ranged from 3.1% to 4.0% and 0% to 0.6%, respectively.
Safety Monitoring and Laboratory Measurements
Twenty-four hours after administration, the clinical laboratory tests performed during screening were repeated on each study day. Adverse events were recorded and graded as mild, moderate, or severe according to World Health Organization grading scales.
Pharmacokinetic Analysis
The pharmacokinetic parameters of indinavir, ritonavir, and didanosine were calculated by noncompartmental methods using Excel version 2000 (Microsoft Corporation 1985-1999). The highest observed plasma concentration was defined as Cmax, with the corresponding sampling time as tmax.Cmin was the concentration at 24 hours after ingestion of the drugs. The terminal, log-linear period (log C vs t) was defined by visual inspection of the last data points (n 
3). The absolute value of the slope (ß/2.303) was calculated by least squares linear regression analysis (ß is the first-order elimination rate constant). The elimination half-life (t1/2) was calculated by the equation 0.693/ß. The area under the concentration versus time curve (AUC) was calculated using the trapezoidal rule from 0 to 24 hours. The AUC0-
value was calculated by extrapolating to infinity by the addition of the last measured plasma concentration divided by ß. The apparent clearance (CL/F, where F is bioavailability) was calculated by dividing dose (D) by AUC, and apparent volume of distribution (Vd/F) was obtained by dividing CL/F by ß. Clearance and volume of distribution were corrected for weight of the subject by dividing these parameters by the subject's body weight in kilograms. For this purpose, body weight was measured on each study day.
The cumulative renal excretion of indinavir and didanosine (Ae) was approximated by the total amount of indinavir and didanosine that was excreted unchanged in the urine during the dosing interval; Ae = 
(volume urine · concentration indinavir or didanosine in urine). Renal clearance (CLR) was calculated using the formula Ae/AUC. The fraction of the total amount excreted unchanged (fe) was calculated using the following formula: fe · F = Ae/D = CLR/CL.
Statistical Analysis
All statistical evaluations were performed with SPSS for Windows, version 10 (SPSS Inc, Chicago). Prior to statistical analysis, the pharmacokinetic parameters of indinavir, ritonavir, and didanosine were logarithmically transformed. Geometric means were calculated for all transformed pharmacokinetic parameters. The tmax values were summarized as medians and ranges and were compared by regimen using the Wilcoxon signed rank test. A P value 
.05 was considered to be significant in all analyses. The AUC and Cmax were tested for bioequivalence over the different regimens. For indinavir, the AUC and Cmax of test regimens C and D were compared to the AUC and Cmax of reference regimen B. For didanosine, the AUC and Cmax of test regimens C and D were compared to the AUC and Cmax of reference regimen A. A general linear method was used to calculate the geometric mean ratios of the AUC and Cmax of test regimens over the reference regimen. Conclusions with regard to bioequivalence were drawn as described by Williams et al.13 The 90% confidence intervals of the geometric mean ratios were compared to the predefined range of 0.80 to 1.25. Bioequivalence was concluded when the geometric mean ratio and the 90% confidence interval fell within the limits of 0.80 to 1.25. Bioequivalence was suggested if the geometric mean ratio fell within the limits of 0.80 to 1.25, but either the lower or the upper limit of the 90% confidence interval failed the limits of 0.80 to 1.25. Bioinequivalence was concluded if the geometric mean ratio and the 90% confidence interval fell outside the limits of 0.80 to 1.25. Bioinequivalence was suggested if the geometric mean ratio fell outside the range of 0.80 to 1.25, but one of the limits of the 90% confidence interval fell within the limits of 0.80 to 1.25.
A power calculation was performed in the development phase of the study. The calculation, based on indinavir Cmin, indicated that data of 6 subjects were needed to detect a 50% difference. As a low dropout rate was assumed, 8 subjects were included in the study.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Adverse Events and Laboratory Measurements
Two out of 8 subjects did not experience any adverse events at all. The single doses given in this study were well tolerated by the subjects. No serious adverse events occurred. During the study, no clinically significant changes were observed in biochemical and hematological parameters.
Pharmacokinetics
The indinavir pharmacokinetic parameters are listed in Table I. Indinavir plasma concentration versus time profiles based on median values for the reference regimen B and the test regimens C and D are shown in Figure 1. Note that data are presented as geometric means in Table I, which may read differently from the medians used in Figure 1. Test regimens C and D relative to reference regimen B showed bioequivalence, with the exception of indinavir Cmax in test regimen C, in which bioequivalence was only suggested. The 14% higher observed indinavir Cmax, when combined with didanosine 2 hours after breakfast, was accompanied by a statistically nonsignificant (P = .12) decreased median indinavir tmax of 1.3 hours when compared to reference regimen B. Reference regimen B (indinavir/ritonavir with breakfast) resulted in a tmax of 2.3 hours. Test regimen D, in which indinavir/ritonavir and didanosine were given simultaneously with breakfast, showed a tmax of 2.0 hours. No statistically significant differences were observed in indinavir renal excretion.
