Delving into the Latest Updates on Amlodipine besilate/Valsartan with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Amlodipine (as besylate)/Valsartan, Amlodipine /Valsartan, Amlodipine/Valsartan

+ [16]

Target

AT1R x VDCCs

Action

antagonists, blockers

Mechanism

AT1R antagonists(Angiotensin II Receptor Type 1 antagonists), VDCCs blockers(Voltage-gated calcium channel blockers)

Therapeutic Areas

Cardiovascular Diseases

Active Indication

HypertensionEssential Hypertension

Inactive Indication-

Originator Organization

Novartis Pharma AG

Active Organization

Novartis Europharm Ltd.

Novartis Pharmaceuticals Corp.

Mylan NV

+ [3]

Inactive Organization

Novartis AG

Drug Highest PhaseApproved

First Approval Date

European Union (15 Jan 2007),

Essential Hypertension

Regulation-

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Structure/Sequence

Molecular FormulaC24H29N5O3

InChIKeyACWBQPMHZXGDFX-QFIPXVFZSA-N

CAS Registry137862-53-4

View All Structures (2)

The American College of Cardiology/American Heart Association hypertension guidelines recommend treatment initiation with dual antihypertensive therapy in adults with stage 2 hypertension (corresponding to grade 1 and 2 in the ESH classification) and an average BP >20/10 mm Hg above target. Amlodipine and valsartan are two of the most commonly prescribed medications for the treatment of hypertension (high blood pressure). In Pakistan multiple studies were conducted on Hypertension and use of Single Pill Combination in uncontrolled Hypertension. However, no study was conducted to assess the role of Single Pill Combination (SPC) like Amlodipine and Valsartan in newly diagnosed hypertension and to assess their quality of life by patients' satisfaction with their medication after managing the hypertension with the SPC.

Start Date28 Sep 2024

Sponsor / Collaborator

The Searle Co. Ltd.

CTR20242402

/ CompletedNot Applicable

缬沙坦氨氯地平片（I）在健康人体空腹/餐后状态下的生物等效性试验

[Translation] Bioequivalence study of valsartan and amlodipine tablets (I) in healthy volunteers in fasting and postprandial states

主要研究目的本研究以石家庄市普力制药有限公司持证的缬沙坦氨氯地平片（I）（规格：每片含缬沙坦 80mg、氨氯地平 5mg）为受试制剂，Novartis Pharma SchweizAG 持证的缬沙坦氨氯地平片（I）（商品名：倍博特，规格：每片含缬沙坦80mg、氨氯地平 5mg）为参比制剂，进行空腹/餐后状态下人体生物等效性试验，评价受试制剂和参比制剂在健康受试者体内的生物等效性。次要研究目的观察受试制剂和参比制剂在健康受试者中的安全性。

[Translation]

Main research purpose This study uses the valsartan amlodipine tablets (I) (specification: each tablet contains 80 mg valsartan and 5 mg amlodipine) certified by Shijiazhuang Puli Pharmaceutical Co., Ltd. as the test preparation and the valsartan amlodipine tablets (I) (trade name: Bebot, specification: each tablet contains 80 mg valsartan and 5 mg amlodipine) certified by Novartis Pharma SchweizAG as the reference preparation to conduct a human bioequivalence test under fasting/postprandial conditions to evaluate the bioequivalence of the test preparation and the reference preparation in healthy subjects. Secondary research purpose Observe the safety of the test preparation and the reference preparation in healthy subjects.

Start Date05 Aug 2024

Sponsor / Collaborator

Shijiazhuang Puli Pharmaceutical Co Ltd.

NCT06193044

/ Not yet recruitingPhase 1

A Single Dose, Randomized, Open-label, Two-treatment, Four-period, Two-sequence, Replicate Crossover Bioequivalence Study of Generic Amlodipine and Valsartan Tablets 10/160 mg and Reference Product (Exforge® 10/160 mg Tablets)

Comparative randomized, Single dose, Two-treatment, Four-period, Two-sequence, Replicate Crossover Bioequivalence Study to determine the bioequivalence of Amlodipine / valsartan from Amlodipine/Valsartan 10/160 film coated tablets and Exforge10/160 mg film coated tablets (Novartis Pharma, USA).

