ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 2004, p. 4328–4331
0066-4804/04/$08.00?0 DOI: 10.1128/AAC.48.11.4328–4331.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.
Vol. 48, No. 11
Effects of Valproic Acid Coadministration on Plasma Efavirenz and
Lopinavir Concentrations in Human Immunodeficiency
Robert DiCenzo,1,2* Derick Peterson,2Kim Cruttenden,2Gene Morse,1Garret Riggs,2
Harris Gelbard,2and Giovanni Schifitto2
University at Buffalo, Buffalo,1and University of Rochester, Rochester,2New York
Received 26 January 2004/Returned for modification 18 March 2004/Accepted 30 June 2004
Valproic acid (VPA) has the potential to benefit patients suffering from human immunodeficiency virus
(HIV)-associated cognitive impairment. The purpose of this study was to determine if VPA affects the plasma
concentration of efavirenz (EFV) or lopinavir. HIV type 1 (HIV-1)-infected patients receiving EFV or lopinavir-
ritonavir (LPV/r) had 9 or 10 blood samples drawn over 8 to 24 h of a dosing interval at steady state before
and after receiving 250 mg of VPA twice daily for 7 days. VPA blood samples drawn before (C0) and 8 h after
the morning dose (8 h) were compared to blood samples from a group of HIV-1-infected subjects who were
taking either combined nucleoside reverse transcriptase inhibitors alone or had discontinued antiretroviral
therapy. Pharmacokinetic parameters were calculated by noncompartmental analysis, and tests of bioequiva-
lence were based on 90% confidence intervals (CIs) for ratios or differences. The geometric mean ratio (GMR)
(90% CI) of the areas under the concentration-time curve from 0 to 24 h (AUC0-24s) of EFV (n ? 11) with and
without VPA was 1.00 (0.85, 1.17). The GMR (90% CI) of the AUC0-8s of LPV (n ? 8) with and without VPA
was 1.38 (0.98, 1.94). The differences (90% CI) in mean C0and 8-h VPA concentrations versus the control (n ?
11) were ?1.0 (?9.4, 7.4) ?g/ml and ?2.1 (?11.1, 6.9) ?g/ml for EFV (n ? 10) and ?5.0 (?13.2, 3.3) ?g/ml
and ?6.7 (?17.6, 4.2) ?g/ml for LPV/r (n ? 11), respectively. EFV administration alone is bioequivalent to EFV
and VPA coadministration. LPV concentrations tended to be higher when the drug was combined with VPA.
Results of VPA comparisons fail to raise concern that coadministration with EFV or LPV/r will significantly
influence trough concentrations of VPA.
Cognitive impairment is the most common complication of
human immunodeficiency virus (HIV) infection affecting the
central nervous system. Although the incidence of HIV-asso-
ciated cognitive impairment has declined with the introduction
of highly active antiretroviral therapy (30), the prevalence of
this disorder is likely to increase given the increased life span
of HIV-infected individuals. Despite numerous preclinical
studies, the relationships between the neuropathogenesis of
HIV-associated cognitive impairment and neurologic disease
remain poorly understood. Extensive loss of neurons within
certain regions of the brain (12, 19) and high levels of neuronal
apoptosis (2, 16, 26, 32) have been reported in persons with
HIV dementia. Neuronal apoptosis is believed to occur as a
result of the production and release of a number of neurotoxic
factors that include viral proteins and products of immune
activation. Among the best characterized of these are the HIV
type 1 (HIV-1) regulatory protein Tat and platelet-activating
factor (PAF). PAF and recombinant Tat protein and peptides
containing the basic Tat domain induce apoptosis in both hu-
man and rat neurons (15, 21, 24, 25, 27, 29, 35).
A number of studies have shown that phosphatidylinositol
3-kinase and Akt protein kinase may play a role in the regu-
lation of cell fate, including neuronal survival (8, 11, 23, 36).
