Papaverine

파파베린 · PAPAVERINE · PAPAVERINE HCL · papaverin · S-M-R · Papacon · Papaveri · papanerin

식별자 및 물리적 특성

CAS No.	58-74-2
분자식	C20H21NO4
평균 분자량	339.4 g/mol
단동위원소 질량	339.14705815 g/mol
SMILES	COc1ccc(Cc2nccc3cc(OC)c(OC)cc23)cc1OC
InChIKey	XQYZDYMELSJDRZ-UHFFFAOYSA-N
PubChem CID	4680
ChEMBL	CHEMBL19224
ChEBI	CHEBI:28241
EC No.	200-397-2
DTXSID	DTXSID4023418

화학 및 물리적 성질

XLogP	3.9
극성 표면적	49.8
수소 결합 공여자 수	0
수소 결합 수용자 수	5
회전 가능 결합 수	6
무거운 원자 수	25
형식 전하	0
복잡도	407
pH	Optimal pH for storage of papverine solutions: 2.0-2.8
LogP(분배 계수)	3log Kow = 2.95
밀도	1.337 g/cu cm at 20 °Cd420 1.337
Color/Form	White prisms from alcohol-diethyl etherneedles from petroleum etherTriboluminescent, orthorhombic prisms from alcohol + etherWhite crystalline powder
용해도	In water, 3.733X10-5 mg/L at 37.5 °CSlightly soluble in watervery soluble in ethanol, chloroformsoluble in acetone, benzene, pyridineAlmost insoluble in water. Soluble in hot benzene, glacial acetic acid, acetoneslightly soluble in chloroform, carbon tetrachloride, petroleum etherIn water, 35 mg/L at 17 °C1.29e-02 g/LH2O: 25 mg/mL
끓는 점	Sublimes at 135 °C475.36°C (rough estimate)
Decomposition	When heated to decomposition it emits toxic fumes of /oxides of nitrogen/.
녹는점	226147.5 °CWhite, monoclinic prisms from water. MP: 224.5 °CVery soluble in water, ethanol /Papaverine hydrochloride/226 °C
굴절률	Index of refraction: 1.625 C/D1.6250 (estimate)
Physical Description	Solid
Stability/Shelf Life	SENSITIVE TO LIGHT & MOISTURE /papaverine/
Dissociation Constants	pKa = 8.07 at 25 °C
pKa(산도 계수)	6.4(at 25℃)
물리적 상태	가루
색상	하얀색
용해도	37.33mg/L(37.5℃)
Merck	14,7019
BRN	312930
헨리 상수	1.3×107 mol/(m3Pa) at 25℃, HSDB (2015)

화학적 성질

White crystalline powder; obtained asorthorhombic prisms from an alcohol–ethermixture; melts at 147°C (296.6°F); sublimesunder vacuum; insoluble in water; soluble inacetone, glacial acetic acid, and benzene.

