The Safety and Tolerance of Herbal Anti-Angina Drug Compound Danshen Droplet Pill in Healthy Volunteers

doi:10.4236/pp.2013.46071

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Pharmacology & Pharmacy, 2013, 4, 490-495

http://dx.doi.org/10.4236/pp.2013.46071 Published Online September 2013 (http://www.scirp.org/journal/pp)

The Safety and Tolerance of Herbal Anti-Angina Drug

Compound Danshen Droplet Pill in Healthy Volunteers

Ying Zhou1, Yimin Cui1*, Xia Zhao1, Yong Huo2, Zhaohong Nie3,4, Min Zhao3,4, Z hixin Guo3,4, He Sun3,4

1Department of Pharmacy, Peking University First Hospital, Beijing, China; 2Department of Cardiology, Peking University First

Hospital, Beijing, China; 3Tasly Pharmaceutical Group Co., Ltd., Tianjin, China; 4Suntech Research Institutes, Rockville, USA.

Email: *[email protected]

Received June 19th, 2013; revised July 25th, 2013; accepted August 16th, 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Background: Compound Salvia Pellet (T89), consisting of Danshen (salvia miltiorrhiza), Sanqi (panax notoginseng),

and Borneol (Cinnamomum camphora), has been used worldwide for 14 years for chronic angina treatment. Purpose:

A dose escalation study to determine the maximum tolerance dose (MTD) in Chinese population to support a proposed

dose regimen change. Methods: Forty-six participants (age 18 to 45 yrs, male to female ratio = 1:1) were divided into a

series of 6 patients cohorts, and sequentially assigned into one of the escalating dose groups, starting from 540 mg, the

clinical doses, until 4 out of 6 subjects experience clinical Adverse Events (AEs) or when the pre-defined 3510 mg dose

level is reached and completed. All doses were given orally as a single dose 2 hours after breakfast. Adverse events,

vital signs, 12-lead ECG, clinical and laboratory parameters and medical evaluation were conducted as outcome meas-

ures. Results: Study completed at the highest pre-defined dose level of 3510 mg dose as never had 4/6 of subject ex-

perience AEs in any dose levels studied. All participants completed the study and data were included in the safety

analysis. The only moderate AE observation (muscle damage) was observed at 2970 mg dose and was recovered with-

out any medical treatment, and all other AEs (ECG, dizziness, muscle damage) were mild and may (5 cases) or may not

(9 cases) be related to testing drug and were all self-resolved within 30 min after dose. Conclusion: Given as single oral

dose, Compound Salvia Pellet is safe and well-tolerated up to the 3510 mg studied. The MTD value of Compound Sal-

via Pellet is unknown from this trial and must be higher than 3510 mg, 13 times higher than its current clinical dose.

Keywords: Compound Salvia Pellet; Safety; Tolerance; Chronic Angina Treatment

1. Introduction

Compound Salvia Pellet (T89), has been widely used in

China for 14 years, and used worldwide for more than 10

years. Compound Salvia Pellet is indicated for chronic

angina treatment [1,2], manufactured and marketed by

Tianjin Tasly Group Co., Ltd of P. R. China. T89 has

been marketed as composite Danshen pill [3], Compound

Danshen droplet pill [4], or Cadiotonic Pill, and Dantonic

Dripping pills. It is an herbal drug consisting of active

herbal ingredients co-extracted from Danshen (salvia

miltiorrhiza) and Sanqi (panax notoginseng), and tiny

amount of Borneol (Cinnamomum camphora) [3]. Ac-

cording to Traditional Chinese Medicine (TCM) concept,

salvia miltiorrhiza in this formula, which is regarded as

the principal drug (known as the “King drug”), can pro-

mote or invigorate blood flow and remove blood stasis.

Experimental studies have shown that salvia miltiorrhiza

can dilate coronary arteries, increase coronary blood flow

[5], and scavenge free radicals [6] in ischemic diseases,

so that it reduces the cellular damage from ischemia and

improves heart functions. Panax notoginseng serves as

“the Minister drug” to reinforce salvia miltiorrhiza’s

therapeutic action, which can inhibit activation of plate-

lets and their adhesion and aggregation [7], and counter-

act free-radical damage associated with atherogenesis

[8,9]. Cinnamomum camphora, for resuscitation, is re-

lated to the heart channel and lung channel, to “open and

revive the spirit” according to TCM. Clinical studies

demonstrated that T89 has numerous clinical effects on

increasing coronary flow rate and superoxide dismutase

activity, expanding the blood vessel, promoting blood

circulation, relieving blood stasis, improving the micro-

cycle and changing the blood viscidity, also decreasing

the consuming oxygen of the cardiac muscle, with the

*Corresponding author.