Glycogen synthase kinase 3 beta (GSK-3?) has been identified
as a major physiological target for Akt (7), and activation of
GSK-3? can induce apoptosis. The finding that the HIV-1
neurotoxins Tat and PAF upregulate the activity of GSK-3?
suggests that activity of this enzyme may play an important role
in the pathogenesis of HIV-1-associated cognitive impairment
(20). Furthermore, PAF-induced neurotoxicity can be reversed
by GSK-3? inhibition, which is particularly important because
PAF receptor activation has been implicated as the principal
initiator of neuronal dysfunction and death by several candi-
date HIV-1 neurotoxins, including tumor necrosis factor alpha
(25). Importantly, in a SCID murine model of HIV-1 enceph-
alitis, we have recently shown that administration of the GSK-
3? inhibitor valproic acid (VPA) ameliorates damage to the
neuronal dendritic arbor induced by inoculation of HIV-1-
infected mononuclear phagocytes into the basal ganglia (10).
Taken together, our in vitro and in vivo data provide a com-
pelling rationale for a trial of VPA as adjunctive therapy for
neuroprotection in patients with HIV-1-associated cognitive
There is evidence of VPA interfering with the metabolism of
concomitant medications. VPA has been shown to be an in-
hibitor of cytochrome P-450 (CYP) hepatic enzymes, including
CYP 2C9, and to inhibit UDP glucuronosyltransferase (UGT)
(3, 4, 31, 34, 37). Being highly bound to albumin, VPA also has
the ability to interact with other drugs via protein displace-
The primary purpose of this study was to determine whether
VPA would reduce the plasma concentrations of protease in-
hibitors (PIs) and nonnucleoside reverse transcriptase inhibi-
* Corresponding author. Mailing address: University of Rochester
Medical Center, Clinical Pharmacology Unit, 601 Elmwood Ave., Box
315, Room 1.6124, Rochester, NY 14642. Phone: (585) 273-2885. Fax:
(585) 275-7896. E-mail: firstname.lastname@example.org.
tors (NNRTIs), as this may preclude any further investigation
of VPA for the treatment of HIV-associated cognitive impair-
ment. Since VPA is also commonly used for headache and
mood control in addition to its primary indication for epilepsy,
we assessed whether PIs and NNRTIs affect trough levels of
VPA. Lopinavir and efavirenz were chosen as representative of
PIs and NNRTIs because of their frequent clinical use at the
time the study was implemented.
MATERIALS AND METHODS
Study subjects. Subjects were recruited from the North East AIDS Dementia
cohort and from the Rochester AIDS Clinical Trials Unit and sub-AIDS Clinical
Trials Unit. Subjects who met the following criteria were eligible for enrollment
in this trial: being seropositive for HIV on the basis of self-report confirmed by
enzyme-linked immunosorbent assay and Western blot assay, having a viral load
of ?400 copies/ml (Roche Amplicor test), being on a stable antiretroviral regi-
men for 4 weeks, being on a regimen containing either lopinavir or efavirenz,
being capable of giving informed consent, and being 18 years old or older.
Subjects with active opportunistic infections, neoplasms, or any other clinically
significant condition or laboratory abnormality that in the investigator’s opinion
would interfere with the subject’s ability to participate in the study; who were
currently participating in other drug studies or had received other investigational
drugs within the previous 30 days; and who were pregnant or nursing or taking
medication known or suspected to interfere with drugs metabolized by the CYP
isoenzyme system (including but not limited to ketoconazole, itraconazole, ci-
metidine, rifampin, and erythromycin) were excluded.
An additional HIV-infected control group was enrolled to assess the impact of
lopinavir and efavirenz on the concentration of VPA in plasma. These subjects were
copies/ml but met all of the other inclusion and exclusion criteria listed above.