Start Date07 May 2024

Sponsor / Collaborator

International Bio Research

100 Clinical Results associated with Amlodipine besilate/Valsartan

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100 Translational Medicine associated with Amlodipine besilate/Valsartan

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100 Patents (Medical) associated with Amlodipine besilate/Valsartan

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45

Literatures (Medical) associated with Amlodipine besilate/Valsartan

01 Jul 2024·BioFactors (Oxford, England)

Sacubitril/valsartan promotes white adipose tissue browning in rats with metabolic syndrome through activation of mTORC1

Article

Author: Lazarevic, Nevena ; Novakovic, Jovana ; Nedeljkovic, Nikola ; Jeremic, Nevena ; Nikolic, Milos ; Nikolic, Marina ; Mitrovic, Slobodanka ; Zivkovic, Vladimir ; Jakovljevic, Vladimir ; Stojanovic, Aleksandra ; Milojevic Samanovic, Andjela

Abstract:

In addition to their usual use in the treatment of cardiovascular disease, weak evidence is available for the potential of combined use of neprilysin inhibitor (sacubitril) and AT1 receptor antagonist (valsartan) to promote browning of white adipose tissue (WAT) in rats with metabolic syndrome (MetS). This study involved 32 male Wistar albino rats divided into four groups: CTRL—healthy control rats; ENT—healthy rats treated with sacubitril/valsartan; MS—rats with MetS; MS + ENT—rats with MetS treated with sacubitril/valsartan. After finishing the experimental protocol, different WAT depots were isolated for further analysis of molecular pathways. Molecular docking and molecular dynamics studies were used for in silico assessment of the binding affinity of sacubitril and valsartan towards subunits of mechanistic target of rapamycin complex 1 (mTORC1). Sacubitril/valsartan treatment markedly diminished morphological changes in adipose tissue, resulting in smaller lipid size and multilocular lipid droplet structure in WAT. We showed significantly higher protein expression of uncoupling protein‐1 (UCP‐1) and mTORC1 in WAT of MS + ENT rats, correlating with increased relative gene expression of browning‐related markers in tissue of rats treated with sacubitril/valsartan compared with MS group of rats. In silico analysis showed that sacubitrilat and valsartan exhibited the highest binding affinity against mTOR and mLST8, forming stable complexes with these mTORC1 subunits. The observed results confirmed strong potential of combined sacubitril/valsartan treatment to increase browning markers expression in different WAT depots in MetS condition and to form permanent complexes with mTOR and mLST8 subunits over the time.

01 Jun 2024·ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS

A structure-based pharmacophore modelling approach to identify and design new neprilysin (NEP) inhibitors: An in silico-based investigation

Article

Author: Sinhari, Apurba ; Gaikwad, Anil Bhanudas ; Thakur, Shikha ; Jadhav, Hemant R

Neutral endopeptidase or neprilysin (NEP) cleaves the natriuretic peptides, bradykinin, endothelin, angiotensin II, amyloid β protein, substance P, etc., thus modulating their effects on heart, kidney, and other organs. NEP has a proven role in hypertension, heart disease, renal disease, Alzheimer's, diabetes, and some cancers. NEP inhibitor development has been in focus since the US FDA approved a combination therapy of angiotensin II type 1 receptor inhibitor (valsartan) and NEP inhibitor (sacubitril) for use in heart failure. Considering the importance of NEP inhibitors the present work focuses on the designing of a potential lead for NEP inhibition. A structure-based pharmacophore modelling approach was employed to identify NEP inhibitors from the pool of 1140 chemical entities obtained from the ZINC database. Based on the docking score and pivotal interactions, ten molecules were selected and subjected to binding free energy calculations and ADMET predictions. The top two compounds were studied further by molecular dynamics simulations to determine the stability of the ligand-receptor complex. ZINC0000004684268, a phenylalanine derivative, showed affinity and complex stability comparable to sacubitril. However, in silico studies indicated that it may have poor pharmacokinetic parameters. Therefore, the molecule was optimized using bioisosteric replacements, keeping the phenylalanine moiety intact, to obtain five potential lead molecules with an acceptable pharmacokinetic profile. The works thus open up the scope to further corroborate the present in silico findings with the biological analysis.