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Didanosine plasma concentration-time profiles can be found in Figure 2, with pharmacokinetic parameters listed in Table II. Note that data are presented as geometric means in Table II, whereas medians were used in Figure 2. For didanosine, it was not possible to determine a reliable Cmin value because no subjects had detectable didanosine levels in plasma more than 12 hours after intake. The didanosine AUC in test regimen D was 4% lower and suggestive of bioequivalence compared to reference regimen A. However, didanosine AUC in test regimen C was suggestive of bioinequivalence compared to reference regimen A (geometric mean ratio and 90% confidence interval = 0.77 [0.60-0.98]). Didanosine Cmax was not bioequivalent in both test regimens C and D relative to reference regimen A. For Cmax, geometric mean ratios and 90% confidence intervals were 0.58 (0.40-0.83) for test regimen C and 0.54 (0.36-0.81) for test regimen D. As such, there was a significant average decrease in Cmax of 42% and 46% for the respective test regimen relative to the reference regimen. A statistically significant increase for tmax was observed for both test regimens as well. Other didanosine pharmacokinetic parameters did not show any statistically significant changes. The total renal excretion was significantly (P = .04) decreased in test regimen C (48.9 mg vs 64.7 mg in reference regimen A).
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Ritonavir pharmacokinetic parameters are displayed in Table III. Apart from a decreased tmax in test regimen C (P = .04), both regimens (C and D) were bioequivalent to reference regimen A for ritonavir pharmacokinetic parameters.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Indinavir exposure (both AUC and Cmax), when administered with didanosine and breakfast, was bioequivalent to reference regimen B. However, when indinavir was given with didanosine 2 hours after breakfast, Cmax was 14% higher but still suggestive of bioequivalence in comparison to reference regimen B. From this study, it becomes apparent that the intake of indinavir/ritonavir with breakfast lowers the indinavir Cmax. This is a desirable effect as indinavir toxicity is at least partly related to the magnitude of Cmax.14 Lowered indinavir Cmax in the fed state has been reported by others as well.5,7,15 Food is also known to delay the absorption of indinavir, resulting in a delayed tmax.5,7,15 The observed differences in indinavir pharmacokinetics following the different study regimens in the current study show that there were differences in the fed state of the subjects following the regimens of being dosed 2 hours after breakfast or together with breakfast. Combining indinavir/ritonavir with didanosine with breakfast did not change indinavir AUC or Cmax relative to the same combination without didanosine, suggesting that there is no pharmacokinetic effect of didanosine on indinavir exposure. A lack of such effect has previously been reported.16
When didanosine is given with breakfast, as in test regimen D, a decreased Cmax and an increased tmax can be expected.17 Given 2 hours after breakfast (test regimen C), didanosine exposure decreased, indicating an interaction between absence of food and concomitant indinavir/ritonavir administration on didanosine absorption. However, such an effect has not been reported elsewhere. No statistical comparisons were made between test regimens C and D. Nevertheless, didanosine AUC in test regimen D is favorable over that in test regimen C, derived from the statistical comparison with reference regimen A. Didanosine Cmax, however, seems to be of the same magnitude in test regimens C and D.
Decreased absorption with test regimen C in comparison to reference regimen A was further supported by the decrease in total renal excretion in test regimen C (48.9 mg vs 64.7 mg in reference regimen A). In a previous study18 comparing didanosine buffered tablets with didanosine EC in both healthy subjects and patients, a decreased Cmax was observed for didanosine EC. However, the AUC showed bioequivalence for both formulations, indicating that the absorption rate was slower, but total absorption remained constant. In this study, data from test regimen D show the most favorable didanosine pharmacokinetics in that the AUC values were similar to the reference regimen.
Although this study was not conducted to investigate possible differences in ritonavir pharmacokinetics, the only statistical significant change observed was a decreased tmax in test regimen C (P = .04), indicating faster absorption. These data indicate that the use of didanosine has no effect on ritonavir pharmacokinetics.
This study had its limitations; first, the sample size was small, with only 8 subjects. Second, considerable variability in pharmacokinetic parameters was observed. Third, we cannot draw conclusions for a steady-state situation. However, the studied effects here mainly concern the absorption phase of the drugs, and these are not likely to be different when steady-state conditions apply. Fourth, at the time we conducted this study, no analytical assay to analyze intracellular triphosphate levels of didanosine was available. Didanosine needs to be converted intracellularly to the active triphosphate. To date, no data are available relating plasma didanosine levels to their intracellular triphosphate levels.