Study design. This study consisted of three groups of HIV-infected subjects: a
group receiving lopinavir-ritonavir, a group receiving efavirenz, and a VPA control
group that received neither lopinavir-ritonavir nor efavirenz. The Research Subject
Review Board at the University of Rochester approved this study, and all subjects
were required to provide informed consent before any study procedures were initi-
ated. Subjects arrived at the General Clinical Research Center in the morning, were
required to fast for at least 8 h, and received a standardized light breakfast 1 h after
observed study drug administration. Blood samples were drawn before and 0.5, 1,
1.5, 2, 3, 4, 6, and 8 h after administration of the morning dose of lopinavir-
ritonavir. The sample strategy for efavirenz was the same except that subjects
took their dose the evening prior to sampling and were required to return for
24-h postdose blood sample collection. Since subjects may have been less likely
to agree to a 12-h stay at the General Clinical Research Center, an 8-h postdose
sampling period was chosen. Trough and 8-h postdose concentrations of VPA
were measured in all participants, including those in the control group. Each
subject had blood samples drawn before and after receiving 250 mg of VPA by
mouth twice daily for 7 days. Subjects who were taking didanosine were required
to take didanosine 2 h after their morning dose of the study drug.
Drug assays. Efavirenz and lopinavir concentrations in plasma were measured
by high-performance liquid chromatography in the Pharmacology Support Lab-
oratory at the University at Buffalo with methods validated within the Adult
AIDS Clinical Trials Group Quality Assurance Proficiency Testing program (18).
The lower limits of quantitation were ?100 and ?200 ng/ml for efavirenz and
lopinavir, respectively. VPA was measured with a standard cloned enzyme donor
immune assay (Microgenic) with a limit of detection of 3 ?g/ml.
Pharmacokinetic analyses. Standard noncompartmental techniques were used
to assess pharmacokinetic parameters with WinNonlin Version 2.1 (Pharsight,
Palo Alto, Calif.). The area under the concentration-time curve (AUC) was de-
termined with the linear trapezoidal method, and the maximum observed con-
centration (Cmax) and time to Cmax(Tmax) were determined by visual inspection.
If the sample drawn at the end of the dosing interval was not available or had an
increased drug concentration compared to that taken at the previous time point,
the concentration reported was determined by extrapolation on the basis of the
estimated terminal elimination rate. Efavirenz 24-h postdose samples were also
used to estimate predose efavirenz concentrations in order to calculate the AUC
during a 24-h dosing interval at steady state (AUC0-24). Tests of bioequivalence
were based on 90% confidence intervals (CIs) for ratios or differences, in accor-
dance with Food and Drug Administration guidelines (90% CI of the geometric
mean ratio [GMR] of the test AUC to the reference AUC within a range of 0.80
to 1.25). Pharmacokinetic parameters, or their log transforms, were compared
between groups with the paired t test, the paired Wilcoxon tests, or the Kruskal-
Wallis test when appropriate with SAS System v8 (SAS Institute, Cary, N.C.).
Assuming a coefficient of variation of approximately 25% for the AUC of lopi-
navir or efavirenz when either drug is taken alone, a sample size of 10 HIV-1-
infected subjects in each arm would be required for 90% power to detect a 30%
decrease in the lopinavir or efavirenz AUC due to the administration of VPA
with a two-sided paired t test with 0.05 type I error.
The genders, ages, ethnicities, Karnofsky performance sta-
tuses, antiretroviral drug use, and CD4 cell counts of subjects
who received efavirenz, lopinavir-ritonavir, or neither efa-
virenz nor lopinavir-ritonavir (VPA control group) are listed in
Table 1. Eleven subjects received 600 mg of efavirenz once
daily with or without VPA. The pharmacokinetic parameters
calculated for efavirenz are listed in Table 2. VPA does not
appear to alter plasma efavirenz concentrations. Efavirenz ad-
ministered with VPA is bioequivalent to efavirenz adminis-
tered alone. The GMR (90% CI) of the AUC0-24s was 1.00
(0.85, 1.17). None of the other pharmacokinetic parameters for
efavirenz listed in Table 2 were found to be significantly dif-
ferent (P ? 0.10).