The Safety and Tolerance of Herbal Anti-Angina Drug Compound Danshen Droplet Pill in Healthy Volunteers 491

effects on anticancer, antibacterial, antiinflammation, etc.

[10-12].

A meta-analysis suggests that compound salvia pellet

is safe and does not develop tolerance over time [13].

However, most of the included trials were using lower

dose levels. Especially, the worldwide commonly used

clinical dosage of T89 is 270 mg each time, 3 times a day,

regardless of race, age, and body weight.

In 10 years of post-marketing safety watch, Composite

Salvia Dropping Pill showed none severe adverse reac-

tion. Meanwhile, clinicians frequently use higher dose in

clinical practice. Based on preclinical studies sponsored

by Tasly Pharmaceutical Group, the LD50 in mice after

single dose is 16.7 mg/kg (Is it 16.7 mg or 16.7 mg/kg?

Is the number correct?). The result of long term toxicity

test indicates that the highest dosage among the three

testing groups used in this animal study is the 50 times

higher than human common dose.

The objective of this dose escalation study was to es-

timate the MTD in Chinese population to support a pro-

posed dose regimen change.

2. Materials and Methods

2.1. Study Drug Administration

Clinical trial material (CTM) was a two herbal mixture

extract preparation and was produced and provided by

Tianjin Tasly Group Co., Ltd. CTM for the phase I type

MTD study was supplied as 27-mg pills. The Batch

Number was 20060908.

2.2. Study Design

This randomized, open label, dose escalation study of

Composite Salvia Dropping Pill was performed in Chi-

nese healthy volunteers. A total of 46 healthy, nonsmok-

ing volunteers, 18 to 45 years of age (difference is not fit

to be 10 years in the same group (I cannot understand

this sentence, please revise)) and with body mass index

(BMI) between 19.0 and 25.0 kg/m2. All participants

were able to give written informed consent before to be

enrolled in the study, same numbers of male and female

subjects were enrolled to ensure gender balance. The

study was conducted in according with Good Clinical

Practice and International Council on Harmonization

guidelines. The study protocols and the informed consent

were approved by the Clinical Drug Trial Ethical Com-

mittee of the Peking University First hospital. Study

personnel obtained written informed consent directly

from all subjects prior to their entry into the study.

The nine single doses of T89 evaluated were 20, 40,

60, 70, 80, 90, 100, 120, and 130 pills of the 27 mg for-

mulation. The doses were administered orally with 500

mL warm water 2 hours before meal. All subjects were

randomly divided into 9 groups, 6 subjects per group.

Volunteers were admitted to the study unit the day before

each scheduled dosing period and remained at the study

site for 24 hours after dosing. Does escalation were

started from the lowest dose, and move to the next dose

until all safety profile were checked and observed. Each

subject only toke one dose and was not repeated for any

other dose level. The stopping criteria for dose escalation

was that if testing drug related adverse reaction were

observed in 4/6 subjects, the same dose will be repeated.

If the same or higher frequency of adverse reaction was

observed again, MTD will be defined as the dose that is

one level lower. If adverse reaction rate was lower than

4/6 in the repeated dose level, dose escalation will con-

tinue to move to a higher dose. All dose groups were

monitored on a combined inpatient/outpatient basis.

During the one week outpatient period, subjects reported

daily to the study unite for scheduled events and proce-

dures.

2.3. Safety and Tolerability Evaluations

The tolerability and safety of T89 were evaluated based

on adverse-event reports, vital signs, electrocardiograms,

clinical laboratory values, and results of physical exami-

nation. Study subjects were monitored carefully through-

out each dosing period for adverse experiences. The rela-

tionship of adverse events to the study drug was assessed

by a qualified physician and is in general based on such

considerations as temporal relationship to study drug

administration, subject’s relevant medical history, and

whether the finding is likely due to any pre-existing con-

ditions.

