ADISINSIGHT (AdisInsight Drugs, formerly Adis R&D Insight)
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RecordContent• Full text reports, i.e., profiles, on drugs in active research and development by theinternational pharmaceutical industry• Generic names, synonyms, trade names• CAS Registry Numbers®
• EphMRA ATC codes, WHO ATC codes• Developing companies, development stages by indication and country• Licensed forecast information from Lehman Brothers

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ADISINSIGHT

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ADISINSIGHT

Search and Display Field Codes
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SearchCode

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Basic Index* (contains single
words from the classification
code (CC), development status(DSTA), text (TX), revision note
(RNTE), company name (CO),chemical name (CN), controlled
term (CT), and geographic term(GT) fields, as well as
molecular formulas (MF) andCAS Registry Numbers (RN))

None(or /BI)S IMMUNOSTIMULANTS
S ANTI-ATHER?
S GLAXO (L) ORIGINATORS MECHANISM(L)IMMUNOMODULATORSS C (1W) GOS VACCINE# (P) USE
S C10H10N2O5
S 47931-85-1

CC, CN, CO,
DSTA, MF, RN,
RNTE, TX

Accession Number
Change Date (1)

/AN
/CDAT

AN
CDAT

Chemical Name (includes
chemical names, genericnames, synonyms, and trade
names)
Chemical Name Segment*/CN

S 1998:9493/AN
S CDAT>19980100
S JULY 2, 1998/CDATS POLOXAMER 188 NF/CN

CNClassification Code (EphMRA
ATC codes and WHO ATC
codes) (code and text) (2)/CC

Company Name (2) (corporatename and location)
Controlled Term (indication)/CO

Development Status(development phase, location,and indication)
Document Number
Element Count, Specific (1)/DSTA

S (METHYL (L) THIAZOL)/CNS
S ?AMINOBUTYRYL?/CNS
S (SALBUTAMOL AND SCHERING)/CNS
S R03/CC
S R3/CC
S "ANTI-ACNE PREPARATIONS"/CC
S TOPICAL PREPARATIONS/CCS SMITHKLINE UNITED KINGDOM/COS LICENSEE (L) INTROGEN/COS ALZHEIMER?/CTS ANXIETY DISORDERS/CT
S (PHASE II (L) GERMANY)/DSTAS (STROKE (L) PRECLINICAL)/DSTA
S 002345/DN
S 1/N AND 3/O

DN
MF
Not displayed
FA

/NC
/OS

S L1 AND ED>=19990700
S EVALUATION/FA
S L1 AND RN/FAS GERMANY/GT
S DE/GTS PHASE III/HDPS ADIS R&D INSIGHT/JTS C10H10N2O5/MF
S C18 H22 N2 O S . Cl H/MF
S L6 AND NC>=2
S "800007351"/OS

/PG
/RE
/RDAT

S T3/PGS JOURNAL OF PHARMACOLOGY/RE
S 19980312/RDAT

MF
RE
RDAT

Entry Date (1)Field Availability(code and text)
Geographic Term(code and text)
Highest Development Phase
Journal Title
Molecular Formula
Number of Components (1)Other Source (Adis Alerts
Accession Number)
Periodic Group
Reference
Revision Date (1)

/CNS

/CT

/DN
/Element
symbol
/ED
/FA
/GT
/HDP
/JT
/MF

CN

CC

CO
DSTA
DSTA

DSTA
HDP
JT, SO
MF
MF
OS

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ADISINSIGHT

Search and Display Field Codes (cont’d)Search Field Name
Revision Note*
SourceTrade Name
Update Date (1)Word Count (1)Search
Code
/RNTE
/SO
/TN
/UP
/WC

Search Examples
S PRECLINICAL DEV?/RNTES ADIS R&D INSIGHT/SOS TANADOPA/TN
S L1 AND UP>=19990600
S L1 AND WC

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Codes
RNTE
SO
CN
Not displayedWC(1) Numeric search field that may be searched using numeric operators or ranges.
(2) Implied (S) proximity is available in this field.
(3) This score is only available in selected records published in November 2010 and earlier.