Three subjects receiving lopinavir-ritonavir did not follow
the protocol concerning the time of dose administration. The
estimated lopinavir pharmacokinetic parameters for eight sub-
jects who received 400 and 100 mg of lopinavir and ritonavir,
respectively, twice daily with and without VPA are listed in
Table 2. Administration of lopinavir-ritonavir alone does not
appear to be equivalent to administration of lopinavir-ritonavir
TABLE 1. Demographics and baseline clinical variables
of the subject in this study
Mean age (yr), SD41.0, 5.345.4, 6.7 43.0, 7.7
% of males81.881.8 83.3
Karnofsky score of
100.0 81.8 91.7
History of HIV-related
Mean CD4 cell
545.9, 214.0 416.7, 463.3340.6, 232.9
Antiretroviral use (%)
aThe numbers of subjects included in the efavirenz plus NRTI, lopinavir-
ritonavir plus NRTI, and VPA without efavirenz or lopinavir groups were 11, 11,
and 12, respectively.
VOL. 48, 2004VALPROIC ACID WITH EFAVIRENZ OR LOPINAVIR-RITONAVIR 4329
with VPA. Our results suggest that plasma lopinavir concen-
trations may be higher during VPA coadministration. The GMR
(90% CI) of the AUC0-8s after administration of the dose of
lopinavir with and without VPA coadministration was 1.38
(0.98, 1.94), and six of the eight subjects achieved higher
plasma lopinavir concentrations during VPA coadministration.
The lopinavir Cmax, minimum observed concentration, Tmax,
and half-life were not significantly different during VPA ad-
ministration (P ? 0.10).
Eleven of the 12 subjects in the group who received VPA
without efavirenz or lopinavir-ritonavir completed the study
and were compared to those taking efavirenz or lopinavir-
ritonavir. Neither administration of efavirenz nor that of lopi-
navir-ritonavir appeared to effect VPA concentrations mea-
sured just before (C0) or 8 h after administration of the dose.
The differences (90% CIs) in the mean C0and 8 h VPA con-
centrations versus the control concentrations (n ? 11) were
?1.0 (?9.4, 7.4) and ?2.1 (?11.1, 6.9) ?g/ml for efavirenz
(n ? 10) and ?5.0 (?13.2, 3.3) and ?6.7 (?17.6, 4.2) ?g/ml for
lopinavir-r (n ? 11), respectively. Although 3 of the 11 control
subjects received antiretroviral therapy consisting of zalcita-
bine-lamivudine-indinavir, nelfinavir-nevirapine, or trizivir-am-
prenavir; when comparing results to those obtained excluding
these subjects, inclusion of these subjects did not appear to
influence the C0(P ? 0.54 versus P ? 0.49) or 8-h (P ? 0.44
versus P ? 0.30) VPA results.
Before beginning a clinical trial to evaluate the use of VPA
for HIV-associated cognitive impairment, we needed to deter-
mine if VPA would alter the disposition of NNRTIs or PIs and
in particular whether VPA would lower the plasma concentra-
tions of these antiretroviral drugs. We chose efavirenz and
lopinavir-ritonavir to represent drugs from the NNRTI and PI
inhibitor class of antiretrovirals because of their frequent use
because part of the requirement for highly active antiretroviral
therapy testing for bioequivalence is a comparison of achiev-
able drug concentrations both with and without coadministra-
tion of the test drug. One of the Food and Drug Administra-
tion definitions of bioequivalence is that the 90% CI of the
GMR of the test AUC to the reference AUC lie within a range
of 0.8 to 1.25. Efavirenz is an NNRTI whose pharmacokinetic
and dynamic properties include a long plasma half-life, a high
level of plasma protein binding (99.5 to 99.75%) primarily to
albumin, the ability to induce the hepatic metabolism of many
drugs metabolized by the CYP enzyme system, and resistance
to pharmacokinetic alterations when administered with other
drugs (33). As expected on the basis of previous evidence that
shows that efavirenz is recalcitrant to altered metabolism, we
were able to show that administration of efavirenz alone is
bioequivalent to administration with VPA (the GMR [90% CI]
of the AUC0-24s was 1.00 [0.85, 1.17]). Although the sampling
strategy used may have limited the estimate of the efavirenz
Cmax, the Cmaxreported here is similar to previously reported
values (median Cmax[interquartile range], 2.83 ?g/ml [1.82 to
3.71] ?g/ml) (9).
