Korean Red Ginseng and HIV

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Korean Red Ginseng Slows Depletion of CD4 T Cellsin Human Immunodeficiency Virus Type 1-InfectedPatients

Heungsup Sung,1Sang-Moo Kang,2Moo-Song Lee,3TaiGyu Kim,4 and Young-Keol Cho1,*

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ABSTRACT

We have previously showed that long-term intake of

Korean red ginseng (KRG) delayed disease progression

in human immunodeficiency virus type 1 (HIV-1)-

infected patients. In the present study, to investigate

whether this slow progression was affected by KRG

intake alone or in combination with HLA factor, we

analyzed clinical data in 68 HIV-1-infected patients who

lived for more than 5 years without antiretroviral

therapy. The average KRG intake over 111.9 31.3

months was 4,082 3,928 g, and annual decrease in

CD4 T cells was 35.0 28.7/l. Data analysis showed

that there are significant inverse correlations between

the HLA prognostic score (0.29 1.19) and annual

decrease in CD4 T cells (r = 0.347;P< 0.01) as well asbetween the amount of KRG intake and annual decrease

in CD4 T cells (r = 0.379;P< 0.01). In addition, KRG

intake significantly slowed the decrease in CD4 T cells

even when influence of HLA class I was statistically

eliminated (repeated-measure analysis of variance;P 2,700 g, respectively.

In the group with a HLA prognostic score 0, CD4 T

cells decreased from 519 201/l to 171 134/l (32.9%

compared to baseline) in the 21 patients with KRG intake

2,700 g and from 456 201/l to 273 212/l (59.9%

compared to baseline) in the 28 patients with KRG

intake > 2,700 g, respectively (Fig.(Fig.3B). 3B). Thus,

we found that KRG intake significantly slowed the

decrease in CD4 T cells even when influence of HLA

class I was eliminated (repeated measure ANOVAP 2,700

g) and separately analyzed the correlations between HLA

prognostic score alone and changes in CD4 T cells. The

HLA prognostic score alone also significantly affected

the change of CD4 T cells (P< 0.05). Thus, our data

show that both KRG intake and HLA factor

independently affected the slow depletion of CD4 T cells

in the present study.

FIG. 2.

Correlation between KRG intake (35.7 28.8 g/month)

and annual decrease in CD4 T cells (35.0 28.7/l).

There was a significant inverse correlation between

amount of KRG intake and annual decrease in CD4 T

cells (r = (more ...)

FIG. 3.

Amount of KRG intake determines the rate of CD4 T cell

depletion irrespective of HLA class I score. Sixty-eight

patients were divided into two groups with HLA scores

of 2,700 g. We independently

analyzed the changes in sCD8. The group of individuals

with high KRG intake showed a more significant

decrease by 32% from 691.8 244.6 U/ml to 475.9

184.0 U/ml (Fig.(Fig.4), 4), whereas individuals with low

KRG intake did not show such decreases in sCD8.

Similarly, analysis of the effects of HLA on changes in

sCD8 did not show any significant correlations between

HLA score and decreases in sCD8 (data not shown).

Therefore, these results suggest that there is a strong

correlation between the decrease in serum sCD8 and

KRG intake (r= 0.620;P< 0.001).

FIG. 4.

Effects of KRG intake on serum sCD8 irrespective of

HLA score. Forty-seven patients were divided into two

groups based only on the amounts of KRG intake. The

first level indicates averages of first measurements of

sCD8, and the end level indicates averages (more ...)

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DISCUSSION

In the present study, we performed analysis of the effects

of KRG intake on CD4 T cells, sCD8, and HLA prognostic

score. We observed that there were strong correlations

between KRG intake and annual decrease in CD4 T cells

and between KRG intake and sCD8, together with a

significant inverse correlation between HLA prognostic

score and annual decrease in CD4 T cells. In addition, we

found that KRG intake alone slows the decrease in CD4 T

cells irrespective of HLA prognostic score. This finding isactually evidenced by the fact that the annual decrease in

CD4 T cells (35/l) with a significant amount of KRG

intake in this study was much lower than the natural

decrease (70/l) in the HIV-1-infected Korean patients

without KRG intake (1).

Progression to AIDS is strongly associated with

generalized activation of the immune system, manifested

by elevated serum concentrations of neopterin, soluble
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IL-2 receptor, sCD8, and 2-microglobulin, and with

activation of a large proportion of CD8 T cells (12). From

the long-term studies with KRG intake, one of the most

consistent findings was a significant decrease in serum

sCD8 (6), which is an immune activation marker

physiologically secreted from CD8 T cells. Moreover, the

significant and consistent decrease in serum sCD8

(19.2%) was maintained as long as KRG was taken

continuously (P< 0.01) (Y. K. Cho, H. J. Lee, W. I. Oh,

and Y. K. Kim, 94th ASM Gen. Meet., abstr. E-44, 1997).

