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Ida Farida
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Product Manager
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TANABE INDONESIA
INDONESIA

Drug Information
INDICATIONS

- Allergic Rhinitis

- Urticaria

DOSAGE and
ADMINISTRATION

Usually, for adults, 10 mg of TALION as a single dose

is orally administered twice daily.
The dosage may be adjusted depending on
the patients age and symptoms.

TALION Mechanism of Action

Antigens /
Non-specific stimuli
Allergic Inflammation
Antigen
Presenting
Cell

Type I Allergic Response

Mast Cell

Lymphocyte

TALION
(Inhibition of
IL-5 Production

Cytokine
Production
IL-5
, IL4

TALION

Chemical Mediator release :

Histamine
Leukotriene
Platelet Activating Factor
Prostaglandin, etc.

(H-1 Antagonism)

TALION
(Inhibition of Eosinophil
Infiltration)

Microvasculature,
Sensory Nerve

Eosinophil

Eosinophil Infiltration

Allergic
Symptoms
Allergic Rhinitis
Urticaria, etc.

Vasodilation,
Enhanced Vasopermiability,
Excitement of Nerve

TALION
FAST ACTION

Absorption Rate of TALION is 7.7 times larger than that

of Fexofenadine at proximal region
Comparison of absorption rates between TALION and Fexofenadine at proximal region
of small intestine 30 min after injection

Effects of P-gp on intestinal absorption of TALION was minimal,

presumably because of high membrane permeability at the
upper region of small intestine where P-gp expression is low .
R. Ohashi et al.: Drug Metabolism and Disposition 34: 793-799, 2006

Comparison of T-max among 2nd Generation Anti Histamines

Desloratadine

3 hours
(Aerius)

TALION
Cetirizine
Levocetirizine
Fexofenadine

Starts on 0.8 - 1.6 hours

1 hours

(Ryzen)

1 hours

(Xyzal)

2.6 hours
(Telfast))

1.3 - 2.5 hours

Loratadine

(Claritin)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

(Hours)

TALIONs Tmax is SHORT

TALIONs Fast Acting can be Expected for Symptomatic Treatment ANYTIME!
Second Generation Antihistamine Products. Statewide Pharmacy & Therapeutic
Committee, May 2011. Ines Chen, et al.

Bepotastine Suppresses Skin Symptoms Sooner

than Fexofenadine does, which is Relatively
Consistent with the Tmax Results.

Clinical Images of Histamineinduced Flare & Wheal

Scanning Laser Doppler Images of Histamineinduced Flare & Wheal

Bepotastine Suppresses Skin Symptoms Sooner

than Fexofenadine does, which is Relatively
Consistent with the Tmax Results.

Bepotastine Suppressed Flare Response

Significantly than Fexofenadine
at 30 min After Administration

Bepotastine more Significantly Suppressed

The Wheal Development than Fexofenadine
starts at 30 min after administration

Bepotastine as Anti Pruritic Effect

with Decreasing Itch Intensity

TALION
Non Sedating Antihistamine

Kazuhiko Yanai: Prog. Med 24, 262-267 (2004)

TALION : NON SEDATING Anti-histamine

Safe
Low Brain Penetration
Histamine H1 receptor

H1
occupation
rate in brain

PET
images
(subjects: 8 normal 8
adults)
PET

placebo

Bepotastine

Diphenhydramine

MRI-T1

p< 0.001

56.4%

14.7%
Bepotastine

Diphenhydramine

TALION
was
confirmed
to be classified as NON 20%
SEDATING
Antihistamine

CONGA

defined
by CONGA (Consensus Group on New Generation Antihistamine :
H1-RO less than 20%)
Tashiro M, et al : British Journal Clinical Pharmacology, 65(8), 2008

Bepotastine : Effects on CNS and Other Systems

As Bepotastine poorly penetrates the blood
brain barrier, it is expected to have only minimal
suppressive effects on CNS.

In 1 day trial, Bepotastine 20 mg/day was associated with

less subjective sedation at 2 hours and less impairment
of psychomotor performance than Olopatadine 10
mg/day, Fexofenadine 120 mg/day, or Cetirizine 10 mg/day

8. Takahashi H, et al. Clin Exp Dermatol 2004. Sept: 29 (5) : 526 32

TALION : Effects on CNS and Other Systems

Bepotastine 2.5 40 mg/day was not
associated with clinically significant changes in
blood pressure, pulse rate, respiratory rate,
body temperature or ECG or laboratory findings
in single 10, and multiple dose 11,12 studies in
healthy male 10, 11 or elderly volunteers 12.