With the exception of nelfinavir, a substrate for CYP 2C19,
PIs are substrates for CYP 3A4, leading to many potential drug
interactions (28). In light of the growing amount of evidence in
support of a correlation between plasma PI concentrations and
virologic response, avoidance of potential drug interactions,
especially those that result in lower achievable plasma PI con-
centrations, is of increasing importance (1, 5, 13, 14; D. Burger
et al., 12th World AIDS Conf., abstr. 42259, 1998). VPA has
been shown to be an inhibitor of hepatic metabolism, including
the CYP 2C9-dependent metabolism of certain drugs such as
phenytoin and phenobarbital (3; S. I. Hurst et al., Int. Soc.
Stud. Xenobiotics Proc., abstr. 12, 1997). VPA has also been
shown to inhibit the UGT-mediated metabolism of drugs such
as zidovudine, lamotrigine, and lorazepam (4, 31, 34, 37). VPA
does not inhibit the metabolism of CYP 3A-dependent drugs
such as cyclosporine and oral contraceptives, suggesting a lack
of influence on CYP 3A-dependent metabolism (6, 17). Being
highly bound to albumin, VPA also has the ability to interact
with other drugs via protein displacement; however, PIs are
thought to be primarily bound to alpha-1-acid glycoprotein,
minimizing the potential for protein displacement by VPA (22,
31). Since lopinavir is primarily metabolized by CYP 3A4, the
potential for VPA to influence blood lopinavir concentrations
was minimal and expected to be one of inhibition, not induc-
tion (3; Si et al., Int. Soc. Stud. Xenobiotics Proc.). Given that
blood lopinavir concentrations showed a statistically insignifi-
cant trend to increase in the presence of VPA, our results
further support the potential for VPA to inhibit the metabo-
lism of concomitant medications. Lopinavir concentrations
may have been influenced indirectly by ritonavir inhibition.
Failure to assay ritonavir concentrations limits the ability to
determine if VPA could influence plasma lopinavir concentra-
tions indirectly by influencing the metabolism of ritonavir.
At clinically achievable concentrations, lopinavir-ritonavir,
primarily because of the actions of ritonavir, is an inhibitor of
CYP 3A4 and to a lesser extent 2C9 whereas efavirenz has
primarily been shown to induce CYP-mediated intestinal or
hepatic metabolism (28; Kaletra package insert; Abbott Lab-
oratories, North Chicago, Ill.). Ritonavir has also been shown
to induce CYP metabolism, including its own, and to induce
TABLE 2. Pharmacokinetic parameters of efavirenz and lopinavir
AUCc(h ? ng/ml)
Efavirenz with VPA
Lopinavir with VPA
aClastis the drug concentration drawn at the last time point. Clastis 24 h after dose administration for efavirenz and 8 h after dose administration for lopinavir.
bThe numbers of subjects given 600 mg of efavirenz every 24 h and 400 and 100 mg of lopinavir and ritonavir twice daily were 11 and 8, respectively.
cTwenty-four-hour and 8-h AUCs at steady state are reported for efavirenz and lopinavir, respectively. The values reported are medians (ranges).
dt1/2, estimated half-life.
4330DICENZO ET AL.ANTIMICROB. AGENTS CHEMOTHER.