In the group assayed here, the decrease in serum sCD8

(27.4%) was even greater than those observed previously

(13.8 and 19.2%) and greatly differed from the rebound

phenomenon observed during zidovudine monotherapy.

Thus, the decrease in serum sCD8 may be indicative of a

lower level of destruction of CD8 T cells in patients

ingesting KRG and suggests that KRG intake is

associated with prolonged maintenance of enhanced

CD8 T lymphocyte activity.

Although the mechanism of ginseng is not well

understood, it is demonstrated that the adaptogenic

properties of ginseng are due to its effects on the

hypothalamic-pituitary-adrenal axis, resulting in

elevated plasma corticotropin and corticosteroid levels

(11,14,25). This action of ginseng might contribute a lot

for suppressing hyperactivation of immune systems. The

important role of suppressing the hyperimmune state inpreventing AIDS progression was recently demonstrated

by a study demonstrating that nonpathogenic simian

immunodeficiency virus infection of sooty mangabeys is

characterized by low-level immune activation despite

chronic high-level viremia compared to other species of

monkey, leading to AIDS progression (30). Intake of

KRG may be associated with a continuous supply of

corticosteroid hormone without side effects as well as

maintaining prolonged CD8 T lymphocyte activity by

less destruction of CD8 T cells, suggesting maintenance

of balance in the immune system.

Despite the enormous efforts for decades aimed at

developing AIDS vaccines, effective vaccines against HIV

are not available yet. Considering the extreme difficulties

involved in developing HIV vaccines and the limitations

of HAART chemotherapy, KRG intake provides an

alternative and effective way of treatment for HIV-

infected patients.

In conclusion, these data show that KRG intake

independently has beneficial effects on the slow decrease

in CD4 T cells and on serum sCD8 levels in HIV-1-

infected patients, although the HLA factor was also

significantly associated with the rate of CD4 T cell

depletion in the Korean population.

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ACKNOWLEDGMENTS

This work was supported by grants from the Korea

Research Foundation Grant (KRF-2002-015-EP0070)

and the Korean Society of Ginseng (2000-2004).

We are grateful to the Korea Ginseng Corporation for

supplying Korean red ginseng for this study.

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Pharmacokinetic and metaboliceffects of American ginseng

(Panax quinquefolius) in healthyvolunteers receiving the HIVprotease inhibitor indinavir

Adriana SA Andrade, 1Craig Hendrix,2Teresa L

Parsons,2Benjamin Caballero,3Chun-Su Yuan,4Charles

W Flexner,2Adrian S Dobs,5 andTodd T Brown5

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Abstract

Background

Complementary and alternative medicine (CAM)

use is prevalent among HIV-infected patients to

reduce the toxicity of antiretroviral therapy.

Ginseng has been used for treatment of

hyperglycemia and insulin resistance, a common

side effect of some HIV-1 protease inhibitors (PI).

However, it is unknown whether American

ginseng (AG) can reverse insulin resistance

induced by the PI indinavir (IDV), and whether

these two agents interact pharmacologically. We

evaluated potential pharmacokinetic interactions

between IDV and AG, and assessed whether AG

improves IDV-induced insulin resistance.

Methods

After baseline assessment of insulin sensitivity

using the insulin clamp technique, healthy

volunteers received IDV 800 mg q8 h for 3 days

and then IDV and AG 1g q8h for 14 days. IDV

pharmacokinetics and insulin sensitivity were

assessed before and after AG co-administration.

Results

There was no difference in the area-under the

plasma-concentration-time curve after the co-

administration of AG, compared to IDV alone (n

= 13). Although insulin-stimulated glucose

disposal per unit of insulin (M/I) decreased by an

average of 14.8 5.9% after 3 days of IDV (from

0.113 0.012 to 0.096 0.014 mg/kgFFM/min

per U/ml of insulin, p = 0.03, n = 11), M/I

remained unchanged after co-administration of

IDV and AG.

Conclusion

IDV decreases insulin sensitivity, which is

unaltered by AG co-administration. AG does not

significantly affect IDV pharmacokinetics.

Go to

Background

Dietary supplements, herbs, and vitamins are

used widely among HIV-infected patients [1].

However, the safety or efficacy of many of these

therapies has not been formally evaluated.

These agents are often used among HIV-infected

patients to prevent or treat the adverse effects of

antiretroviral therapy [2]. Among these adverseeffects are disorders of glucose metabolism,

including insulin resistance[3], glucose

intolerance [4], and diabetes mellitus[3], which

were described soon after the introduction of

highly active antiretroviral therapy (HAART)[5].