In conclusion, didanosine EC + indinavir/ritonavir with breakfast (test regimen D) show the most favorable pharmacokinetics and could serve as the basis of a HAART regime. Didanosine exposure was slightly lower in test regimens C and D. However, the confidence intervals for the didanosine AUC ratios (regimens D and A) were within 1% of the bioequivalence range, suggesting that a large sample size may have demonstrated bioequivalence. Indinavir exposure was bioequivalent for the 2 fed conditions compared to reference, with the exception of Cmax in test regimen C. These results indicate that this HAART regimen could be administered with food without decreased bioavailability.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Submitted for publication May 28, 2003; Revised version accepted April 28, 2004.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000;133: 21-30.
2. Mehta S, Moore RD, Graham NM. Potential factors affecting adherence with HIV therapy. AIDS. 1997;11: 1665-1670.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3. Stone VE. Strategies for optimizing adherence to highly active antiretroviral therapy: lessons from research and clinical practice. Clin Infect Dis. 2001;33: 865-872.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
4. Crixivan [product information]. Whitehouse Station, NJ: Merck & Co; 2002.
5. Hsu A, Granneman GR, Cao G, et al. Pharmacokinetic interaction between ritonavir and indinavir in healthy volunteers. Antimicrob Agents Chemother. 1998;42: 2784-2791.
6. van Heeswijk RP, Veldkamp AI, Hoetelmans RM, et al. The steady-state plasma pharmacokinetics of indinavir alone and in combination with a low dose of ritonavir in twice daily dosing regimens in HIV-1-infected individuals. AIDS. 1999;13: F95-F99.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
7. Burger DM, Hugen PW, Aarnoutse RE, et al. A retrospective, cohort-based survey of patients using twice-daily indinavir + ritonavir combinations: pharmacokinetics, safety, and efficacy. J Acquir Immune Defic Syndr. 2001;26: 218-224.
8. Hugen PW, Burger DM, ter Hofstede HJ, et al. Dose-finding study of a once-daily indinavir/ritonavir regimen. J Acquir Immune Defic Syndr.. 2000;25: 236-245.
9. Burger DM, Aarnoutse RE, Dieleman JP, et al. A once-daily HAART regimen containing indinavir + ritonavir plus one or two nucleoside reverse transcriptase inhibitors (PIPO study). Antivir Ther. 2003;8: 455-461.[Medline] [Order article via Infotrieve]
10. Videx EC [summary of product characteristics]. Woerden, the Netherlands: Bristol-Myers Squibb BV; 2003.
11. Hugen PW, Verweij-van Wissen CP, Burger DM, Wuis EW, Koopmans PP, Hekster YA. Simultaneous determination of the HIV-protease inhibitors indinavir, nelfinavir, saquinavir and ritonavir in human plasma by reversed-phase high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl. 1999;727: 139-149.[Medline] [Order article via Infotrieve]
12. Aarnoutse RE, Grintjes KJ, Telgt DS, et al. The influence of efavirenz on the pharmacokinetics of a twice-daily combination of indinavir and low-dose ritonavir in healthy volunteers. Clin Pharmacol Ther. 2002;71: 57-67.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
13. Williams RL, Chen ML, Hauck WW. Equivalence approaches. Clin Pharmacol Ther. 2002;72: 229-237.[CrossRef][Medline] [Order article via Infotrieve]
14. Dieleman JP, Gyssens IC, van der Ende ME, de Marie S, Burger DM. Urological complaints in relation to indinavir plasma concentrations in HIV-infected patients. AIDS. 1999;13: 473-478.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
15. Saah A, Winchell G, Seniuk M, Mehrotra D, Deutsch P. Multiple-dose pharmacokinetics and tolerability of indinavir-ritonavir combinations in healthy volunteers [abstract 362]. Paper presented at: 6th Conference on Retroviruses and Opportunistic Infections; January-February 1999; Chicago.
16. Damle BD, Mummaneni V, Kaul S, Knupp C. Lack of effect of simultaneously administered didanosine encapsulated enteric bead formulation (Videx EC) on oral absorption of indinavir, ketoconazole, or ciprofloxacin. Antimicrob Agents Chemother. 2002;46: 385-391.
17. Damle BD, Yan JH, Behr D, et al. Effect of food on the oral bioavailability of didanosine from encapsulated enteric-coated beads. J Clin Pharmacol. 2002;42: 419-427.[Abstract]
18. Damle BD, Kaul S, Behr D, Knupp C. Bioequivalence of two formulations of didanosine, encapsulated enteric-coated beads and buffered tablet, in healthy volunteers and HIV-infected subjects. J Clin Pharmacol. 2002;42: 791-797.[Abstract]
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