UGT (Kaletra package insert). VPA is primarily hepatically Download full-text
metabolized by UGT enzymes and ?-oxidation and to a much
lesser extent by CYP 2C9 and 2C19; therefore, except for
potential UGT induction by ritonavir, neither lopinavir-ritona-
vir nor efavirenz was expected to influence blood VPA concen-
trations (28). We were unable to detect a significant influence
of either efavirenz or lopinavir-ritonavir on the trough (C0) or
8-h postdose plasma VPA concentrations. It should be noted
that the study was not able to determine VPA bioequivalence
or designed to sample plasma VPA concentrations throughout
an entire dosing interval. VPA concentrations appear to be on
a downward trend in the presence of lopinavir-ritonavir, which
could be due to ritonavir inducing UGT. However, our results,
taken together with the reported wide therapeutic plasma con-
centration range of VPA (30 to 100 ?g/ml), are reassuring for
those HIV-infected individuals currently taking VPA for epi-
lepsy, headache, or mood disorders (22).
In summary, coadministration of VPA with either efavirenz
or lopinavir-ritonavir does not result in decreased plasma con-
centrations of efavirenz or lopinavir. Furthermore, since nei-
ther efavirenz nor lopinavir significantly altered the trough or
8-h postdose plasma concentrations of VPA, a clinically signif-
icant interaction is doubtful. These results encourage further
investigation of VPA for the treatment of HIV-associated cog-
This work was supported by grant P01 MH64570 and in part by
General Clinical Research Center grant 5M01-RR 00044 from the Na-
tional Center for Research Resources, National Institutes of Health.
Additional research personnel who participated in this study were
Connie Orme, Larry Preston, and Janice Bausch at the University of
Rochester and Robin DiFrancesco at the State University at Buffalo.
1. Acosta, E., J. Gerber, and The Adult Pharmacology Committee of the AIDS
Clinical Trials Group. 2002. Group position paper on therapeutic drug
monitoring of antiviral agents. AIDS Res. Hum. Retrovir. 18(12):825–834.
2. Adle-Biassette, H., Y. Levy, M. Colombel, F. Poron, S. Natchev, and C. Keo-
hane. 1995. Neuronal apoptosis in HIV infection in adults. Neuropathol.
Appl. Neurobiol. 21:218–227.
3. Anderson, G. 1998. A mechanistic approach to antiepileptic drug interac-
tions. Ann. Pharmacother. 32:554–563.
4. Anderson, G. D., B. E. Gidal, E. Kantor, and A. J. Wilensky. 1994. Loraz-
epam-valproic acid interaction: studies in normal subjects and isolated per-
fused rat liver. Epilepsia 35:221–225.
5. Burger, D. M., P. W. Hugen, P. Reiss, I. Gyssens, F. K. Schneider, G. Schreij,
K. Brinkman, C. Richter, J. Prins, R. Aarnoutse, and J. M. Lange. 2003.
Therapeutic drug monitoring of nelfinavir and indinavir in treatment-naive
HIV-1-infected individuals. AIDS 17(8):1157–1165.
6. Crawford, P., D. Chadwick, P. Cleland, J. Tjia, and A. Cowie. 1986. The lack
of effect of valproate on the pharmacokinetics of oral contraceptive steroids.
7. Cross, D. A., D. R. Alessi, P. Cohen, M. Andjelkovic, and B. Hemmings.
1995. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein
kinase B. Nature 378:785–789.
8. Crowder, R., and R. Freeman. 1998. Phosphatidylinositol 3-kinase and Akt
protein kinase are necessary and sufficient for the survival of nerve growth
factor-dependent sympathetic neurons. J. Neurosci. Res. 18:2933–2943.
9. DiCenzo, R., A. Forrest, K. E. Squires, S. M. Hammer, M. A. Fischl, H. Wu,
R. Cha, G. D. Morse, and The Adult AIDS Clinical Trials Group Protocol
368/886 Study Team. 2003. Indinavir, efavirenz, and abacavir pharmacoki-
netics in human immunodeficiency virus-infected subjects. Antimicrob.