Although the etiology of these problems is

multifactorial [6], exposure to protease inhibitors

(PIs) likely contributes directly. Indinavir (IDV),

for example, can worsen insulin sensitivity even

after a single dose in healthy volunteers[7].Ginseng is one of the most commonly used herbs

in the United States [8] and has long been used

for the treatment of hyperglycemia in Traditional

Chinese Medicine [9]. Experimental evidence for

its efficacy comes from several studies in both

animals and humans [10]. In two small clinical

trials,Panax ginseng[11] and AG [12] given daily

over 8 weeks significantly reduced fasting blood
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glucose and hemoglobin A1c in patients with type

2 diabetes. While the mechanisms by which

ginseng affects glucose metabolism have not been

fully elucidated, most recent evidence from

animal models suggests that improvement in

insulin sensitivity may underlie its hypoglycemic

effects [13]. It is not known whether ginseng can

reverse insulin resistance induced by PIs.Herbals treatments, like ginseng, are perceived to

be safe by patients, but pharmacologic

interactions with concomitant conventional

drugs are a major concern. Ginseng was recently

found to reduce the anticoagulant effect of

warfarin [14]. However, its potential interaction

with antiretrovirals has not been investigated.

Other herbs, such as St. Johns' wort [15] and

garlic [16] dramatically reduce the concentrations

of PIs in healthy volunteers, in the case of St.

John's wort, through the induction of their

common metabolic pathway, cytochrome P450

3A4 (CYP450 3A4). This could lead to a decrease

in effectiveness and potentially result in

treatment failure.

The goals of this study were to evaluate potential

PK interactions between IDV and AG, and assess

whether AG improves IDV-induced insulin

resistance.

Go to:

Methods

Study Participants

Healthy volunteers, male and female, 1864

years of age, were recruited through newspaper

advertisement, flyers and word of mouth.

Exclusion criteria included a history ofnephrolithiasis, use of any prescription

medications, over the counter medications, or

dietary supplement within 14 days of enrollment,

body mass index (BMI, weight (kg)/height (m2))

30 kg/m2, or blood donation within 30 days of

study enrollment. Prior to enrollment, subjects

were required to have a negative HIV-1 antibody

test, normal values for serum creatinine,

aspartate aminotransferase (AST), alanine

aminotransferase (ALT), and hemoglobin, and a

normal physical examination. The study was

approved by the Institutional Review Board at

Johns Hopkins University School of Medicine

and all participants signed informed consent.

Study Design

After initial screening, participants were

admitted to the Johns Hopkins inpatient General

Clinical Research Center (GCRC) on three

separate occasions over a 21 day period for PK

and metabolic studies. During the first inpatient

visit, baseline insulin sensitivity was assessed.

Subjects were then discharged with instructions

to take IDV 800 mg by mouth (Crixivan, Merck

and Company, Rahway, New Jersey, USA) every8 hours (0600, 1400, 2200) on an empty

stomach beginning three days before the

subsequent inpatient visit. During the second

inpatient visit, insulin sensitivity was reassessed

and an 8-hour PK IDV sampling was obtained.

Subjects were then instructed to take IDV, as

taken previously, and to co-administer

encapsulated AG ground root, 1 gram by mouth

every 8 hours. Outpatient safety visits with

laboratory assessments occurred 7 days beforeand 7 days after the final inpatient visit.

Dried whole-root AG was obtained from a single

batch through the Wisconsin Ginseng Board

(Wausau, Wisconsin). The identity of the dried

whole root of AG was verified by the Wisconsin

ginseng Board prior to encapsulation. Following

verification the dried whole-root AG was ground

and encapsulated in 500 mg capsules by the

American Pharmaceutical NutraceuticalLaboratories (Wausau, Wisconsin) and dispensed

by the Johns Hopkins Hospital Investigational

Drug service. AG was administered under

Investigational New Drug Application # 69,866

granted by the Food and Drug Administration.

The dose of AG was selected based on previous

studies investigating the effect of AG on glucose

tolerance in humans[12,17]. The dose of IDV was
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selected according to its package insert.

Following 14 days of IDV and AG, subjects

returned to the inpatient GCRC for reassessment

of insulin sensitivity and IDV PK.

Ginseng Analyses

The concentrations of six common ginsenosides

(Rg1, Re, Rb1, Rc, Rb2, and Rd) were measured,

following procedures described by Chuang [18],

in the Analytical Laboratory of the Johns

Hopkins University Division of Clinical

Pharmacology. Briefly, five different capsules

were randomly selected from five separate

bottles. The content of each capsule was

extracted with 3 mL of ethanol:water (50:50,

vol:vol), sonicated, and centrifuged. The pellet

was extracted two more times and the resultingliquid was filtered. Samples and ginsenoside

standards (Sigma-Aldrich, St. Louis, Missouri)

were analyzed by High Performance Liquid

Chromatography (HPLC) using Beckman

Ultrasphere 5 m, 250 4.6 mm column. The

amount of each ginsenoside assayed in the

capsules was as follows (expressed as percent per

gram of ginseng): Rg1 0.11, Re 1.06, Rb1 0.91, Rc

0.08, Rb2 0.19, Rd 0.08, Total ginsenosides 2.43.