8. Takahashi H, et al. Clin Exp Dermatol 2004. Sept: 29 (5) : 526 32

10. Yokota H, et al. Rinsho Iyaku 1997; 13 (5) : 1137 53
11. Kadosaka, et al. Rinsho Iyaku 1997; 13 (5) : 1155 - 68

Oral Bepotastine (10 mg), with its

relatively low H1RO & thus
minimal sedation, has the
potential for use as a mildly or
slightly sedative antihistamine in
the treatment of various allergic
disorders

- Bepotastine merupakan substrat

utk P-gp, dimana P-gp secara jelas
membatasi distribusi Bepotastine
ke otak.
- P-gp tidak memiliki pengaruh
thdp absorpsi Bepotastine
di usus karena tingginya
permeabilitas membran pada
bagian atas usus halus.
- Berbeda dengan Fexofenadine yg
memiliki permeabilitas membran
yang rendah pada substrat P-gp

TALION
High Selectivity to Histamine H1 Receptor

M. Kato et al.: Arzneimittel-Forschung/Drug Research

47 (), 10, 1116, 1997

Histamine H1 Receptor Antagonistic Action

Receptor Binding Inhibitory Action by TALION and its Competitors (IC 50)
H1
Bzd

H1

-9
-8
-7
-6

H3

Bzd
1

H1

-9
-8
-7
-6

Bzd

H3
1

-9
-8
-7
-6

H3
1

H1:Histamine H1,
2

5-HT

5-HT

5-HT

Triludan

Bzd

H3
1

5-HT

:Adrenergic ,
D2L:Dopamine D2L,

H1

-9
-8
-7
-6

2:Adrenergic 2,

600nM

H1

-9
-8
-7
-6

Triludan

Terfenadine
52nM

H1

1:Adrenergic 1,

L
Fexofenadine

TALION
101nM
Bzd

Bzd

H3
1

5-HT

H3:Histamine H3,

-9
-8
-7
-6

H3

5-HT2: Serotonin 2,
1

M:Muscarinic,
Bzd:Benzodiazepine

5-HT

D
L

Zaditen

Ketotifen
2.2nM

Cetirizine

(253nM

Zyrtec

Alesion

Epinastine
3.6nM

M. Kato et al.: Arzneimittel-Forschung/Drug Research 47 ( ), 10, 1116, 1997

Bepotastine showed a high

selectivity & potent
antagonistic action to H1receptor and exerted an
excellent antiallergic action

(Honda, et al, 1997; Kato, et al, 1997; Sakai, et al, 1997)

Inhibitory Effects on Histamine

Induced Intradermal Reaction
Subjects : 10 healthy adult males
Methods : 10 mg of Bepotastine besilate (oral administered single dose)
In 10 healthy adult males, 1g/mL of Histamine solution was injected
on backs of subjects at following times :
Before administration of TALION and 1, 2, 4, 6, 8, 12, 24 hours after
administration of TALION.
15 minutes after Histamine injection, induced wheal areas were measured.
As control, 0.1 mL of normal saline was Intradermally injected.
Results : Single oral administration of TALION inhibited wheals
induced by histamine Intradermal injection and
SIGNIFICANT INHIBITION was observed even at 12 hours
after TALION administration

Y. Ishibashi et al.: J Clin Therap Med 13 (5), 1187, 1997

Inhibitory Effects on Histamine

Induced Intradermal Reaction

Time course change in wheal areas (%)

Wheal areas

150
100
50
0

50%
TALION 10 mg

1%
0 1

10 12

15

Time after administration

Placeb
o
20
25

(hours)

Mean
n=10

Y. Ishibashi et al.: J Clin Therap Med 13 (5), 1187, 1997

Anti-inflammatory Actions
of

TALION

Kazuhiko Yanai: Prog. Med 24, 262-267 (2004)

Suppressive Effects on IL-5 Production

In-vitro, Bepotastine inhibited antigen induced
production of IL-5 by human peripheral blood
mononuclear cells 28, suppressed the production
of Interleukin-1 and T helper 1 (Th1) & Th2
chemokines in human epidermal keratinocytes 29,
and inhibited the expression of intercelullar
adhesion molecule-1 (ICAM-1) in human epidermal
keratinocytes 29 & vascular endothelial cells 26.