안전 및 규제

GHS 분류	WarningH302: Harmful if swallowed [Warning Acute toxicity, oral]P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)
규제 정보	Status: Active Update: 23-06-2016 https://echa.europa.eu/registration-dossier/-/registered-dossier/18037
기타 안전 정보	IMAP assessments - Isoquinoline, 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-: Environment tier I assessmentIMAP assessments - Isoquinoline, 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-: Human health tier I assessment
Hazard Classes and Categories	Acute Tox. 4 (100%)Acute toxicity - category 4Acute Tox. 4 *
소화 절차	As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing.Water spray, dry chemical, carbon dioxide or foam as appropriate for surrounding fire and materials.
보관 조건	Papaverine hydrochloride preparations should be stored at a temperature less than 40 °C, preferably between 15-30 °Cfreezing of the injection should be avoided. ...Papaverine hydrochloride injection should be stored at room temperature and protected from temperatures of 40 °C or higher and from freezing. It should not be refrigerated because of a reduction in solubility with possible precipitation. The solution should be clear and colorless to pale yellow.OPTIMAL PH FOR STORAGE OF PAPAVERINE SOLN: 2.0-2.8. /papaverine/Store in tight, light-resistant container as defined in the USP-NF. This material should be handled and stored per label instructions to ensure product integrity.
정리 방법	Wear approved respiratory protection, chemically compatible gloves and protective clothing. Wipe up spillage or collect spillage using a high-efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately-labelled container for disposal. Wash spill site.
처리 방법	SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.SRP: Wastewater from contaminant suppression, cleaning of protective clothing/equipment, or contaminated sites should be contained and evaluated for subject chemical or decomposition product concentrations. Concentrations shall be lower than applicable environmental discharge or disposal criteria. Alternatively, pretreatment and/or discharge to a permitted wastewater treatment facility is acceptable only after review by the governing authority and assurance that "pass through" violations will not occur. Due consideration shall be given to remediation worker exposure (inhalation, dermal and ingestion) as well as fate during treatment, transfer and disposal. If it is not practicable to manage the chemical in this fashion, it must be evaluated in accordance with EPA 40 CFR Part 261, specifically Subpart B, in order to determine the appropriate local, state and federal requirements for disposal.
Preventive Measures	Chemically compatible gloves. Safety glasses or goggles. Protect exposed skin.As a general rule, when handling USP Reference Standards avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling.This material is assumed to be combustible. As with all dry powders it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity.
Personal Protective Equipment (PPE)	Use a NIOSH approved respirator, if it is determined to be necessary by an industrial hygiene survey involving air monitoring. In the event that a respirator is not required, an approved dust mask should be used.Engineering controls such as exhaust ventilation are recommended.
상호 작용	The effects of different concentrations of beta-cyclodextrin (beta-CyD), hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-CyD) on percutaneous absorption of papaverine hydrochloride (PAP) were investigated. Abdominal rat skin mounted in Franz cells was used for in vitro experiments. To evaluate CyD interaction with a bilayer structure model, dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and DPPC-Chol (8:2 mole ratio) vesicles were used. CyD vesicle interaction was evaluated by differential scanning calorimetry. Permeation through rat skin and calorimetric experiments demonstrated that at low concentrations DM-beta-CyD shows higher enhancer activity as a possible result of a perturbing action on the skin by a complexation of its lipid components, but at higher concentrations HP-beta-CyD is the most effective. By considering that HP-beta-CyD presents a very moderate destabilizing action on the skin, /it was concluded/ that a 10% aqueous solution of this macrocycle appears to be the most suitable transdermal absorption enhancer for PAP....The effect of papaverine ... was investigated on the naloxone-precipitated withdrawal contracture of the acute morphine-dependent guinea-pig ileum in vitro. Furthermore, the effect of papaverine was also considered on DAGO (highly selective mu -agonist) and U50-488H (highly selective k-agonist) withdrawal to test whether the possible interaction of papaverine on opioid withdrawal involves mu - and/or k-opioid receptors. Following a 4 min in vitro exposure to opioid agonist, the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone. Papaverine treatment (1 x 10(-7) - 5 x 10(-7) - 1 x 10(-6) M) before or after the opioid agonists was able of both preventing and reversing the naloxone-induced contracture after exposure to mu (morphine and DAGO) or k (U50-488H) opiate agonists in a concentration-dependent fashion. Both acetylcholine response and electrical stimulation were not affected by papaverine treatment whereas the final opiate withdrawal was still reduced. The results ... indicate that papaverine was able to influence the opiate withdrawal in vitro and papaverine was able to exert its effect both at mu and k opioid agonists./Investigators sought/ to determine the influences of papaverine and buffered papaverine on passage of dexamethasone administered intratympanically to