The intra- and interassay coefficients of variation(CV) were < 10.5% and < 8.5%, respectively with

> 85% accuracy.

Bioassay for Hypoglycemic Activity

The hypoglycemic activity of the batch of AG

used in the study was assessed in diabetic mice

prior to initiation of the clinical studies, as

previously described [13]. Briefly,

male ob/ob mice (n = 6) received AG extract

dissolved in distilled water by daily

intraperitoneal injection at a dose of 250 mg/kg.

Fasting serum glucose was measured from blood

obtained from tail samples at baseline, day 5 and

day 12. The hypoglycemic response in AG-treated

mice was compared to that observed

in ob/ob mice who received vehicle following the

same protocol. Animals were fed rodent chow

and housed in environmentally stable conditions

in metabolic cages. Food consumption and

weight were monitored daily. All animal

experiments were carried out at the Tang Center

for Herbal Medicine Research, University of

Chicago in the laboratory of Chun-Su Yuan, MD,

PhD.

PK Sampling and Analysis

During the second and third inpatient GCRC

visits, nine blood samples were collected

immediately before administration of the

morning dose of IDV and at 0.5, 1,2,3,4,5,6, and

8 hours post-dose after an overnight fast. The

previous observed dose was given at 2200. PK

data were analyzed using non-compartmental

methods using WinNonlin (Pharsight, Cary,

NC). IDV PK parameter estimates included areaunder the plasma-concentration-time curve from

time 0 to 8 hours after the dose, (AUC08 hrs),

maximum plasma concentration (Cmax), minimum

plasma concentration (Cmin), and time to

maximum plasma concentration (Tmax).

Metabolic Assessments

Body composition, including fat-free mass

(FFM), was assessed at baseline using dual x-ray

absorptiometry (Hologic-QDR 4500W, Hologic

Co, Bedford, MA, intra-subject CV < 2%). BMI

was assessed during each inpatient admission

and was calculated as the weight in

kilograms/height in meters squared.

Peripheral sensitivity to glucose was assessed by

the hyperinsulinemic euglycemic clamp

technique [19]. Subjects were admitted to the

GCRC in the afternoon prior to the clamp

procedure and maintained on a eucaloric diet(50% carbohydrate, 30% fat, and 20% protein).

After an overnight fast, an intravenous catheter

was placed in the antecubital vein for infusion of

glucose and insulin. A second catheter for blood

sampling was inserted in a dorsal vein of the

hand in a retrograde fashion. The hand was

placed into a 50C warming box to "arterialize"

the samples [20]. After baseline blood samples
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were obtained, a primed, continuous infusion of

regular insulin (40 mU/m2/min) was started,

followed by a constant infusion of 20% dextrose

at a variable rate, based on 5-minute

measurements of blood glucose, in order to

maintain blood glucose concentrations at each

subject's baseline level 5%. Infusion continued

for a total of 180 minutes.

Glucose utilization (M) was calculated as the

average glucose infusion rate (milligrams of

glucose/kilograms of FFM/minute) during the

last 60 minutes of the infusion (i.e. steady state

portion). FFM was derived from the baseline

evaluation by dual energy X-ray absorptiometry

(DXA).

During the final 60 minutes of the insulin clamp

procedure, samples were obtained at 10 minutes

intervals to determine insulin concentrations. M

divided by the average insulin concentration in

the final 60 minutes (I), which represents the

amount of glucose metabolized per unit of

insulin, was used as the primary measure of

insulin sensitivity. During the second and third

inpatient visits, the morning dose of IDV (and AG

for the third inpatient visit) was given

immediately prior to the beginning of the insulinclamp procedure. Fasting serum glucose and

homeostasis model assessment of insulin

resistance (HOMA-IR), a widely used marker of

insulin sensitivity [21], were assessed prior to the

insulin clamp procedure at each of the inpatient

study visits.

The serum glucose concentration during the final

60 minutes of the clamp was 89.8 1.0 mg/dL

which was 97.8 0.3% of the targeted glucoseconcentration with a coefficient of variation of

4.2 0.3% (n = 32 clamp studies). The average

insulin concentration during the final 60 minutes

of the infusion was 69.2 1.7 U/mL.

Measurements

Serum glucose was measured using the glucose

oxidase method (Beckman Instruments,

Fullerton, CA). Serum insulin concentrations

were determined by enzyme immunoassay, using

a TOSOH 1800 (Tosoh Corporation, Tokyo,

Japan). Intra-assay and inter-assay CVs range

from 1.42.3% and 56%, respectively. IDV

concentrations were measured by HPLC-mass

spectrometry. The intra- and inter-assay CVs

were < 9% and < 8%, respectively with > 94%accuracy.