26. Shinichi, et al. Arzneimittelforschung, 47 (8) : 954 8, 1997

28. Kaminum
a O, et al.: Biolo ical & Pharmaceutical Bulletin 21 4 411 3 1998
Kaminuma
29. Kobayashi, et al. Skin Pharmacol Physiol, 22 (1) : 45 8, 2009

Suppressive Effects on Interleukin-5 Production

Methods : Effects on mite antigen (Df) induced IL-5 production by PBMC derived from Df-sensitive were investigated.
Results : TALION significantly suppressed mite antigen (Df) at 10 and 100 M.
By pre-incubating PBMC with TALION for 120 min before adding Df antigen, significant suppression of IL-5
production was observed event at 0.1 M.
(in-vitro)

Rate of Suppression of
IL-5
Production

(%)
100
**

80

Ketotifen
Cetirizine

60

TALION
TALION

( Zyrtec)
Zyrtec)

**

(pre-treatment for 120 min)

40
20

(Zaditen
(Zaditen))

**

**
**

MeanS.E.
n36

**

Paired t test

(Compared with control)

control)
* p<0.05

** p<0.01

20
0.1

10

Drug Concentration

100 (M)

(O. Kamimura et al.: Biolo ical & Pharmaceutical Bulletin 21 4 411 1998

TALION
Not have Drug-to-Drug Interaction

Kazuhiko Yanai: Prog. Med 24, 262-267 (2004)

Bepotastine : No Report Drug Interaction

Generic Name
Loratadine

Drug Interaction
- Erythromycin, Cimetidine, Ketokonazole
- CNS depressant, Alcohol CNS depressant effect may be enhanced
- Amiodarone --> increase Loratadine serum concentration

Desloratadine

Bepotastine
TALION

- CNS depressant, Alcohol CNS depressant effect may be enhanced

No Report
Drug
Interaction
No Drug
Interation

Cetirizine

- Theophylline small decrease in the clearance of cetirizine

Levocetirizine

- CNS depressant, Alcohol CNS depressant effect may be enhanced

- Ritonavir --> increased plasma AUC Cetirizine (42%),
increase half-life (53%), decrease Cetirizine clearance (29%)

Fexofenadine

- Erythromycin, Ketoconazole, Omeprazole, Verapamil

- Aluminium hydroxide / Magnesium hydroxide-containing product
- CNS depressant, Alcohol CNS depressant effect may be enhanced

Bepotastine can be administered ANYHOW!

References: Package Inserts of each anti-histamine

TALION
Not have Drug-to-Food Interaction

Kazuhiko Yanai: Prog. Med 24, 262-267 (2004)

Bepotastine : Not Influenced by Meals

Decreased blood concentration by administration in fasting
Emidastin

10%

Twice daily

Cmax: 42%, AUC: 51%

Once daily

After breakfast &

before bedtime

(Remicut)

Loratadine

After meal

(Claritin)

Increased blood concentration by administration in fasting

Azelastine

(Azeptine)

Epinastine
Cetirizine

(Alesion)

(Zy
(Zyrtec)
rtec)

Olopatadine

Tendency

Twice daily

After breakfast &

before bedtime

Tendency, not tested

Once daily

No description

Tendency, 10%

Once daily

Before bedtime

Twice daily

Morning & before

bedtime

Cmax: Not influenced, AUC

(Allelock)

Decreased blood concentration by administration after meal

Fexofenadine

(Allegra)

Cmax: 14% , AUC: 15%

Once
Once daily

No description

Not influenced by meal

Bepotastine
(TALION)

Not influenced

Twice daily

No description

M. Hide: Allergy & Immunology 12 (8) 103, 2005

32

Metabolism

2)

At dosages of 10 mg
: little metabolites were detected in plasma and urine
At dosages of 20 mg or more : metabolites detected in urine 1% of the original dosages

Excretion

3)

The Cumulaive Excretion

Rate in Urine

(%)

The Cumulative Excretion Rate in Kidney

(TALION 10 mg, single oral administration)

100

84.4 1.4% until 24 hrs

80
60

Healthy adult men

n=6
MeanS.E.