01 Dec 2023·Life sciences

LCZ696 attenuates sepsis-induced liver dysfunction in rats; the role of oxidative stress, apoptosis, and JNK1/2-P38 signaling pathways

Article

Author: Mohyeldin, Reham H ; Elhamadany, Eyad Y ; Fathy, Moustafa ; Sharata, Ehab E ; Alaaeldin, Rania ; Attya, Mina Ezzat

AIM:

Sepsis is a serious inflammatory response to infection with an annual incidence rate of >48 million cases and 11 million fatalities worldwide. Furthermore, sepsis remains the world's fifth-greatest cause of death. For the first time, the current study aims to evaluate the possible hepatoprotective benefits of LCZ696, a combination of an angiotensin receptor blocker (valsartan) and a neprilysin inhibitor prodrug (sacubitril), on cecal ligation and puncture (CLP)-induced sepsis in rats.

MAIN METHODS:

CLP was employed to induce sepsis. Hepatic malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), interleukin-6 (IL-6), IL-1β, tumor necrosis factor-alpha (TNF-α), and caspase 3 were assessed using ELISA. Serum alanine transaminase (ALT) and aspartate transaminase (AST) were also measured. Western blot assay was used to determine the expression of JNK1/2 and P38 proteins. The histology of liver tissues was also examined.

KEY FINDINGS:

CLP resulted in significant elevation of AST, ALT, MDA, IL-6, IL-1β, TNF-α, and caspase 3 levels, and up-regulation of p/t JNK1/2, and p/t P38 proteins, as compared to the sham group. However, level of GSH, and SOD activity were reduced in CLP group. LCZ696 significantly improved all the previously mentioned biochemical and histological abnormalities better than using valsartan alone.

SIGNIFICANCE:

LCZ696 substantially ameliorated CLP-induced liver damage, compared to valsartan, by reducing proinflammatory mediators, inhibiting the JNK1/2 and P38 signaling pathway, and attenuating apoptosis.

1

News (Medical) associated with Amlodipine besilate/Valsartan

29 Dec 2022

·www.reuters.com

Novartis to pay $245 mln to end antitrust cases over Exforge drug generics

NEW YORK, Dec 28 (Reuters) - Novartis AG (NOVN.S) said on Wednesday it will pay $245 million to end antitrust litigation accusing the Swiss drugmaker of trying to delay the launch in the United States of generic versions of its Exforge hypertension drug. The settlements with so-called direct purchasers, indirect purchasers and retailers require approval by a federal judge in Manhattan, and will resolve all outstanding claims against the company over the matter, Novartis said. CVS Health Corp (CVS.N) , Kroger Co (KR.N) , Rite Aid Corp (RAD.N) and Walgreens Boots Alliance Inc (WBA.O) are among the plaintiffs in the civil litigation, which began in 2018. The class-action litigation stemmed from a 2011 licensing agreement between Novartis and Endo International Plc's (ENDPQ.PK) Par Pharmaceutical unit. Novartis and Par were accused of entering an illegal "reverse payment" agreement to delay launches of less expensive, generic versions of Exforge, which treats hypertension to lower blood pressure and reduce the risk of strokes. Plaintiffs said Par agreed not to launch an Exforge generic for two years after the expiration of one of Novartis's patents, and Novartis agreed not to compete with Par by launching its own Exforge generic during the 180-day exclusivity period following Par's entry into the market. Novartis's annual U.S. sales of brand-name Exforge exceeded $400 million before generic versions were sold, court papers show. The case is In re Novartis and Par Antitrust Litigation, U.S. District Court, Southern District of New York, No. 18-04361. Our Standards: The Thomson Reuters Trust Principles.

License out/inPatent Infringement

100 Deals associated with Amlodipine besilate/Valsartan

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External Link

KEGG	Wiki	ATC	Drug Bank
-	Amlodipine besilate/Valsartan	C09DB01	-

R&D Status

10 top approved records.

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Indication	Country/Location	Organization	Date
Hypertension	United States	Novartis Pharmaceuticals Corp.	20 Jun 2007
Essential Hypertension	European Union	Novartis Europharm Ltd.	15 Jan 2007
Essential Hypertension	Iceland	Novartis Europharm Ltd.	15 Jan 2007
Essential Hypertension	Liechtenstein	Novartis Europharm Ltd.	15 Jan 2007
Essential Hypertension	Norway	Novartis Europharm Ltd.	15 Jan 2007