Statistical Calculations

Paired comparisons between outcome measures

obtained during the first and second inpatients

visits (i.e. Baseline vs. IDV Condition) and during

the second and third inpatient visits (IDV vs IDV

+ AG) were made using a paired t-test. Univariate

relationships between continuous variables wereassessed with linear regression. All data are

presented as mean standard error of the mean

(SEM). Differences were regarded as statistically

significant if p < 0.05. All data analysis was

performed using Stata (Version 8.1, Stata

Corporation, College Station, TX).

Pharmacokinetic parameter estimates were

summarized using geometric means with 95%

confidence intervals; values obtained with and

without AG were compared using a geometricmean ratio and 90% confidence interval.

Go to

Results

Preclinical Studies

In ob/ob mice receiving AG extract, fasting

glucose concentrations decreased (Baseline vs

Day 12; 235 11 mg/dL vs 193 9 mg/dL,between group t-test, p = 0.003), but remained

constant in the vehicle-treated group (243 10

mg/dL vs 251 12 mg/dL) (Figure (Figure1).1).

Weight did not change over the study interval in

the AG-treated mice (data not shown).
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Figure 1

Fasting Glucose Concentrations in Leptin-

Deficient (ob/ob) Mice Treated with AG-Extract(250 mg/kg) and Vehicle Over 12 Days (n = 6 in

both groups).

Clinical Studies

Fourteen healthy volunteers were evaluated

(Table (Table1).1). All participants were male, 12

were African-American, and two were white. Age

ranged from 2653 years with a mean of 42.9

1.9. The average BMI was 26.1 0.8 kg/m2 (range

21.929.9).

Table 1

Demographic Characteristics of Study

Participants

PK Analysis

Thirteen participants were included in the

analysis of the comparison of IDV PK with and

without AG. Subject 9 was noted to develop

transaminitis after the second inpatient study

visit and did not complete the remainder of the

study. Table Table22 shows the average IDV PK

parameters after 3 days of IDV following the

morning dose, and after co-administration of 14

days of IDV and AG. All PK parameters were

similar in the two periods.

Table 2

PK parameter estimates of IDV before and after

co-administration with AG (1 gram every 8

hours), n = 13

Metabolic Studies

Insulin Sensitivity: Effect of IDV

Eleven subjects were included in the analysis to

assess the effect of IDV on insulin sensitivity. The

calculated M and M/I values for subject 414 is

presented in Table Table3.3. The data from

subjects 13 were excluded since the protocol

was changed after these subjects completed their

participation in protocol. The protocol was

changed to better match peak IDV concentrations

with the steady state portion of hyperinsulinemia

during the insulin clamp. Specifically, for

subjects 4 14, the morning dose of IDV was

administered immediately prior to the beginningof the insulin clamp procedure, rather than two

hours before the start of the insulin clamp as

originally planned and executed for subjects 1

3.

Table 3

Glucose Utilization (M) and Insulin Sensitivity

(M/I) Measured by the Hyperinsulinemic

Euglycemic Clamp in Healthy Volunteers at

Baseline, After 3 Days of IDV, and After Co-

Administration of IDV and AG (1 gram every 8

hours) for 14 Days
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Compared to baseline measurements, IDV was

associated with an average decrease in insulin

sensitivity (M/I) of 14.8 5.9%, from 0.113

0.012 to 0.096 0.014 mg/kg FFM/min per

U/ml of insulin, p = 0.03) (Figure (Figure2).2).

We also detected a decrease in average glucose

utilization (M) with IDV administration when

compared to baseline (from 7.73 0.75 to 6.32 0.78 mg/kg FFM/min, p = 0.005). Fasting

glucose and HOMA-IR did not change when

comparing baseline to the second admission

(92.4 1.8 mg/dL vs 95.0 2.4 mg/dL, p = 0.27;

1.34 0.32 vs 1.34 0.23, p = 0.97, respectively).

Figure 2

Insulin Sensitivity (Glucose Infusion Rate Per

Kilogram of Free-Fat Mass Per Unit of Insulin) at

Baseline, After 3 Days of Indinavir, and After 14

Days of Co-Administration of AG in Healthy

Volunteers (p-values represent the average mean

difference by(more ...)

Insulin Sensitivity: Effect of AG

Ten subjects were included to assess the effect of

AG on IDV-induced insulin resistance (Table

(Table3).3). One subject (subject 9) did not have

complete data for this analysis because he was

discontinued from the study after the second

insulin clamp procedure, as previously noted.

There was no difference in insulin sensitivity

between the second (IDV alone) and third (IDV +

AG) insulin clamp procedures, 0.102 0.013 vs

0.099 0.016 mg/kg FFM/min per U/ml of

insulin, respectively (p = 0.72) (Figure(Figure2).2). Glucose utilization (M) with IDV

administration also did not change when AG was

co-administered, 6.68 0.76 vs 6.47 0.84

mg/kg FFM/min, respectively (p = 0.62).