40
20
0

(hours)

02 4

10

24

Plasma Protein Binding Rate (in vivo) 1 )

55% (at 1 hours after administration)

Time
1 R. Ohashi et al.: Pharmacokinetics 12 (5), 417, 1997
2 T. Kadosaka et al.: J Clin Therap Med 13 (5), 1155, 1997
3) H. Yokota et al.: J Clin Therap Med 13 (5), 1137, 1997

Handling / Storage / Packaging

Use only pursuant to the prescription or direction of a physician
Storage at below 30 C
Avoid exposure to humidity after opening the package

Shelf Life :

3 years
Packaging :

1 box @ 30 tablets TALION 10 mg

Price :

HNA = Rp. 65.010/box = Rp. 2.167/tablet

TALION
CLINICAL STUDIES

Bepotastine Inhibitory Effects

on Cytokine/Chemokine Production & ICAM-1 (CD54) Expression

(Kobayashi, et al.: Skin Pharmacol Physiol 2009; 22 : 45-48)

Bepotastine Inhibitory Effects

on Cytokine/Chemokine Production of IL-1

The Production of IL-1

Significantly Suppressed by The Addition of Bepotastine
(Kobayashi, et al.: Skin Pharmacol Physiol 2009; 22 : 45-48)

Bepotastine Inhibitory Effects

on Cytokine/Chemokine Production of CXCL10

The Production of CXCL10

Significantly Suppressed by The Addition of Bepotastine
(Kobayashi, et al.: Skin Pharmacol Physiol 2009; 22 : 45-48)

Bepotastine Inhibitory Effects

on Cytokine/Chemokine Production of CCL17

The Production of CCL17

Significantly Suppressed by The Addition of Bepotastine
(Kobayashi, et al.: Skin Pharmacol Physiol 2009; 22 : 45-48)

Bepotastine Suppressing Th1 & Th2 Chemokine

and The Expression of ICAM-1

Bepotastine Downregulates
The Production of Th1 & Th2 Chemokines :
Its Beneficial Effect on Acute and Chronic Atopic Skin Lesions
(Kobayashi, et al.: Skin Pharmacol Physiol 2009; 22 : 45-48)

(Andoh, et al.: European Journal of Pharmacology 547 (2006) : 59-64)

The Anti Pruritic Effects of Bepotastine

Histamine

Substance-P

Serotonin

Leukotriene

Time Course of Scratching after The Injection of Pruritogens.

Histamine, Serotonin, Substance-P were Injected Intradermal at a dose of 100 nmol/site,
and Leukotriene at a dose of 0.03 nmol/site.
(Andoh, et al.: European Journal of Pharmacology 547 (2006) : 59-64)

The Anti Pruritic Effects of Bepotastine

Histamine

Serotonin

Substance-P

VH = Vehicle
BB = Bepotastine Besilate
Leukotriene
*P<0.05 when compared
with VH

Pre-treatment with BB Significantly Inhibited Scratching induced by Histamine.

The action of Substance-P and Leukotriene was Dose-dependently Inhibited by BB.
(Andoh, et al.: European Journal of Pharmacology 547 (2006) : 59-64)

1st CLINICAL STUDIES for SKIN

Clinical Efficacy on Chronic Urticaria,
Eczema / Dermatitis, Prurigo, Pruritis Cutaneus

Clinical Studies Result

Subject

Methods

: 250 Urticaria chronic patients

41 Prurigo patients

;
;

103 Ezceme/dermatitis patients

40 Pruritis cutaneus patients

434 pts

: TALION tablet 10 mg (b.i.d) for 2 weeks

(itching & eruption were judged compare before & after therapy)

The Final Global Improvement Rates

0

10

20

Chronic urticaria
n=250)
Eczema/dermatitis
n=103
Prurigo
n=41

30

40

50

60

49.6

70

26.8

Moderately Improved or more

76.4

32.0

31.1

80

90

12.0

22.3

10.4
1.2
10.7
3.9

Moderately Improved or more 63.1

19.5

53.7

9.8

37.5

9.8
7.3

Moderately Improved or more 73.2

Pruritis Cutaneus
n=40

100

22.5

25.0

15.0

Moderately Improved or more 60.0

Remarkably
Improved

Moderately
Improved

Slightly
Improved

Not
changed

Aggravate
d

(Y. Ishibashi et al.: J Clin Therap Med 13 (5) 1199, 1997/13 (5) 1237, 1997/13 (5) 1287, 1997/13 (5) 1383, 1997)

Kriteria Penilaian

Kriteria penilaian untuk kasus Eksema / Dermatitis, Prurigo :

penilaian ditetapkan dengan memperhatikan perubahan pada

gejala, terutama pada rasa gatal.

