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Candesartan cilexetil

Description Uses The precursor drug of Antihypertensive drug Candesartan---Candesartan cilexetil Candesartan cilexetil tablets Appendix I Appendix II Side effects and adverse reactions Precautions References
Candesartan cilexetil
Candesartan cilexetil structure
CAS No.
145040-37-5
Chemical Name:
Candesartan cilexetil
Synonyms
tcv116;Atacand;TCY 116;Blopress;Candestartan;Candesartan cilexeti;Candesartanciletexil;Cadesartan cilexetil;CANDESARTAN CILEXETIL;CANDESARTAN CILEXITIL
CBNumber:
CB3209325
Molecular Formula:
C33H34N6O6
Formula Weight:
610.66
MOL File:
145040-37-5.mol

Candesartan cilexetil Properties

Melting point:
168-170?C
storage temp. 
-20°C Freezer
solubility 
DMSO: ≥15mg/mL
pka
pKa 3.55 (H2O t=25.0 I=0.025) (Uncertain);5.91(H2O t=25.0 I=0.025) (Uncertain)
form 
powder
color 
white to beige
λmax
304nm(EtOH)(lit.)
Merck 
14,1739
InChIKey
GHOSNRCGJFBJIB-UHFFFAOYSA-N
CAS DataBase Reference
145040-37-5(CAS DataBase Reference)
SAFETY
  • Risk and Safety Statements
  • Hazard and Precautionary Statements (GHS)
Hazard Codes  Xn,N,T
Risk Statements  20/21/22-36/37/38-50-48/20-61
Safety Statements  26-36-61-45-53
RIDADR  UN 3077 9 / PGIII
WGK Germany  3
RTECS  DD6672500
HS Code  29339953
Symbol(GHS):
Signal word: Warning
Hazard statements:
Code Hazard statements Hazard class Category Signal word Pictogram P-Codes
H360 May damage fertility or the unborn child Reproductive toxicity Category 1A, 1B Danger
H361 Suspected of damaging fertility or the unborn child Reproductive toxicity Category 2 Warning P201, P202, P281, P308+P313, P405,P501
H362 May cause harm to breast-fed children Reproductive toxicity, effects on or via lactation Additional category P201, P260, P263, P264, P270,P308+P313
H400 Very toxic to aquatic life Hazardous to the aquatic environment, acute hazard Category 1 Warning P273, P391, P501
Precautionary statements:
P201 Obtain special instructions before use.
P202 Do not handle until all safety precautions have been read and understood.
P260 Do not breathe dust/fume/gas/mist/vapours/spray.
P263 Avoid contact during pregnancy/while nursing.
P264 Wash hands thoroughly after handling.
P264 Wash skin thouroughly after handling.
P270 Do not eat, drink or smoke when using this product.
P273 Avoid release to the environment.
P280 Wear protective gloves/protective clothing/eye protection/face protection.
P281 Use personal protective equipment as required.
P308+P313 IF exposed or concerned: Get medical advice/attention.
P405 Store locked up.
P501 Dispose of contents/container to..…

Candesartan cilexetil price More Price(13)

Manufacturer Product number Product description CAS number Packaging Price Updated Buy
Sigma-Aldrich PHR1854 Candesartan cilexetil Pharmaceutical Secondary Standard; Certified Reference Material 145040-37-5 200mg $164 2018-11-13 Buy
Sigma-Aldrich 1087803 Candesartan cilexetil United States Pharmacopeia (USP) Reference Standard 145040-37-5 100mg $1140 2018-11-13 Buy
TCI Chemical C2635 Candesartan Cilexetil >98.0%(HPLC)(T) 145040-37-5 1g $272 2018-11-22 Buy
TCI Chemical C2635 Candesartan Cilexetil >98.0%(HPLC)(T) 145040-37-5 200mg $80 2018-11-22 Buy
Cayman Chemical 10489 Candesartan cilexetil ≥98% 145040-37-5 1g $114 2018-11-13 Buy

Candesartan cilexetil Chemical Properties,Uses,Production

Description

Candesartan cilexetil is a kind of prodrug being hydrolyzed to candesartan during absorption from the gastrointestinal tract. It appears as a white or off-white powder with a molecular weight of 610.67. It is soluble in methanol but insoluble in water. It is a kind of selective AT1 subtype angiotensin II receptor antagonist, mainly used for the treatment of hypertension and heart failure. Candesartan cilexetil takes effects through selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland, further blocking the vasoconstrictor and aldosterone-secreting effects of angiotensin II. Therefore, its mode of action is not through interfering with the pathways for angiotensin II synthesis. Candesartan cilexetil may lead to various kinds of adverse reactions including headache, back pain, dizziness, upper respiratory tract infection, pharyngitis, rhinitis, bronchitis, coughing, sinusitis, nausea, abdominal pain, diarrhea, vomiting, arthralgia and albuminuria. It should be warned that candesartan cilexetil might have remarkable fetal toxicity. Therefore, upon pregnancy, candesartan cilexetil should be discontinued. It could also cause hypotension for heart-failure patients.