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spaces or commas, e.g., D L1 1-5 CN TX. The fields are displayed or printed in the order requested.
Hit-term highlighting is available for all fields except FA, STF, STR, and STS. Highlighting must be ON during
SEARCH in order to use the HIT, KWIC, and OCC formats.
FormatAN
CC
CDAT (1)
CN
CO
DN
DSTA
FA (2)HDP
JT (2)MF
OS
RDAT (RNTE)
RE
RN
SO
STF
STR (3)
STS (2,3)
TN (2)TX

WC
ALL (3)DALL (3)
IALL (3)IDE (3)
IIDE (3)
ISTD (3)January 2022

Content

ExamplesAccession Number
Classification Code (EphMRA ATC codes and WHO ATC codes)
Change Date
Chemical Name (Generic Names, Synonyms, Chemical Name, and Trade Names)(includes TN)
Company Name (corporate name and location) (Originator, Parent, Licensee,
and Other)
Document Number
Development Status (development status, location, and indication)
Field Availability
Highest Development Phase
Journal Title
Molecular Formula
Other Source (Adis Alerts Accession Number)
Revision Date and Revision Note
Reference
CAS Registry Number and Related CAS Registry Number
SourceFlat Structure (no stereo indicated)
Structure Diagram (includes stereo bonds and R/S/E/Z labels when available)
Stereo Structure (includes stereo bonds when available)
Trade Name
Text (Introduction, Evaluation, Commercial Summary (table with Company, Major
Markets, Launch Date, Commercial Value, and Patent Expiry), Pharmacology
Overview (Mechanism of action, Route of Elimination), Clinical Overview, Adverse
Events, Pharmacology (Pharmacokinetics, Clinical Studies), and Therapeutic
Trials) (includes EVAL)
Word Count

D AN
D 1-3 CCD CDAT
D CN STR

AN, SO, DN, CDAT, CN, MF, RN, STR, related RN, CC, HDP, DSTA, CO, OS, WC,
TX, RDAT, RNTE, RE
ALL, delimited for post-processing
ALL, indented with text labels
AN, SO, DN, CDAT, CN, MF, RN, STR, related RN, CC, HDP, CO, OS, WC

D ALL

IDE, indented with text labels(IIDE is the default)
STD, indented with text labels

D L2 3 IIDEDD ISTD

D CO 1,3-5
D AN DN
D DSTA
D FA
D HDP
D JT 2
D CN MF
D OS
D RDAT
D RE L1 4
D RN 3,4
D SO
D L9 1 3
D L4 STR
D STS
D TN
D TX

D WC

D DALLD IALLD IDE

5ADINSIGHTDISPLAY and PRINT Formats (cont’d)FormatSCAN (1,4)
STD (3)
TRIAL (1)
(SAM, TRI)
HIT
KWIC
OCC (1)

Content

ExamplesCN (Generic Name) (random display, no answer number)
AN, SO, DN, CDAT, CN, MF, RN, STR, related RN, CC, HDP, DSTA, CO, OS, WC,
TX
CN (Generic Name), CDATD SCAND STD

Fields containing hit terms
Hit terms with 20 words on either side (KeyWord-In-Context)
Number of occurrences of hit terms and fields in which they occur

D HIT
D KWIC NOH
D OCC

D TRIALTOTAL(1) No online display fee for this format.
(2) Custom display format only.
(3) Stereo structure diagrams are available only on graphics terminals and offline prints.
(4) SCAN must be entered on the command line, i.e., DISPLAY SCAN, D SCAN.

SELECT, ANALYZE, and SORT Fields
The SELECT command is used to create E-numbers containing terms taken from the specified field in ananswer set.
The ANALYZE command is used to create an L-number containing terms taken from the specified field in ananswer set.
The SORT command is used to rearrange the search results in either alphabetic or numeric order of thespecified field(s).
Field Name

Field Code

Accession Number
CAS Registry Number
CAS Registry Number and Chemical Name
Change Date
Chemical Name

AN
RN
CHEM
CDAT
CN

Classification Code (EphMRA and WHO ATC codes)
Company Name (Corporation Name)Controlled Term (Indication)
Development Status
Document Number
Geographic Term
Highest Development Phase
Journal Title
Molecular Formula
Occurrence Count of Hit Terms
Other Source (Adis Alerts Accession Number)
Reference
Revision Date
Revision Note
SourceText
Trade Name
Word Count