Kriteria Penilaian

2nd CLINICAL STUDIES

Long term Administration Study on Chronic Urticaria

Clinical Studies Result

Subjects

: 77 Chronic Urticaria patients

Methods

: TALION tab 10 mg (b.i.d) for 12 weeks

Itching & eruption (wheal / erythema) were compared before & after therapy

The Final Global Improvement Rate

0

10

20

30

40

50

60

62.0

70

80

25.4

Moderately Improved or more 87.3 (68/77 pts)

Remarkably
Improved

Moderately
Improved

Slightly
Improved

Not changed

90

100

9.9

n=71

1.4
1.4

Worsening

In general, the global improvement rate at 12 week treatment would be the final global
improvement rate.
Y. Ishibashi et al.: J Clin Therap Med 13 5 ,1337,1997

Skin Disease

Results/Clinical Study
(Long-term Treatment Study-2)

Time Course of the Global Improvement Rates

0

1 week n=63
2 weeks n=71
4 weeks n=68

10

20

30

20.6

40

50

60

70

41.3

100

11.1
1.6

Moderately Improved or more 61.9

28.2

43.7

Moderately Improved or more 71.8

33.8

28.2
47.1

6 weeks n=63
8 weeks n=64

Moderately Improved or more 82.5

48.4

16.2
1.5 1.5
17.5

38.1
37.5

Moderately Improved or more 85.9

52.6
Moderately Improved or more 87.7
63.3

12 weeks n=60

90

25.4

Moderately Improved or more 80.9

44.4

10 weeks n=57

80

10.9
3.1

35.1

8.8
3.5

26.7

10.0

Moderately Improved or more 90.0

Remarkably
Improved

Moderately
Improved

Slightly
Improved

Not changed

Aggravated

Y. Ishibashi et al.: J Clin Therap Med 13 5 , 1337, 1997

3rd Clinical Studies :

Placebo-controlled double blind

Comparative Study on Chronic Urticaria

Clinical Studies
(Double-blind placebo-controlled comparative study)
Subjects : Chronic Urticaria
TALION group: 55 cases , Placebo group : 54 cases
Methods The double blind comparative study was carried out using 10mg (b.i.d) of TALION and
Placebo (b.I.d.) for one week. Degrees of itching and of eruption (wheal/erythema) were
judged based on the patients diaries.

Evaluation of The Patients Diary and Criteria

Score of eruption

Score of itching : The higher score between day and night was adopted
Score

Symptoms in the Daytime

Symptoms in the Night

Excruciating itching
(not allowing housework or job.)

Hardly able to sleep due to itching

(hard to fall asleep, and even after
feeling asleep, I waking up soon)

Considerable itching
(irritated and hard to concentrate
on housework or my work.)

Waking up due to itching

(Even after falling asleep, waking
up due to itching)

Feeling itchy
(not so concerned, but sometimes
scratching myself unconsciously.)

Not waking up due to itching.

(feeling itchy, but being able to
sleep).

Sometimes feeling itchy.

(not so much as scratching)

Not feeling itchy

Score

Degree of Eruption
(Dermal Symptom)

Very severe in appearance

(swelling is obvious and
redness is clear)

Severe in appearance
(swelling is recognized and
redness is distinct from the
surrounding area)

Being able to sleep well

(Sometimes feeling itchy, but not
so much as scratching)

Not very severe in appearance

(swelling is slightly observed
and existing redness is
recognized.)

Not feeling itchy

No symptoms

M. Kawashima et al.: J Clin Therap Med 18(4), 501, 2002

Evaluation of the Patients Diary and Criteria

- Score of Eruption (Wheal/Erythema) Score

Degree of Eruption (Dermal Symptom)

Very severe in appearance

(Swelling is obvious and rednessis clear)

Severe in appearance
(Swelling is recognized and redness can be
distinguished from the surrounding area)

Not severe in appearance

(Swelling is slightly observed and redness can
be recognized.