Uses

  1. Candesartan cilexetil is a prodrug of the potent, long-acting, and selective angiotensin II type 1 receptor AT1 antagonist, candesartan. It is rapidly hydrolyzed to candesartan during gastrointestinal absorption. After hydrolysis of candesartan cilexetil to candesartan during gastrointestinal absorption, candesartan selectively competes with angiotensin II for the binding of the angiotensin II receptor subtype 1 AT1 in vascular smooth muscle, blocking angiotensin II-mediated vasoconstriction and inducing vasodilatation. In addition, antagonism of AT1 in the adrenal gland inhibits angiotensin II-stimulated aldosterone synthesis and secretion by the adrenal cortex; sodium and water excretion increase, followed by a reduction in plasma volume and blood pressure.
  2. Candesartan cilexetil can be used as pesticide and pharmaceutical intermediates.
  3. It can be used as the raw material of antihypertensive drugs.
  4. Candesartan is an angiotensin-receptor blocker (ARB),Angiotensin receptor blockers effectively protect against the harmful effects of the activation of the renin-angiotensin-aldosterone system that occur with hypertension or diabetes.It may be used alone or with other agents to treat hypertension. Unlike angiotensin-converting enzyme (ACE) inhibitors, ARBs do not have the adverse effect of dry cough.
  5. Candesartan may be used to treat hypertension, isolated systolic hypertension, left ventricular hypertrophy and diabetic nephropathy. It may also be used as an alternative agent for the treatment of heart failure, systolic dysfunction, myocardial infarction and coronary artery disease.

The precursor drug of Antihypertensive drug Candesartan---Candesartan cilexetil

Hypertension disease, due to its high incidence, high morbidity and high mortality as well as the resulted various kinds of issues including medical, social, family, economic, has changed from purely personal disease to serious social issues. Study and development of first-line drug treatment of hypertension has increasingly become the focus of the world's major competing focus of many major manufacturers. The main purpose of the treatment of hypertension is to minimize the total risk of cardiovascular disease death and disability with its goal being able to restore blood pressure to 140/90mmHg or less.
Currently, there are many kinds of clinical anti-hypertensive drugs and can be primarily divided into five categories, namely, diuretics, β-blockers, angiotensin-converting enzyme inhibitors (ACE-Ⅰ), calcium antagonists, and α-blockers. They all have certain limitations and side effects in use. Since the 1980s, ACE-I have been widely used to treat a variety of cardiovascular diseases and have been demonstrated to have excellent pressure-lowering effect on high blood pressure. However, since the ACE-Ⅰ also inhibits the degradation of bradykinin, and thus often resulting dry cough during the treatment of patients.
Currently, a new class of anti-hypertensive drugs-angiotensin Ⅱ receptor antagonist has been listed. A typical representative of such drugs includes losatran (Merck), valsartan (Novartis) and eprosartan (SmithKline). As the role of these drugs are more specific than the ACE-I, increasing the antihypertensive effect with reduced side effects as well as not causing cough. It also has protective effects on blood vessels, kidneys and heart. Therefore, this type of drug has become a competition protagonist in the hypertension drug market.
Candesartan cilexetil is the pro-drug of candesartan with the action strength being 10 times as high as losatran. Its action has a good selectivity (has a 10000 time higher affinity to AT1 receptor than AT2), long duration of action (take it one time daily). As a pro-drug, it can release its activity in a relatively mild way after oral administration, making it be a kind of ideal drug for treatment of hypertension.
According to the foreign prediction, the annual sales of this kind of goods can reach up to $ 2 billion so the development of this product will surely achieve good economic and social benefits.