NAME
CC
CO
CT
DSTA
DN
GT
HDP
JT
MF
OCC
OS
RE
RDAT
RNTE
SO
TX
TN
WC

ANALYZE/
SELECT (1)
Y
Y (2)
Y (3)
Y
Y (4)
(default)
Y (5)
Y
Y
Y (6)
Y
Y
Y (6)
Y
Y
Y
N
Y (7)
Y
Y (6)
Y (6)
Y
Y (8)
Y
N

SORT
N
N
N
Y
N
N
Y
Y
N
N
Y
N
Y
Y
Y
Y
Y
N
N
N
N
N
N
Y

(1) HIT may be used to restrict terms extracted to terms that match the search expression used to create the answer set, e.g., SEL HIT
CN.
(2) Selects or analyzes the CAS Registry for the substance and the related CAS Registry Numbers with /BI appended to the terms
created by SELECT.
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ADISINSIGHT(3) Selects or analyzes the CAS Registry for the substance, the related CAS Registry Numbers, Generic Names, Synonyms, ChemicalName, and Trade Names) with /BI appended to the terms created by SELECT.
(4) Selects or analyzes the Generic Names, Synonyms, Chemical Name, and Trade Names).
(5) Selects or analyzes the Generic Names, Synonyms, Chemical Name, and Trade Names with /BI appended to the terms created by
SELECT.
(6) SELECT HIT and ANALYZE HIT are not valid with this field.
(7) Appends /DN to the terms created by SELECT.
(8) Appends /BI to the terms created by SELECT.

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ENTER (DIS), ANSWER NUMBERS, OR END:

NOVICE version

D BRO

EXPERT version

Answer number(s)=> D BRO L1::1-3

Answer number(s) and format
Format only

:4 HIT:TI TX

Change default format:*KWIC

Forward n fields
Backward n fields
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stringSearch backward for character
stringEnd DISPLAY BROWSE:F3:B1:S BONE MARROW

January 2022

:S -NAUSEA:END=>

display answers 1, 2, and 3 indefault format
display answer 4 in HIT format
display title and text of lastanswer displayedchange default to KWIC
no answer displayed
move forward 3 fields
move backward 1 fieldsearch forward within record for'bone marrow'search backward within record
for 'nausea'
exit DISPLAY BROWSE andreturn to => prompt

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ADINSIGHT

Sample Records
DISPLAY ALL
AN
1998:1 ADISINSIGHT
SO
Adis R&D Insight
DN
000001
CDAT Sep 14, 2016
CN
Benidipine
CN
Benidipine hydrochloride; KW 3049; KW3049; Nacadipine; Nakadipine
CN
3,5-Pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl), methyl 1-(phenylmethyl)-3-piperidinyl ester, monohydrochloride,(R*,R*)-(+-)CN
Caritec(R); Coniel(R)MF
C28 H31 N3 O6 . Cl H
RN
91599-74-5
STR
Relative stereochemistry.

RN
105979-17-7 (Benidipine)CC
EPHMRA ATC CODE: C8A Calcium Antagonists, PlainCC
WHO ATC CODE: C08C-A Dihydropyridine derivatives
HDP Launched
DSTA Launched, China, Angina pectoris
Launched, India, Angina pectoris
Launched, Japan, Angina pectoris
Launched, Philippines, Angina pectoris
Launched, Turkey, Angina pectoris
Launched, China, Essential hypertension
Launched, India, Essential hypertension
Launched, Japan, Essential hypertension
Launched, Philippines, Essential hypertension
Launched, Turkey, Essential hypertension
Discontinued III, Italy, Angina pectoris
Discontinued III, Italy, Essential hypertension
Discontinued II, Germany, Angina pectoris
Discontinued II, United Kingdom, Angina pectoris
Discontinued II, United States, Angina pectoris
Discontinued II, Germany, Essential hypertension
Discontinued II, United Kingdom, Essential hypertension
Discontinued II, United States, Essential hypertension
ORIGINATOR:
Kyowa Hakko (Japan)
PARENT:
Kyowa Hakko
LICENSEE:
Bristol-Myers Squibb; Deva Holding; Sun PharmaceuticalIndustries
WC
1018
TX