No symptoms
( M. Kawashima et al.: J Clin. Therapy Med 18 (4), 501, 2002)

Results of Clinical Study

(Double-blind placebo-controlled comparative Study)
Changes in Scores
At the final administration

2.5

2.70

2.0

TAON
-1.42

1.5

*
2.56

2.33

Placebo
-0.41

2.30

2.0

Placebo
- 0.14

Itching

3.0

2.75

2.5

2.70

TAON
-1.31

1.5

1.02

1.0
0.5

Day 3

1.5

TAON
-1.62
1.13

2.30

0.0

Day 1

TALION group n = 55
Placebo group n = 54

*
Placebo
-0.47

Day 3

TAON
-1.49

1.0

0.84

0.5

0.5

0.0

Day 1

Placebo
-0.14
2.0

2.33

1.83

1.0

0.0

2.56

Eruption

2.0

1.0
0.5

2.5

1.89

1.5

1.33

Eruption

Score
s

2.75

2.5

Score
s

Itching

3.0

Scores

Scores

At the 3rd administration day

0.0

Day 1

Day 7

Day 1

Day 7

Mean S.E. *p<0.0001 Unrestricted LSD method

M. Kawashima et al.: J Clin Therap Med 18(4), 501, 2002

THANK YOU

Evaluation of Efficacy and Safety TALION

For Pediatric
Efficacy
Satisfied

Almost satisfied

45.4%

0%

20%

44.1%)

40%

60%

Dissatisfied
10.5%)

80%

100%

Efficacy rate (Almost satisfied or better) was 89.5% (1,171 / 1,309)

Incidence of adverse reaction and their major symptoms

Incidence of
Adverse reaction

Special Surveillance
for child patients

Major adverse reactions

1.1% (14/1,316)

Sleepiness (0,4%), Thirst (0,2%)

56

Evaluation of Efficacy and Safety TALION

For Pediatric

Efficacy rate (Almost satisfied or better)

was 89.5%

Incidence of adverse reactions was 1.1%

This study made it clear that TALION was
SAFE in child patients for wide range of
dosages 0.1 mg/kg to 1.5 mg/kg.
57

Bepotastine secara umum

dapat ditoleransi baik untuk
kasus alergi, baik pada
pasien dewasa maupun
pediatri

58

Bepotastine terbukti efektif untuk

terapi Rhinitis Alergi, baik untuk
pediatri maupun untuk pasien
dewasa41, 42.
Pada post marketing surveillance
pada kasus perennial dan atau
seasonal rhinitis alergi, tingkat
efikasi untuk kepuasan / sangat
puas telah dilaporkan pada
89.5% dari 1.309 pasien
pediatri42 dan 91.3% dari 2.766
pasien dewasa dan pediatri43.
59

Pharmacokinetics in Patients with renal dysfunction

Single Oral Administration

Time course of Plasma Concentration

(5mg of TALION in patients with three categorized renal function)
Normal renal function n=5

(ng/mL)

Mild renal inpairment n=5

Plasma Concentration

80

CCr = 51 70 mL/min

M/S = 66.3

M = 61

Tmax = 1 1.2 hours

60
N = 55.1

T1/2 = 3 hours
Moderate to severe impairment n=6
CCr = 6 50 mL/min

40

Tmax = 3.3 hours

T1/2 = 8.5 hours
MeanS.D.

20

0
0

12

18

24

hours

Time after administration

K. Kawashima et al.: J Clin Therap Med 19 (6), 637, 2003

Pharmacokinetics in The Elderly

Pemberian Dosis Ulang - Oral
Konsentrasi Plasma berdasarkan Lama Terapi
Pemberian TALION 10 mg b.i.d pada pasien pria lanjut usia sehat pada hari ke-1 & ke-2
dan 10 mg O.D pada hari ke-3.

Plasma Concentration

(ng/mL)
120

at the 1st
administration
at the 3rd

103.8

100
82.9

day
MeanS.D.
n=10

80
60
40

17

20

15

(hours)

12

18

24

Time after administration

Y. Kumagai et al.: J Clin Therap Med 13 (5), 1169, 1997