Agents Chemother. 47:1929–1935.
10. Dou, H., K. Birusingh, I. Faraci, S. Gorantla, L. Y. Poluektova, and S.
Maggirwar, et al. 2003. Neuroprotective activities of sodium valproate in a
murine model of HIV-1 encephalitis. J. Neurosci., 23:9162–9170.
11. Dudek, H., S. R. Datta, T. F. Franke, M. J. Birnbaum, R. Yao, and G. M.
Cooper. 1997. Regulation of neuronal survival by the serine-threonine pro-
tein kinase Akt. Science 275:661–665.
12. Everall, I., P. Luthert, and P. Lantos. 1991 Neuronal loss in the frontal
cortex in HIV infection. Lancet 3357:1119–1121.
13. Fletcher, C. V., P. L. Anderson, T. N. Kakuda, T. W. Schacker, K. Henry, C. R.
Gross, and R. C. Brundage. 2002. Concentration-controlled compared with
conventional antiretroviral therapy for HIV infection. AIDS 16(4):551–560.
14. Flexner, C., and S. Piscitelli. 2002. Concentration-targeted therapy and the
future of HIV management. AIDS 16(Suppl. 1):S1–S3.
15. Gelbard, H. A., H. S. L. M. Nottet, S. Swindells, M. Jett, K. A. Dzenko, P.
Genis, R. White, L. Wang, Y.-B. Choi, D. Zhang, S. A. Lipton, W. W.
Tourtellotte, S. G. Epstein, and H. E. Gendelman. 1994. Platelet-activating
factor: a candidate human immunodeficiency virus type 1-induced neuro-
toxin. J. Virol. 68:4628–4635.
16. Gelbard, H. A., H. J. James, L. R. Sharer, S. W. Perry, Y. Saito, and A. M.
Kazee. 1995. Apoptotic neurons in brains from pediatric patients with HIV-1
encephalitis and progressive encephalopathy. Neuropathol. Appl. Neurobiol.
17. Hillebrand, G., L. A. Castro, W. van Scheidt, D. Beukelmann, W. Land, and
D. Schmidt. 1987. Valproate for epilepsy in renal transplant recipients re-
ceiving cyclosporine. Transplantation 43:915–916.
18. Keil, K., V. A. Frerichs, R. DiFrancesco, and G. D. Morse. 2003. Reverse phase
high performance liquid chromatography method for the analysis of amprena-
vir, and saquinavir in heparinized human plasma. Ther. Drug Monit. 25:340–346.
19. Ketzler, S., S. Weis, H. Haug, and H. Budka. 1990. Neuronal loss in the
frontal cortex in HIV infection. Acta Neuropathol. 80:92–94.
20. Maggirwar, S. B., N. Tong, S. Ramirez, H. A. Gelbard, and S. Dewhurst.
1999. HIV-1 Tat-mediated activation of glycogen synthase kinase-3 beta
contributes to Tat-mediated neurotoxicity. J. Neurochem. 73:578–586.
21. Magnuson, D. S. K., B. E. Knudson, J. D. Geiger, R. M. Brownstone, and A.
Nath. 1995. Human immunodeficiency virus type 1 tat activates non-N-
methyl-D-aspartate excitatory amino acid receptors and causes neurotoxicity.
Ann. Neurol. 37:373–380.
22. McNamara, J. 2001. Drugs effective in the therapy of epilepsies, p. 536–537.
In A. Goodman Gilman (ed.), The pharmacological basis of therapeutics.
McGraw-Hill, New York, N.Y.
23. Miller, T. M., M. G. Tansey, E. M. Johnson, Jr., and D. J. Creedon. 1997.
Inhibition of phosphatidylinositol 3-kinase activity blocks depolarization-
and insulin-like growth factor I-mediated survival of cerebellar granule cells.