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


CHINA STATUS III (ESC2018)	Not Applicable	Hypertension	985	Valsartan/amlodipine fixed-dose combination	gzjspwlfbc(dknqzfixvf) = AEs were reported in 23.3% of patients apfykqlauo (igtiwzcbat ) View more	-	26 Aug 2018
NCT02062645 (CTgov)	Phase 4	Essential Hypertension	115	amlodipine/valsartan	dkwwtlnglb = vqzskcvuwv mvfufceboc (cxsqndzfvn, aewitrsfwv - waenzqgwof) View more	-	28 Mar 2017
PP.07.32 (ESH2015)	Not Applicable	Hypertension	-	Amlodipine 5 mg/valsartan 80 mg combination	ayykfsqsoy(wpckhfruia) = The adverse events(AEs) were reported in 13.9 % of participants. The majority of AEs were reported as mild or moderate in severity. lnujjuiilz (asjwiaeibu )	Positive	01 Jun 2015
NCT01030458 (NOAAH, CTgov)	Phase 4	Hypertension	183	amlodipine 5/10 mg per day plus valsartan 160 mg/day (Amlodipine Plus Valsartan)	ajxkzyqwxr(panzyrufxv) = fhwwpvpuyq bmfgsgrqbl (xudcujqwfl, 10.7) View more	-	15 Nov 2013
				hydrochlorothiazide 6.25 mg/day plus bisoprolol 5/10 mg/day (Hydrochlorothiazide Plus Bisoprolol)	ajxkzyqwxr(panzyrufxv) = qjhlocvgrf bmfgsgrqbl (xudcujqwfl, 13.1) View more
NCT01167153 (EXAM STUDY \| EXAM, CTgov)	Phase 4	Hypertension	564	Valsartan/Amlodipine (Valsartan/Amlodipine)	jceqnqtjrf(sdzcpybnrc) = dlmptuwysf ooamljvjca (wgnkwmfuez, 11.69) View more	-	01 Jun 2012
				Nifedipine (Nifedipine)	jceqnqtjrf(sdzcpybnrc) = hisckojvac ooamljvjca (wgnkwmfuez, 12.02) View more
NCT01070043 (CTgov)	Phase 4	Hypertension	60	Valsartan	ifejmdwqpw(iayueshero) = dnoooyieed uzmpgpcbvo (ugdeewqkcz, 12.71) View more	-	19 Oct 2011
NCT01001572 (CTgov)	Phase 3	Essential Hypertension	932	Placebo+Valsartan/amlodipine 160/5 mg (Valsartan/Amlodipine 160/5 mg)	nqnbjvapwd(tmpipyrmip) = ijbudofgqc xnorjugvnl (tknkddvfow, 0.39) View more	-	24 May 2011
				Placebo+Valsartan 160 mg (Valsartan 160 mg)	nqnbjvapwd(tmpipyrmip) = ghrqtynkiu xnorjugvnl (tknkddvfow, 0.40) View more
NCT00413049 (CTgov)	Phase 3	Essential Hypertension	698	Valsartan/amlodipine 80/5 mg (Valsartan/Amlodipine 80/5 mg)	didtbstefp(fstxtvvonm) = szyabwqjjc tgemgfstac (uwccjqjaga, 0.42) View more	-	08 Feb 2011
				Amlodipine 5 mg (Amlodipine 5 mg)	didtbstefp(fstxtvvonm) = uxxwelwrdv tgemgfstac (uwccjqjaga, 0.42) View more
NCT00425373 (CTgov)	Phase 2/3	Essential Hypertension	1,474	Valsartan + amlodipine 40/2.5 mg (Valsartan + Amlodipine 40/2.5 mg)	qyrgekngkl(cohzuujzdg) = nubobtybar chojvkqbpq (vmqpxmgxeg, 0.62) View more	-	04 Feb 2011
				Valsartan + amlodipine 40/5 mg (Valsartan + Amlodipine 40/5 mg)	qyrgekngkl(cohzuujzdg) = gwybywqujm chojvkqbpq (vmqpxmgxeg, 0.60) View more
NCT00687973 (EXPLOR, CTgov)	Phase 4	Essential Hypertension	393	Valsartan/amlodipine 80/5 mg tablets (Valsartan/Amlodipine 160/10 mg)	iguwkbutiu(sepootuwst) = wvaoofmurj fbskflyslp (scvjfmnvxf, 1.15) View more	-	21 Jan 2011
				Atenolol 100 mg tablets+Amlodipine 5 mg capsules (Atenolol/Amlodipine 100/10 mg)	iguwkbutiu(sepootuwst) = dfuugoghwr fbskflyslp (scvjfmnvxf, 1.09) View more