Candesartan cilexetil tablets

[Appearance] it is white or white-like drug.
[Pharmacological and toxicological effects] Candesartan cilexetil is rapidly hydrolyzed in vivo to become active metabolite-----candesartan. Candesartan is a selective angiotensin Ⅱ receptor (AT1) antagonist and can antagonize the with the vasoconstriction effect of angiotensin II through binding to the vascular smooth muscle AT1 receptor, thereby reducing peripheral vascular resistance. Others also suggest that: candesartan can suppress the adrenal secretion of aldosterone and thus playing a role of lowering the blood pressure. Candesartan neither inhibits kininase Ⅱ nor affects bradykinin degradation. Experiments of hypertensive patients have demonstrated that: multi-administration of this drug by the patients can cause increase of the plasma renin activity, angiotensin I concentration and angiotensin Ⅱ concentration; taking this drug continuously for 2-8 mg per day can reduce the systolic blood pressure, diastolic blood pressure, left ventricular mass, as well as peripheral vascular resistance while having no significant effect on cardiac output, ejection fraction, renal vascular resistance, renal blood flow, glomerular filtration rate; It also has no significant effect on the cerebral blood flow of patients of original sexual hypertensive patients with cerebral vascular disorder. Toxicological studies: mice, rats and dogs with oral administration of 2000 mg/kg candesartan cilexetil once have no deaths. The maximal tolerated dose of this drug of the NIH mice through oral administration can reach up to 6750mg/kg. The non-toxic dose of long-term (26 weeks) oral administration of this drug by rats is 10mg/kg.d. The non-toxic dose for beagle dogs being subject to long-term oral administration of this drug is 20mg/kg. d. Tests on mutagenic, carcinogenic, reproductive harm have demonstrated that candesartan cilexetil has no mutagenic effects in separation tests including microbial mutation, chromosomal aberrations and gene mutations in mammalian DNA. When rats and mice were given the product of 300 and 1000 mg/kg for continuous 2 years (104 weeks) showed no carcinogenic effect (this dose was 7 fold and 70 fold of the recommended human daily maximum dose of 32mg/d, respectively). When male and female rats were fed 300 mg/kg.d of this drug (83 fold of the maximum recommended human dose), no effect on fertility and fecundity has been observed. Reproductive and embryo toxicity test has showed: oral administration by rats during late pregnancy and lactation in a dose of 10mg/kg. d can reduce the number of viable offspring as well as cause rising incidence of hydronephrosis (2.8 fold of the maximum recommended human dose). Oral administration of this drug by pregnant rabbits in a dose of 3mg/kg/d (approximately 1.7 fold of the maximum recommended human dose) can cause maternal toxicity (weight loss or death), but have no negative effects on the survival rate of the maternal fetal, weight, shape, visceral and skeletal development. Oral administration of this drug by pregnant until 1000mg/kg/d (approximately 138 fold of the maximum recommended human dose) cause no maternal toxicity and any adverse effects on fetal development.

Appendix I

[Pharmacokinetics] candesartan cilexetil is the pro-drug of candesartan. It is rapidly and totally hydrolyzed into candesartan during the absorption in gastrointestinal tract. The absolute bioavailability of candesartan is about 15%. The time for candesartan plasma concentration to reach peak is 3 to 4 hours. Candesartan has a plasma protein binding rate of being greater than 99% with the apparent volume of distribution of 0.13L/kg. Rat tests have shown that candesartan rarely penetrates through blood-brain barrier but can penetrate through the placental barrier and be distributed in fetal. Candesartan is mainly excreted in its prototype from the urine and feces with a very small part in the liver being metabolized into inactive metabolites through O-Alkylation reaction. The excretion half life of candesartan is about 9 hours. Data have shown that candesartan total clearance rate was 0.37mL/min. kg, renal clearance rate of 0.19mL/min.kg. After oral administration of 14C-labeled candesartan cilexetil, about 33% and 67% of the radioactivity were recovered from urine and feces, respectively. Special Populations Elderly and gender: The pharmacokinetics parameters analysis about the product used in 65 years of age or older and different genders have shown that: upon the same drug dose, older group has a higher plasma concentration than youth group while there is no significant difference between men and women. For patients of liver, renal insufficiency and patients with severe hepatic, renal insufficiency, it is necessary to adjust the initial dose.
[Indications] it can be used for the treatment of essential hypertension. It can be used alone or with combined with other antihypertensive drugs.
[Usage and dosage] Oral, generally take once per day for adult 1, 1 4~8 mg per time; increase the dose to 12 mg if necessary.
[Pediatric Use] The safety of children's medication has not been determined (no experience).
[Treatment of elderly patients] it is generally believed that the elderly should not be treated with excessively lowering blood pressure (may cause cerebral infarction, etc.). Patients should be treated cautiously during the observation of their state. For elderly people with normal liver and kidney function, use an initial dose of 4mg; for those with renal insufficiency or liver function, it is recommended that the initial dose of 2mg; the dose should be increased or decreased according to the actual status of the disease.
The above information is edited by the Chemicalbook of Dai Xiongfeng.