Fasting glucose and HOMA-IR did not change

after 2 weeks of AG (93.0 1.4 mg/dL vs 92.0

2.6 mg/dL, p = 0.65; 1.4 0.25 vs 1.4 0.28, p =

0.95). Body weight did not change during the

trial (baseline vs third inpatient study visit, 83.1

3.1 kg vs 83.2 3.1 kg, p = 0.88).

Insulin Sensitivity: Effect of AG after

Normalization for IDV Concentrations

Because of the variability of IDV concentrations

with and without co-administration of AG, we

evaluated the potential effect of AG on insulin

sensitivity after adjustment for IDV

concentrations. In apost hoc analysis, we

standardized the measurement of insulin

sensitivity for IDV concentrations by dividing

M/I for the second and third insulin clamp

procedures by the corresponding IDV AUC

between 23 hours (AUC23). We then multiplied

this value by 106 for ease of interpretation.

We chose the 23 hour IDV AUC since it is the

same time period during the clamp procedure inwhich insulin sensitivity is assessed and there

was a trend toward correlation between insulin

sensitivity (M/I) and IDV AUC23 during the third

insulin clamp procedure (r = 0.58, p = 0.078).

The IDV AUC23was not correlated with M/I (r =

0.04, p = 0.90) during the second clamp

procedure (IDV alone). No other IDV PK

parameters or other fractional AUCs were

correlated with M/I for either the second or third

clamp procedure (data not shown).For the 10 subjects with measurable M/I

estimates normalized for IDV AUC23, the average

difference in IDV AUC23was similar when

comparing the period of IDV alone to the period

with concomitant IDV and AG (2353 389 vs

1923 483 nghr/mL; difference: 430 330

nghr/mL, p = 0.22). When each subject's M/I

was divided by the IDV AUC23, which can be

interpreted as insulin sensitivity per unit of

plasma IDV, a significant increase was seen after

AG co-administration (60.9 15.4 vs 92.2 20.9

mg Glucose106/kg FFM/min/U/ml of

insulin/nghr/mL IDV, p = 0.03). A similar

increase was seen when comparing M (multiplied

times 106) divided by the IDV AUC23between the

IDV alone period and the concomitant IDV plus

AG period (4240.6 1180.0 vs 6100.5 1526.8
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mg Glucose106/kg FFM/min/nghr/mL IDV, p =

0.05).Safety Assessment

Both IDV and AG were well tolerated. There were

no serious adverse events. Three subjects

developed transaminitis. In one subject (as

previously mentioned), an AST elevation 3 timesthe upper limit of normal (Grade 2) after 3 days

of IDV required study discontinuation. Three

subjects were noted to have mild elevations in

bilirubin. One subject had a mild increase in

serum creatinine. One patient reported an

episode of vomiting and one subject reported

dyspepsia after dose administration. All

laboratory abnormalities and symptoms

normalized after discontinuation of the study

drugs. With the exception of the Grade 2transaminites, all adverse events occurred during

the co-administration of IDV and AG.

Adherence Assessment

By pill count assessed on three occasions during

the study (i.e., the second and third inpatient

visit and the intervening outpatient safety visit),

IDV overall mean adherence was 97.7 1.5%. AG

adherence, as assessed on two occasions (interim

outpatient visit and visit three), was 96.6 2.5%.

Go to:

Discussion

In this prospective study of healthy volunteers,

we found that 14 days of co-administration of AG

did not significantly impact IDV PK. We also

found that, although IDV acutely reduced insulin

sensitivity by an average of 15%, AG did not

change insulin sensitivity in IDV-treated healthy

volunteers, providing evidence against its use in

the treatment of PI-induced disorders of glucose

metabolism.

Potential drug-herb interactions are an

important safety concern for many clinicians and

HIV-infected patients. Although herbal remedies

are perceived as safe by many patients, some can

inhibit and/or induce the CYP3A4 enzyme, the

main metabolic pathway for most PIs and non-

nucleoside reverse transcriptase inhibitors

(NNRTIs), potentially leading to increased

toxicity or therapeutic failure [15,16]. The

metabolic pathways of ginseng components are

not well known. Ginsenosides, which are steroid-

like molecules of the saponin class, are thought tobe the active compounds of all ginseng species

[22]. There are more than 20 different types of

ginsenosides in ginseng root and their relative

concentrations varies depending on the species,

the batch, and the part of the plant assayed (eg.

root vs berry)[23,24]. The ginsenosides also

differ in their effects on metabolism. In in

vitro models investigating the catalytic activity of

c-DNA expressed CYP450 isoforms, the

ginsenoside, Rd, has been shown to be a weak

inhibitor of CYP3A4, while Rf increased CYP3A4

activity by 54% [25]. In addition, metabolites of

ginsenosides as well as non-ginsenoside

components of ginseng have also been shown to

inhibit CYP3A4 in experimental models [26,27].