TEXT
Introduction:
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ADISINSIGHT
Company Agreements
In October 2013, Bristol-Myers Squibb licensed the exclusive Chinese
marketing rights for benidipine from Kyowa Hakko Kirin. Financial detailsof the agreement were not disclosed/1/.
Benidipine appears to have been licensed to Deva (an EastPharma
subsidiary) for commercialisation in Turkey, and to , Sun PharmaceuticalIndustries for commercialisation in India.
Crinos (later Sirton Pharmaceuticals) had licensed benidipine fordevelopment in Italy. However, this agreement no longer appears to be
active.
In March 2015, Sun Pharmaceutical Industries acquired Ranbaxy/2/.
Introduction
Benidipine is an orally bioavailable dihydropyridine antagonist of
L-type, N-type and T-type calcium channels. The drug was developed by
Kyowa Hakko (now Kyowa Hakko Kirin) for the treatment of essential
hypertension and angina pectoris, and gained approval in Japan in 1991. It
has subsequently been launched in Japan, China, Philippines and Turkey (asConiel sup((R))), and in India (as Caritec sup((R))) for these
indications.
In October 2008, Kyowa Hakko merged with Kirin Pharma to form Kyowa Hakko
Kirin/3/.
Generic versions of Coniel sup((R)) were launched in Japan in July 2006,
following expiry of patent protection in the region.
Key Development Milestones
Benidipine was approved in China in September 2008 for the treatment ofangina pectoris, following the filing of an application for regulatory
approval in 2007/4/. The drug had been launched in China for the treatmentof hypertension in December 2004, after gaining regulatory approval in
March 2004. Kyowa Hakko had launched benidipine in the Philippines forboth indications by April 2002.
In July 2006, Deva was granted marketing authorisation for benidipine inangina pectoris and essential hypertension, and subsequently launched the
product in that country during 2007. Ranbaxy launched the drug in India,
in October 2000.
Kyowa Hakko announced in its 2003 annual report that a special
investigation evaluating the efficacy and safety of long-term (1 year)
administration of benidipine in 10 000 older patients with hypertension
had been initiated. A second large-scale clinical trial in collaboration
with Yamaguchi University had also been initiated to investigate
benidipine in combination with one of three types of antihypertensives(beta-blockers, angiotensin II receptor blockers and antihypertensive
diuretics) over a three-year period (COPE; NCT00135551). The effectivenessand safety of the three combination regimens was to be compared andevaluated. This trial enrolled 3501 patients with hypertension in Japan,
and was completed in November 2010.
Benidipine was undergoing phase III clinical trials in Italy and phase II
trials in Germany, the United Kingdom and the USA for angina pectoris andessential hypertension. However, development appears to have been
discontinued in these countries.
TX

PHARMACOLOGY OVERVIEW:
Pharmacodynamics:
Coronary and cerebral vasodilatory effects in vivo; marked BP-lowering
effects; diuresis; natriuresis
Mechanism of action:
L-type calcium channel antagonists
L-type calcium channel modulators
Calcium channel antagonists
Calcium channel modulators

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ADINSIGHT
Ion channel antagonists
Ion channel modulators
Membrane glycoprotein inhibitors
Membrane transport protein inhibitors
Membrane glycoprotein modulators
Membrane transport protein modulators
Glycoprotein inhibitors
Membrane protein inhibitors
Carrier protein inhibitors
Glycoprotein modulators
Membrane protein modulators
Carrier protein modulators
Protein inhibitors
Glycoconjugate inhibitors
Glycoconjugate modulators
Protein modulators
Carbohydr-ate metabolism inhibitors
Carboh-ydrate metabolism modulators
N type calcium channel antagonists
N-type calcium channel modulators
Calcium channel antagonists
Calcium channel modulators
Ion channel antagonists
Ion channel modulators
Membrane glycoprotein inhibitors
Membrane transport protein inhibitors
Membrane glycoprotein modulators
Membrane transport protein modulators
Glycoprotein inhibitors
Membrane protein inhibitors
Carrier protein inhibitors
Glycoprotein modulators
Membrane protein modulators
Carrier protein modulators
Protein inhibitors
Glycoconjugate inhibitors
Glycoconjugate modulators
Protein modulators
Carbohydr-ate metabolism inhibitors
Carboh-ydrate metabolism modulators
T type calcium channel antagonists
T-type calcium channel modulators
Calcium channel antagonists
Calcium channel modulators
Ion channel antagonists
Ion channel modulators
Membrane glycoprotein inhibitors
Membrane transport protein inhibitors
Membrane glycoprotein modulators
Membrane transport protein modulators
Glycoprotein inhibitors
Membrane protein inhibitors
Carrier protein inhibitors
Glycoprotein modulators
Membrane protein modulators
Carrier protein modulators
Protein inhibitors
Glycoconjugate inhibitors
Glycoconjugate modulators
Protein modulators
Carbohydr-ate metabolism inhibitors
Carboh-ydrate metabolism modulators
Activity versus parent drug:
unspecified parent
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ADISINSIGHT
TX