Appendix II

[Medication of pregnant women and lactating women] upon the administration of this preparation for perinatal and lactating rats, you can see that, for groups with more than 10mg/kg/day dose, there is increase in the incidence of newborn hydronephrosis, it has also been reported that during middle and late pregnancy, for hypertension patients of administration of angiotensin II receptor antagonists (including candesartan) or angiotensin-converting enzyme inhibitors, there were many kinds of adverse reactions including oligohydramnios disease, fetal, neonatal death, neonatal hypotension, renal failure, hyperkalemia, skull hypoplasia, and may also limb contractures, craniofacial malformations due to too little amniotic fluid. Pregnant or possible pregnant women should be banned for using the drug. In addition only when administration of this drug at late pregnancy or lactating rats at 300mg/kg/day dose group will the newborn hydronephrosis increase. Lactating women should avoid medication and stop breastfeeding when necessary medication is inevitable.
[Drug interactions] pay attention to combination (concomitant medication should be paid attention to). This good has no obvious interaction with glyburide, nimodipine, digoxin, warfarin, and hydrochlorothiazide and other drugs. In the case of healthy people with simultaneous oral administration of contraceptives, no significant interactions have been found.
[Overdosage] According to pharmacological studies, the main behavior of overdose is symptomatic hypotension and dizziness. If symptomatic hypotension occurs, symptomatic treatment must be conducted and some important living signs should be monitored. Patients should be place in the supine with low head and high feet. The patient should also be subject to isotonic saline injection to increase his/her plasma volume if necessary. If the above measures still don’t work, the patients can be subject to the treatment of sympathomimetic drugs.
[Storage] stored after being sealed and dried.
[Prescription or not]: prescription

Side effects and adverse reactions

Serious adverse effects (incidence unknown) :
1, angioedema: sometimes neovascularization edema located in face, lips, tongue, pharynx, and larynx; this should be carefully observed and stop medication upon abnormal cases with taking further appropriate treatment.
2, Syncope and loss of consciousness: excessively lowing blood pressure may cause temporary loss of consciousness and fainting. In this case, the medication should be stopped and the patients should be subject to appropriate treatment. Especially for patients undergoing hemodialysis, patients undergoing strict salt restriction therapy as well as patient who have recently started taking diuretic antihypertensive drugs, rapid reduction of blood pressure can occur. Therefore, these patients using this drug should start from a lower dose. If it is necessary to increase the dose, the patient should be closely observed the situation and slowly increases the dose.
3, Acute renal failure: acute renal failure can occur; we should closely observe the patient's condition and the medication should be stopped upon unusual cases with further taking appropriate treatment.
4, Patients with hyperkalemia: Given that hyperkalemia may occur, the patient should be closely observed for their conditions. If abnormal conditions happen, the patients should stop medication and be subject to appropriate treatment.
5, Deterioration of liver function or jaundice: since there may be liver dysfunction or jaundice with AST (GOT), ACT (GPTO, γ-GTP) value being elevated; If abnormal conditions happen, the patients should stop medication and be subject to appropriate treatment.
6, Agranulocytosis: there may be agranulocytosis occurring, the patient should be closely observed for their conditions. If abnormal conditions happen, the patients should stop medication and be subject to appropriate treatment.
7, Rhabdomyolysis: it may be manifested as muscle pain, weakness, CK increase and myosin showing in blood and urine. When that happens, the patients should stop medication and be subject to appropriate treatment.
8, Interstitial pneumonia: it may occur with fever, cough, difficulty breathing, and chest X-ray abnormalities. When these above conditions occur, the patients should stop medication and be subject to appropriate treatment such as adrenal corticosteroids.
[Taboo]
1, Patients who have allergic history on the components of this formulation.
2, pregnant or possibly pregnant women (refer to the part of [pregnant women and lactating women drug]).
3, Patients of severe liver, renal insufficiency or patients with cholestasis.