The clinical significance of these in

vitro observations is not clear.

In previous human studies, Siberian ginseng

(Eleutherococcus senticosus) has been shown toincrease concentrations of nifedipine [28], a

CYP3A4 substrate, but does not affect

concentrations of midazolam [29], another

CYP3A4 probe drug. It should be noted that

Siberian ginseng is not a species of the

genusPanax, contains no ginsenosides, and

therefore the effects of Siberian ginseng are not

generalizable to members of thePanaxgenus,

such as AG. However, human studies in healthy

volunteers usingPanax ginseng (C.A. Meyer)have shown no interaction with midazolam [30]

and no change in urinary 6-beta-OH-

cortisol/cortisol ratio [31], both measures of

CYP3A4 activity.

We also found that 3 days of IDV administration

decreased insulin sensitivity by 15% in healthy

volunteers. Our findings are similar to another

healthy volunteer study, showing a 17% decrease
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in insulin sensitivity with IDV administration

(800 mg q 8 hours)[32], but smaller in

magnitude when compared to another study

using a higher dose (34% decrease with a single

dose of 1200 mg) [33]. In in vitro studies and

animal models, PIs, such as IDV, impede glucose

movement through the major glucose transporter

in skeletal muscle, GLUT4, thereby inducinginsulin resistance[34]. The observations in

humans, including ours, are consistent with this

mechanism, although the extent to which it is

clinically relevant in the pathogenesis of

hyperglycemia among HIV-infected, HAART-

treated patients remains unclear.

Although we observed that insulin sensitivity

decreased with IDV administration, we did not

find any change in insulin sensitivity with co-

administration of AG. In previous studies,

Vuksan, et al. showed that AG administration

immediately prior to an oral glucose tolerance

test was associated with 20% decrease in glucose

AUC in both patients with type 2 diabetes

mellitus and healthy volunteers [35], but this

effect appears to be dependent on the batch of

ginseng used [23]. To rule out an inert batch of

AG, we conducted a bioassay of our batch using

an ob/ob mouse model and a hypoglycemic effectwas observed, suggesting that our batch

possessed some active components.

The mechanism underlying the previously

observed effects of AG on glucose metabolism

remains unknown and may be multifactorial. The

modulation of digestion and enhancement of

insulin secretion have been proposed based on

findings in some animals models [36,37], but

ginseng administration has also been shown to

improve insulin sensitivity in ob/ob mice bymore than two-fold [13]. It has been postulated

that ginsenosides may intercalate into the cellular

plasma membrane, thus modulating the cell

signaling, electrolyte transport, and receptor

binding [22]. It is not known whether this effect

could also modulate the effect of IDV on the

glucose flux through the GLUT4 transporter.

Another factor that may have contributed to the

lack of effect is the variability of IDV plasma

concentrations between the two clamps, which

has been previously observed [38]. The effect of

AG on IDV-induced insulin resistance would be

best determined if IDV plasma concentrations

were the same when it was given alone and when

it was co-administered with AG. For this reason,we normalized the measure of insulin sensitivity

for drug concentration in apost hoc analysis, by

dividing M/I by the IDV concentration during the

steady state portion of the clamp and found that

this ratio was significantly higher in the IDV +

AG condition.

Although the interpretation of ratios can be

challenging [39] and should be done with

caution, one explanation of this finding is that

insulin sensitivity per unit of IDV concentration

modestly improved with the administration of

AG. Given the known effect of IDV on GLUT4

blockade, AG components may work directly at

the plasma membrane to allow glucose to enter

cells, either by improving glucose movement

through GLUT4, increasing the concentration of

GLUT4 in the plasma membrane, or facilitating

glucose entry through alternate pathways.

Another possible mechanism of AGs effect maybe through the enhancement of local blood flow.

Increased capillary recruitment mediated though

nitric oxide is an important mechanism of

increasing glucose and insulin delivery to skeletal

muscle [40,41]. IDV has been shown to cause

endothelial dysfunction in healthy volunteers,

likely by reducing nitric oxide production [42].

Ginseng species have been shown in

experimental models to increase nitric oxide

production [43,44] and therefore, may effectinsulin sensitivity by this mechanism. This

hypothesis requires further investigation.

Our study had additional limitations which may

have implications for the generalizability of its

findings. Although both men and women were

eligible for participation, only men enrolled. In

previous studies, inducibility of CYP3A4 by

herbal compounds has shown an interaction by
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sex, whereby women showed a 74% increased

effect of St. John's wort on CYP3A4 activity using

a midazolam probe compared to men [45]. In the

same study, however,Panax ginseng showed no

effect on the midazolam metabolism in either

men or women. Further PK interaction studies in

women may be necessary. In addition, our

population was mostly African-American.Although there is evidence for genotypic

differences in CYP3A4 between Caucasians and

African-Americans, phenotypic differences in

CYP3A4 activity have not been found [46].