Electrocardiograms monitoring was performed using

Twelve-lead ECG (PHILIPS Page Writer Trim III, USA

Philips Co. Ltd.). The measurements were made at the

first screening visit, pre-administration, 0.5, 1, 2, 3, 4, 6,

8, 24 h and 7 d after test drug administration and any

other time if necessary. Except for adverse events,

12-lead ECG, vital signs and clinical laboratory, includ-

ing CK, CK-MB, HBDH, CTN I were evaluated.

2.4. Statistics

A paired t test was used to evaluate the safety data within

each group (within each group or for each subject?), and

P-values of less than 0.05 were considered as statistically

significant.

3. Results

3.1. Enrollment and Demographics

A total of 46 Chinese male or female healthy subjects

were enrolled in the study with the age of 26 to 39 years,

22 males and 24 females. Subjects for these study were

similar in age (35.1 ± 3.43 years); weight (60.0 ± 8.25

The Safety and Tolerance of Herbal Anti-Angina Drug Compound Danshen Droplet Pill in Healthy Volunteers

492

kg); height (1.62 ± 0.079 m); and body mass index (22.8

± 1.92) (Table 1).

As shown in Table 1, 9 of the subjects were current

smokers. All smoking subjects were aged between 20

and 25, except for subject 120 who was 19 upon screen-

ing. This subject was discontinued from the study upon

discovery of that he started smoking was outside the age

range for inclusion criterion. The average height of all

subjects was 171 cm (range: 163 - 183 cm), with an av-

erage weight of 65.3 kg (range: 53.0 - 82.0 kg). The BMI

ranged between 19.2 - 27.0 kg/m2 with a mean of 22.4

kg/m2.

3.2. Safety Observations

Safety was monitored at 0.5, 1, 2, 3, 4, 6, 8, 24 h and 7

days postdose. Adverse events (ADR) in all dose levels

were recorded. All participants completed the study and

were included in the safety data analysis. Any clinically

significant change in laboratory values post drug admini-

stration compared to baseline were recorded as ADR and

are summarized in Table 2.

Overall, during the course of the study, there was no

significant change in vital signs when compared to pre-

dose baseline. Specifically, thirteen out of 46 subjects

reported a total of 14 treatment-emergent mild or moder-

ate adverse events (all causalities) during the study. Five

out of the 14 events were judged by the investigator to be

related to study drug, while the other 9 were considered

unrelated. All of the reported adverse events were mild

except for that the muscle damage was rated as moderate.

All the adverse events disappeared spontaneously.

There were no clinically significant ECG findings re-

ported except one case of ST-T change. (Please provide a

little more information, such as what types of change,

degree, recovery and etc.).

There were also no clinically significant alterations in

laboratory values except one subject showed a single lift

of ALT, HBDH, CK, CK-MB, TBIL, TG, WBC, LEU

values after the 120 pills dose level. This subject’s CK,

CK-MB and MB have significant clinical differences 2

days after drug administration. The subject was in-

structed to take a lot of water after the diagnosis. All the

laboratory values were improved 5 days afterwards.

Double check on day 11 showed everything are back to

normal. Table 3 summarizes CK, CK-MB, MB and other

laboratory values for baseline, day 1 and day 7 for this

subject. It can be seen that the CK levels increased after

both day 1 and day 7 post dose comparing baseline.

However, they were still within the normal range and

was not clinically significant alterations.

3.3. MTD Value

Although 120 × 27 mg dose group had one subject ex-

perienced muscle injury with moderate degree, this does

not warrantee to stop the trial. Next dose of 130 × 27 mg

dose was continued with caution. Neither ADRs, nor CK

ascending symptoms were observed in the 130 pills

group.

According to pre-defined study protocol, if in the ac-

celerative process, more than 4/6 of the subjects indicate

severe adverse reaction directly related to the trial drugs,

the acceleration must be stopped and repeated. The trial

reached its final termination dose level at 130 pills with-

out any clinical severe adverse reaction. Therefore, the

MTD should be greater than 130 pills.

4. Discussion

Chronic stable angina is a major health problem that af-

fects over 7 million adults in the United States, with an

estimated 400,000 new cases annually [14], and it results

in a considerable burden for both the individual and

Table 1. Subjects studied.