J. Biol. Chem. 272:9847–9853.
24. New, D. R., S. B. Maggirwar, L. G. Epstein, S. Dewhurst, and H. A. Gelbard.
1998. HIV-1 Tat induces neuronal death via tumor necrosis factor-alpha and
activation of non-N-methyl-D-aspartate receptors by a NF?B-independent
mechanism. J. Biol. Chem. 273:17852–17858.
25. Perry, S. W., J. A. Hamilton, L. W. Tjoelker, G. Dbaibo, K. A. Dzenko, and
L. G. Epstein. 1999. Platelet-activating factor receptor activation: an initiator
step in HIV-1 neuropathogenesis. J. Biol. Chem. 273:17660–17664.
26. Petito, C., and B. Roberts. 1995 Evidence of apoptotic cell death in HIV
encephalitis. Am. J. Pathol. 146:1121–1130.
27. Philippon, V., C. Vellutini, D. Gambarelli, G. Harkiss, G. Arbuthnott, and D.
Metzger. 1994. The basic domain of the lentiviral Tat protein is responsible
for damages in mouse brain: involvement in cytokines. Virology 205:519–529.
28. Raffanti, S., and D. Haas 2001. Antimicrobial agents: antiviral agents, p.
1364–1373. In A. Goodman Gilman (ed.), The pharmacological basis of
therapeutics. McGraw-Hill, New York, N.Y.
29. Sabatier, J.-M., E. Vives, K. Mabrouk, A. Benjouad, H. Rochat, A. Duval, B.
Hue, and E. Bahraoui. 1991. Evidence for neurotoxic activity of tat from
human immunodeficiency virus type 1. J. Virol. 65:961–967.
30. Sacktor, N., M. P. McDermott, K. Marder, G. Schifitto, O. A. Selnes, J. C.
McArthur, Y. Stern, S. Albert, D. Palumbo, K. Kieburtz, J. A. De Marcaida,
B. Cohen, and L. Epstein. 2002. HIV-associated cognitive impairment before
and after the advent of combination therapy. J. Neurovirol. 8:136–142.
31. Scheyer, R., and R. Mattson. 1995. Valproate: interactions with other drugs, p.
621–631. In R. Levy, H. Mattson, and B. Meldrum (ed.), Antiepileptic drugs.
Raven Press, New York, N.Y.
32. Shi, B., U. De Girolami, J. He, S. Wand, A. Lorenzo, and J. Busciglio. 1996.
Apoptosis induced by HIV-1 infection of the central nervous system. J. Clin.
33. Smith, P., R. DiCenzo, and G. Morse. 2001. Clinical pharmacokinetics of non-
nucleoside reverse transcriptase inhibitors. Clin. Pharmacokinet. 40(12):893–905.
34. Trapnell, C. B., R. W. Kleckner, C. Jamison, and J. M. Collins. 1998. Glucu-
ronidation of 3?-azido-3?-deoxythymidine (zidovudine) by human liver micro-
somes: relevance to clinical pharmacokinetic interactions with atovaquone, flu-
conazole, methadone, and valproic acid. Antimicrob. Agents Chemother. 42:
35. Weeks, B. S., D. M. Liebermann, B. Johnson, E. Roque, M. Green, and P.
Lowenstein. 1995. Neurotoxicity of the human immunodeficiency virus type
1 tat transactivator to PC12 cells requires the Tat amino acid 49 to 58 basic
domain. J. Neurosci. Res. 42:34–40.
36. Yao, R., and G. Cooper. 1995. Requirement for phosphatidylinositol-3 kinase
in the prevention of apoptosis by nerve growth factor. Science 267:2003–2006.
37. Yuen, A. 1995. Lamotrigene: interactions with other drugs, p. 883–887. In B.
Meldrum (ed.), Antiepileptic drugs. Raven Press, New York, N.Y.
VOL. 48, 2004VALPROIC ACID WITH EFAVIRENZ OR LOPINAVIR-RITONAVIR 4331