CLINICAL OVERVIEW:
Route(s) of Administration: PO
Adverse events:
rare: Diarrhoea, Oedema.
Drug Interactions:Unknown.

TX

Adverse Events:
In 55 patients with essential hypertension receiving benidipine 2-8
mg/day for <= 1 year, adverse events included lightheadedness (n = 1),
diarrhoea (1) and peripheral oedema (1)/5/.

TX

PHARMACOLOGY:
Pharmacodynamics (Hypertension):
Preclinical studies: the long term effects of ceronapril 40 mg/kg/day, AE
0047 20 mg/kg/day and benidipine 10 or 20 mg/kg/day were examined instroke-prone spontaneously hypertensive rats. In treated rats, theincidence of cerebrovascular lesions was significantly depressed and theirlife-spans were extended compared to the untreated control rats. AE 0047
sustained BP under 210mm Hg without developing fibrinoid deposition onarterial walls. After benidipine, thickened arterial walls were observedand BP remained over 250mm Hg. In contrast to benidipine, ceronapril
reduced the occurrence of smooth muscle proliferation and BP levels weresimilar to those of benidipine/6/.
Clinical studies: a randomised, single-blind, crossover study in 15
salt-sensitive patients with essential hypertension assessed the efficacy
of benidipine and controlled release nifedipine on sodium-induced changes
in systemic and regional haemodynamics. Oral benidipine 4-8 mg/day once
daily for 73 days significantly reduced MAP and increased CI, superior
mesenteric blood flow and renal blood flow during low and high sodium
intake. Nifedipine 10-30 mg/day also significantly reduced MAP during low
sodium intake, but had no effects on HR, CI or regional blood flow. The
high sodium diet increased MAP, CI and terminal aortic flow (all p <0.05), and reduced mesenteric and renal blood flows (p < 0.05) during
nifedipine administration/7/.
In 15 patients with essential hypertension, benidipine 4 mg/day andtrandolapril 1 mg/day for 12 weeks similarly decreased BP, and increased
concentrations of nitrite/nitrate (NOx) and cGMP. Neither agent affected
HR, lipid profiles and renal functions/8/.
In 10 elderly patients with essential hypertension undergoing mentalarithmetic test, administration of oral benidipine 4mg od for 12 weeks
significantly decreased 24-h BP , and had no marked effect on HR. However,the decrease in night-time DBP was not significant, and the decrease innight-time SBP was minimal. In benidipine recipients, the increase in SBP
induced by mental arithmetic test was significantly decreased comparedwith baseline/9/.

Pharmacodynamics (Ischaemic Heart Disease):
Benidipine suppresses ischaemic ECG changes and attenuates ST and T wave
elevation in animal models. Mild and long lasting dose-dependent increases
in coronary sinus outflow and decreases in BP are seen at doses > 1
microg/kg IV. Benidipine protects the ischaemic canine myocardium andmaintains global cardiohaemodynamics. Other animal studies have shown thatbenidipine exhibits preferential coronary and cerebral vasodilating
activity, and has a longer duration of action than nifedipine or
nicardipine.