T89

20 × 27 mg

group

40 × 27 mg

group

60 × 27 mg

group

70 × 27 mg

group

80 × 27 mg

group

90 × 27 mg

group

100 × 27 mg

group

120 × 27 mg

group

130 × 27 mg

group

Total subjects 4 4 4 4 6 6 6 6 6

Male 2 2 2 2 3 3 2 4 2

Female 2 2 2 2 3 3 4 2 4

Age (years)

Mean 30.8 37.8 34.8 35.3 35.7 33.8 37.3 34.7 36.8

Range 30 - 32 37 - 38 31 - 38 32 - 38 31 - 38 31 - 39 37 - 38 30 - 39 26 - 39

BMI (kg/m2)

Mean 22.8 23.7 22.9 22.3 22.3 22.2 22.9 23.5 23.1

Range 20.7 - 24.7 21.7 - 25.0 21.0 - 25.021.2 - 23.619.5 - 24.419.2 - 24.919.5 - 25.0 20.1 - 25.0 19.5 - 25.0

Race

Asian 4 4 4 4 6 6 6 6 6

The Safety and Tolerance of Herbal Anti-Angina Drug Compound Danshen Droplet Pill in Healthy Volunteers 493

Table 2. Frequency of treatment-emergent drug-related* adverse events by type.

Number of adverse events

[number of subjects with adverse event]

MedDRA term 20 × 27 mg

group

(N = 4)

40 × 27 mg

group

(N = 4)

60 × 27 mg

group

(N = 4)

70 × 27 mg

group

(N = 4)

80 × 27 mg

group

(N = 6)

90 × 27 mg

group

(N = 6)

100 × 27 mg

group

(N = 6)

120 × 27 mg

group

(N = 6)

130 × 27 mg

group

(N = 6)

Vascular disorders

abnormal ECG 1 [1]

Nervous system disorders

Dizziness 1 [1] 1 [1]

Dizziness and sweat 1 [1]

Musculoskeletal and

connective tissue disorders

muscle damage 1 [1]

Total 1 [1] 1 [1] 1 [1] 2 [2]

N = Number of subjects; *Adverse events with possible or probable relationship to study drug.

Table 3. Level of clinical laboratory by subjects in 130 × 27 mg group.

Special

laboratory (unites) Reference

range Baseline Change from

baseline to1d 1 d Change from

baseline to 7 d 7 d

PT (s) 10 - 14 10.5 ± 0.4 −0.6 ± 0.5* 9.9 ± 0.4 −0.2 ± 0.1 10.3 ± 0.4*

APTT (s) 23 - 35 26.3 ± 0.9 0.1 ± 2.2 26.4 ± 1.9 0.8 ± 2.0 27.1 ± 1.8

AST (U/L) 0 - 45 25.3 ± 3.4 −2.5 ± 4.5 22.8 ± 4.2 −6.1 ± 5.6 19.2 ± 2.3*

ALT (U/L) 0 - 40 14.6 ± 5.8 1.6 ± 7.2 16.2 ± 8.6 0.5 ± 9.8 15.1 ± 6.4

CREA (μmol/L) 35 - 97 51.1 ± 11.6 11 ± 14.6* 62.1 ± 13.5 1.1 ± 14.2 52.2 ± 7.8

BUN (μmol/L) 2.9 - 7.2 3.9 ± 0.3 0.5 ± 0.5 4.4 ± 0.7 0.3 ± 1.7 4.2 ± 1.1

GLu (mmol/L) 3.31 - 6.1 5.8 ± 0.9 −0.8 ± 1.0* 5.0 ± 0.2 −0.5 ± 1.2 5.3 ± 0.8

TCHO (mmol/L) 3.1 - 5.66 4.86 ± 0.58 −0.23 ± 0.34 4.63 ± 0.67 −0.57 ± 0.66 4.29 ± 0.64*

TG (mmol/L) 0.14 - 1.8 0.9 ± 0.47 0.58 ± 0.86* 1.48 ± 0.74 0.04 ± 0.82 0.94 ± 0.56

HDL-C (mmol/L) 1.00 - 1.55 1.39 ± 0.18 −0.14 ± 0.25 1.25 ± 0.16 −0.13 ± 0.12 1.26 ± 0.08

LDL-C (mmol/L) 2.1 - 3.1 2.9 ± 0.39 −0.22 ± 0.56 2.68 ± 0.47 −0.37 ± 0.66 2.53 ± 0.42*