Finally, although we quantified the amount of

common ginsenosides, there is substantial

variability of composition even within species. As

a result, as is the case in all botanical research

using non-standardized complex compounds

whose active component is unknown, the extent

to which our findings are generalizable to other

AG products is not clear.

In conclusion, this study in healthy volunteers

found no evidence of a significant PK interaction

between AG and IDV. Because CYP3A4 is the

principal metabolic pathway of most HIV PIs and

NNRTIs, significant drug-herb interactions with

these antiretrovirals are unlikely. The metabolic

effects of AG are more difficult to interpret.

Although IDV significantly reduced insulin

sensitivity, there was no change in insulin

sensitivity with AG administration. However,

after normalization for IDV concentrations,

insulin sensitivity improved in the AG condition,

leaving open the possibility of a modest effect on

glucose metabolism. Further studies to clarify

this question should attempt to reduce variability

in IDV plasma concentrations, either by givingmultiple doses of IDV at shorter intervals to

maintain plasma IDV concentrations constant

while insulin sensitivity is assessed, or using an

IDV regimen boosted with ritonavir. Until these

issues are resolved, there is no clear scientific

basis to recommend AG for the treatment of

glucose abnormalities in HIV-infected patients.

Go to:

Competing interests

Drs. Dobs, Parsons, Caballero, and Yuan declared

that they have no competing interests. Dr.

Hendrix received research support from Merck

and Company. Dr. Andrade served as a

consultant for Abbott Laboratories. Dr. Brown

served as a consultant or has received researchsupport from Merck and Company, Abbott

Laboratories, Reliant Pharmaceuticals, Glaxo

Smith Kline, EMD-Serono, and

Theratechnologies. Dr. Flexner served on a

Scientific Advisory Board for Merck and

Company.

Go to

Authors' contributions

TTB performed the insulin clamps. CSY carried

out the animal studies. TLP carried out the

measurements of ginsenoside and IDV plasma

concentrations. TTB and ASAA drafted the

manuscript. ASAA, TTB, CWF, CH CSY, ASD

and BC participated in the design of the study.

TTB, ASAA, and CH performed the statistical

analysis. ASAA, TTB, ASD, CH and BC

participated in the data interpretation. TTB and

ASAA conceived of the study and participated inits coordination. All authors read and approved

the final manuscript.

Go to

Pre-publication history

The pre-publication history for this paper can be

accessed here:

http://www.biomedcentral.com/1472-6882/8/50/prepub

Go to

Acknowledgements

We would like to thank Chryssanthi

Stylianopoulos, PhD and Margia Arguello for

their technical expertise in measuring glucose

during the insulin clamp procedure and Alice
http://www.ncbi.nlm.nih.gov/pubmed/12235448http://www.ncbi.nlm.nih.gov/pubmed/14515058http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2542349/?tool=pubmed#ui-ncbiinpagenav-2http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2542349/?tool=pubmed#ui-ncbiinpagenav-2http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2542349/?tool=pubmed#ui-ncbiinpagenav-2http://www.biomedcentral.com/1472-6882/8/50/prepubhttp://www.biomedcentral.com/1472-6882/8/50/prepubhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2542349/?tool=pubmed#ui-ncbiinpagenav-2http://www.ncbi.nlm.nih.gov/pubmed/12235448http://www.ncbi.nlm.nih.gov/pubmed/14515058http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2542349/?tool=pubmed#ui-ncbiinpagenav-2http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2542349/?tool=pubmed#ui-ncbiinpagenav-2http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2542349/?tool=pubmed#ui-ncbiinpagenav-2http://www.biomedcentral.com/1472-6882/8/50/prepubhttp://www.biomedcentral.com/1472-6882/8/50/prepubhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2542349/?tool=pubmed#ui-ncbiinpagenav-2


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Ryan, PhD for her guidance with the insulin

clamp procedure. We are thankful to Andrea

Weiss for dispensing study drugs and preparation

of solutions used in the insulin clamp procedure.

Finally, we also would like to acknowledge Dr

Angela Kashuba for the analysis of the indinavir

assays. Her work is supported by #9P30 AI

50410-04, University of North Carolina at ChapelHill Center for AIDS Research (CFAR). This work

was supported by a National Center for

Complementary and Alternative Medicine

supplement to the National Cancer Institute

Grant # P30CA06973, the National Center for

Complementary and Alternative Medicine K23

AT002862-01 (TTB), and the Johns Hopkins

University School of Medicine General Clinical

Research Grant M01-RR00052 from the National

Center for Research Resources/National

Institutes of Health.

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