TX

THERAPEUTIC TRIALS:
Hypertension:
In patients with essential hypertension (n = 21), oral once daily
benidipine 4 mg/day for 2 weeks produced a long lasting reduction in BP

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ADINSIGHT
compared with baseline/10/.
In an open, multicentre study in 78 patients with essential hypertension,
monotherapy with oral benidipine 2-8 mg/day od for <= 1 year significantly
decreased BP from baseline. Similar effect was achieved when benidipine
was used in combination with other antihypertensive agents (n = 19)(details not provided). 42% of patients in the benidipine monotherapy
group and 44% of patients in the combination therapy group had their BP
normalised at 1 year (BP < 150/90mm Hg)/5/.
In a randomised study in 86 patients with essential hypertension,beta-blockers arotinolol, bisoprolol, ACE inhibitors captopril, imidapril
and calcium antagonists nisoldipine and benidipine for 12 weeks
significantly and similarly decreased 24h ambulatory BP. 24h HR decreased
significantly with the beta-blockers arotinolol and bisoprolol. There were
no differences in circadian and ultradian variations among the major
first, second and third peaks of SBP, DBP and HR in patients receiving
beta-blockers or ACE inhibitors. Calcium antagonists shortened theperiodicity of ultradian variations in second and third peaks of
SBP/11//9/.

RDAT
30 Oct 2000
30 Oct 2000
26 Jan 2000
05 Jul 1999
05 Jul 1999
30 Apr 1999
29 Sep 1998
11 Nov 1994
14 Sep 1994
RE

RNTE
Launched for Angina pectoris in India (PO)
Launched for Essential hypertension in India (PO)Two studies have been added to the Hypertension therapeutic
trials section (720623, 746001)
Registered for Angina pectoris in India (PO)Registered for Essential hypertension in India (PO)A study has been added to the Hypertension pharmacodynamics
section (746001)
A study has been added to the Hypertension pharmacodynamics
section (691650)
A preclinical study has been added to the hypertension
pharmacodynamics section (307950)
New profile

1. Bristol-Myers Squibb. Bristol-Myers Squibb Signs Licensing Agreement
for Coniel (benidipine) in China. Media Release. : 22 Oct 2013.
Available from: URL: http://www.bms.com.cn. (English).
2. Sun Pharmaceutical Industries. Sun Pharma announces closure of merger
deal with Ranbaxy. Media Release. : 25 Mar 2015. Available from: URL:
http://www.sunpharma.com. (English).
3. Kyowa Hakko Kogyo Co Ltd, Kirin Pharma Company Limited, et al.
Strategic Alliance Between Kyowa Hakko Group and Kirin Group Maximizing
Synergy Through an Alliance Centered Around the PharmaceuticalBusiness. Media Release. : 22 Oct 2007. Available from: URL:
http://www.kyowa.co.jp. (English).
4. Kyowa Hakko Kogyo Co Ltd. Kyowa Hakko Interim Operating Income up
25.2%. Media Release. : 29 Oct 2007. Available from: URL: http://
www.kyowa.co.jp. (English).
5. Imazu M, Yamabe T, et al. Antihypertensive effects and safety oflong-term treatment with benidipine hydrochloride in essential
hypertensive patients. Shinryo to Shinyaku. 32: 995-1005, 1995.
(Japanese).
6. Ohta Y, Chikugo T, et al. Long term therapeutic effects of ACE
inhibitor and calcium antagonists on hypertensive vascular lesions in
M-SHRSP. Clinical and Experimental Pharmacology and Physiology. (Suppl.
1): 103, 1994. (English).
7. Shimamoto H, Shimamoto Y. Benidipine counteracts sodium-induced
alterations in systemic and regional hemodynamics. Blood Pressure. 6:18-23, Jan 1997. (English).
8. Takase H, Sugiyama M, et al. Effect of antihypertensive therapy withbenidipine or trandolapril on serum nitrite/nitrate levels in essential
hypertension. Journal of Hypertension. 16 (Suppl. 2): 99, Jun 1998.
(English).
9. Muneta S, Kohara K, et al. Effects of benidipine hydrochloride on
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ADISINSIGHT
24-hour blood pressure and blood pressure response to mental stress inelderly patients with essential hypertension. International Journal of
Clinical Pharmacology and Therapeutics. 37: 141-147, Mar 1999.
(English).
10. Nakanishi T, Takahashi H, et al. Effects of benidipine hydrochloride
on 24-hour blood pressure. Current Therapeutic Research - Clinical andExperimental. 53: 270-276, Mar 1993. (English).
11. Kawamura H, Mitsubayashi H, et al. Calcium channel blockers shorten
the periodicity of ultradian variation in blood pressure in patientswith essential hypertension. Koketsuatsu. 21: 179-186, Sep 1998.
(English).

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