MB (ng/ml) <100 18.75 ± 4.08−1.32 ± 3.64 17.43 ± 1.58 −3.2 ± 2.89 15.55 ± 3.53

CK (U/L) 24 - 170 123.9 ± 25.6−49.5 ± 19.2* 74.4 ± 17.4 −25.7 ± 22.9 98.2 ± 17.3*

CK-MB (U/L) 2 - 25 9.5 ± 8.0 −4.1 ± 6.4 5.4 ± 4.2 −3.0 ± 5.4 6.5 ± 4.4

Baseline, change (baseline to 1 d, baseline to 7 d), and 1 d, 7 d, means ± SD, for levels of clinical laboratory by Subjects in 130 × 27 mg Group, the maximum

tolerated dose (MTD) group are shown. *p < 0.05, within groups. There were statistically significant differences not clinically significant alterations, still in the

normal range.

society. At present, organic nitrates are indicated as the

firstline therapy for the long-term management of chro-

nic stable angina [15-18]. Organic nitrates have been

prescribed to patients with stable angina in the last 100

years or more and are still widely used in the treatment of

such patients. However, some adverse effects have also

been reported. The major problem with long-term used of

nitroglycerin and long-acting nitrates is development of

tolerance. Although in some clinical trials intermittent

therapy seems to be a hopeful strategy in preventing ni-

trate tolerance and has proved superior to continuous

therapy [19,20], it still has problems, such as possible

association with rebound myocardial ischemia during the

nitrate-free period and adverse effects on performance on

treadmill exercise tests during the period of withdrawal

from nitrates [16]. In search of better treatment options,

many patients in both east and west have turned to alter-

native medicines in the hopes of identifying “natural”

substances with less toxicity but equal effectiveness. T89,

as one of the alternative therapies, is widely used in

China and worldwide, as drug or dietary supplement, but

the best clinical dose to ensure the efficacy and safety of

T89 for the treatment of chronic stable angina pectoris

needs further investigation. Until now, many randomized

controlled trials (RCTs) have been completed or pub-

lished which indicate that T89 may be effective in

The Safety and Tolerance of Herbal Anti-Angina Drug Compound Danshen Droplet Pill in Healthy Volunteers

494

patients with chronic stable angina pectoris compared

with the organic nitrates [21]. But most of the included

trials were at lower doses or inclusive [13]. This study

demonstrated that T89 was well tolerated after admini-

stration as a single oral dose across the 20 × 27 mg to

130 × 27 mg dose range. Moreover, rigorously designed,

multi-center, large, randomized, double-blind, controlled

trial is being performed in the USA.

In a retrospective meta-analysis, adverse events were

described in 17 of the 27 trials (63.0%). Adverse events

were reported in 26 of 1093 (2.4%) patients treated with

CSP [13]. Abdominal complaints, nausea, dyspepsia and

dizziness were reported most often, and which com-

pletely alleviated without any treatment [13,21,22]. Diz-

ziness was the most adverse events that have been re-

ported, and duration prolonged as the dosage ascends. In

this trial, the 40 × 27 mg group, 70 × 27 mg group, and

120 × 27 mg group each had one case of adverse event,

and the attacking time was about 1 hour to 2 hours after

administration with duration of 3 minutes, 7 minutes or

20 hours, accompanied with deficient sweating. It seems

the degree of sweating is related to dose. All the three

subjects were female, who might be more sensitive to the

drugs. The first and only moderate AE (muscle damage)

was observed at 120 × 27 mg dose and were recovered

without medical treatment. None CK ascending symp-

toms occurred in the following 130 × 27 mg group. How-

ever, such observation suggests muscle damage could be

observed and should be monitored in case of overdose.

The mechanism of muscle damage is waiting to be inves-

tigated.

Clinical Tolerance Study usually are conducted before

large clinical phase 2 or phase 3 trials. Mice LD50 of sin-

gle dose was 16.7 mg/kg. Long term toxicity study indi-

cates that highest dose is 50 times higher than human

dose. At single oral dose, T89 is safe and well-tolerated

up to 130 × 27 mg dose. The MTD value of T89 in this

study was not reached, is unknown, and must be higher

than 130 × 27 mg.

5. Conclusion

In conclusion, T89 was well tolerated after administra-

tion as a single dose to across the 20 × 27 mg to 130 × 27

mg dose rage. T89 was safe and well tolerated at the

highest dose level studies: 130 × 27 mg. The MTD value

of T89 was not reached in this trial, which was unknown,

and must be higher than 130 × 27 mg.

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