Precautions

1, Use it with caution (following patients should use caution)
(1) Patient of bilateral or unilateral renal artery (see important basic precautions in 2).
(2) There is hyperkalemia in patients (see important basic precautions in part 2).
(3) Patients with liver dysfunction (possible deterioration of liver function. And, this is presumably the reduced clearance rate of the active metabolite candesartan occurring and therefore the patients should start from small dose and take medication with caution, refer to [Pharmacokinetics] item).
(4) Patients of renal dysfunction (due to excessively lowered blood pressure, it has the potential to worsen renal function, so once per day and start taking careful medication from 2 mg).
(5) Patients with a history of drug allergy.
(6) Elderly patients (see item [elderly patients]).
(7) Renal transplantation: For patients who have been recently subject to kidney transplant, there is still no experience of using this drug product.
(8) Patients of aorta and the left atrioventricular valve stenosis (obstructive hypertrophic cardiomyopathy disease): Patients using other vasodilators, patients with hemodynamic-related artery or left atrioventricular valve stenosis or obstructive hypertrophic cardiomyopathy should particularly take with caution.
(9) Patients with mild to moderate adrenal hyperandrogenism: patients with mild to moderate adrenal hyperandrogenism usually don't respond to antihypertensive drugs which suppress the renin-angiotensin-aldosterone system. Therefore, it is not recommended to use this drug.
2, Some important basic precautions
(1) for patients of bilateral or unilateral renal artery stenosis, upon taking renin-angiotensin-aldosterone system drugs, due to the reduction of renal blood flow and reduction of the filtration pressure, it can increase the risk of kidney function; Unless the treatment is necessary, the patients should avoid taking the drug.
(2) Since it may aggravate hyperkalemia, unless treatment is considered to be essential, patients with hyperkalemia should avoid taking the drug. In addition, patients of renal dysfunction, uncontrolled diabetes should be closely monitored about their serum potassium level as these patients tend to develop hyperkalemia
(3) Since upon taking this preparation, sometimes there may be a sharp decline in blood pressure, especially for the following patients, it should start from small dose and when increase the dose, we should carefully observe the condition of the patient and conduct slowly. A, patients undergoing hemodialysis; B, Patients undergoing strict salt restriction therapy; C, Patients taking diuretic antihypertensive drugs (particularly patients who have recently started taking diuretic antihypertensive drugs).
(4) Because of the antihypertensive effect, it can sometimes cause dizziness, staggering; thus upon high-altitude operations, we should pay attention to driving and other operations.
(5) It is better to stop taking it at 24 hours before surgery
(6) For the drug delivery: drug of PTP packaging should be taken after being moved out from PTP sheet (it has been reported that the mistakenly oral intake PTP sheet penetrate the hard acute esophageal mucosa, thereby causing perforation, and mediastinitis).

References

https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020838s022lbl.pdf
http://www.rxlist.com/atacand-drug.htm

Description

Atacand was launched in Australia, Belgium, Canada, Denmark, Finland, the Netherlands, Norway, Sweden, S. Africa and the US as an antihypertensive agent. It can be prepared from 3-nitrophthalic acid in about eight steps. Pharmacological studies have indicated Atacand is about 10-fold more potent than Losartan and has a long elimination half-life. Like losartan, Atacand is converted to its active form during GI absorption (via ester hydrolysis). It is a potent antagonist of angiotensin II type 1 receptors. This occurs through tight binding and slow dissociation, and is more potent than ACE inhibitors. It is well tolerated (can be taken by elderly and those with type II diabetes) and has no gender effects.

Chemical Properties

White Solid

Originator

Takeda (Japan)

Uses

Anti-hypertensive/Anti-anginal

Uses

Ester prodrug; hydrolized in vivo to the active carboxylic acid. Used in treatment of congestive heart failure. Antihypertensive

brand name

Atacand (AstraZeneca).

Candesartan cilexetil Preparation Products And Raw materials

Raw materials

Preparation Products


Candesartan cilexetil Suppliers

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View Lastest Price from Candesartan cilexetil manufacturers

Image Release date Product Price Min. Order Purity Supply Ability Manufacturer
2018-07-26 Candesartan cilexetil
145040-37-5
US $100.00 / KG 1KG 99% Customized career henan chemical co
2018-03-28 Candesartan Cilexetil
145040-37-5
US $10.00 / KG 10G 99% 10MT Hubei XinRunde Chemical Co., Ltd.
2018-10-24 High purity Antihypertensive Powder Candesartan cilexetil CAS 145040-37-5 CAS NO.145040-37-5
145040-37-5
US $1.00 / G 100G 99.9% 50000 tons Hebei Ruishun Trade Co.,Ltd

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