the inner ear. Twenty-seven Vienna white rabbits were divided into five groups: eight received intratympanic dexamethasone (4 mg/mL) (group 1), seven received intratympanic papaverine (10 mg/mL) + dexamethasone (2 mg/mL) (group 2), six received buffered (with sodium bicarbonate 8.4%) intratympanic papaverine (7.5 mg/mL) + dexamethasone (1.5 mg/mL) (group 3), three had basal cortisol levels in venous blood and perilymph measured (group 4), and three received intravenous papaverine + dexamethasone (group 5). At 1 hr after the administration of the drugs, dexamethasone levels in ipsilateral and contralateral perilymph and venous blood were measured by radioimmunoassay. Animals in group 3 demonstrated the highest levels of ipsilateral perilymph dexamethasone. Ipsilateral perilymph levels were significantly higher in groups 1 and 3 than they were in the other groups (p<0.05). Although the perilymph levels observed in animals in group 2 were slightly higher than those in group 4, no significant difference existed (p = 0.160). /It was concluded/ that when papaverine is intratympanically administered together with dexamethasone after buffering, passage of dexamethasone to the inner ear is increased..../Investigators studied/ the combined effect of various cAMP reagents on LNCaP human prostate carcinoma cells. Papaverine and prostaglandin E2 (PGE2), combined synergistically induced morphological changes. Electron microscope study suggested that cells treated with both reagents become like neuroendocrine cells. The effect of both reagents on proliferation and malignancy of LNCaP cells /was then investigated/. The malignancy of cells was analyzed by soft agar colony-forming assay and an in vitro invasion assay. Proliferation and malignancy of LNCaP cells treated with both reagents were significantly decreased in comparison to the proliferation and malignancy of untreated cells. Furthermore, the expression of oncogenes such as c-myc and Bcl-2 was suppressed in differentiated LNCaP cells. These results suggest that papaverine combined with PGE2 can synergistically induce neuronal differentiation as well as decrease the malignancy of human prostatic cancer LNCaP cells.For more Interactions (Complete) data for PAPAVERINE (12 total), please visit the HSDB record page.
환경 거동	TERRESTRIAL FATE: Based on a classification scheme(1), a log Koc of 5.18(2), corresponding to a Koc of 151,365(SRC), indicates that papaverine is expected to have moderate mobility in soil(SRC). The pKa of papaverine is 8.07(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of papaverine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.5X10-13 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Papaverine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.3X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(6). Biodegradation data in soil were not available(SRC, 2012).AQUATIC FATE: Based on a classification scheme(1), a log Koc of 5.18(2), corresponding to a Koc of 151,365(SRC), indicates that papaverine is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.5X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4) According to a classification scheme(5), an estimated BCF of 41(SRC), from its log Kow of 2.95(6) and a regression-derived equation(7) suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2012).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), papaverine, which has an estimated vapor pressure of 2.3X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase papaverine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC)the half-life for this reaction in air is estimated to be 0.7 hours(SRC), calculated from its rate constant of 1.9X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase papaverine may be removed from the air by wet or dry deposition(SRC). Papaverine absorbs light at wavelengths as high as 327 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).
Plant Concentrations	Papaverine has been detected in the Opium Poppy (Papaver somniferum L.), with 20 ppm being reported in the fruit. It has also been detected not quantified in the Great Scarlet Poppy plant (Papaver bracteatum L.) and in the root of Indian Snakeroot (Rauvolfia serpentina L>)(1).
Soil Adsorption/Mobility	A log Koc of 5.18 has been reported for papaverine(1), corresponding to a Koc of 151,365(SRC). According to a classification scheme(2), this estimated Koc value suggests that papaverine is expected to be immobile in soil. The pKa of papaverine is 8.07(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). A Kd of 5442 has been reported using an agricultural soil from Corrstown, Co. Dublin, Ireland(1).
Natural Pollution Sources	Papaverine has been detected in various poppy species (Papaver sp.) and Indian snakeroot (Rauvolfia serpentina)(1).
Human Toxicity Excerpts	/HUMAN EXPOSURE STUDIES/ Papaverine is used for the evaluation of functional status of the coronary arteries but it may provoke severe ventricular tachyarrhythmias (VTAs). This study compared the clinical and ECG characteristic of patients with papaverine-induced VTAs. The study involved 25 patients who underwent a fractional flow reserve (FFR) study. FFR was determined as the ratio of blood pressure at the distal and the proximal site of stenosis after intracoronary papaverine administration at 12 mg into the left and 8 mg into the right coronary artery. The QT and QTU intervals were measured manually in the limb leads and in the precordial leads, respectively and corrected by the R-R interval to obtain QTc and QTUc. The clinical and ECG data were compared between the patient groups with and without VTAs. After papaverine administration into the left (20), right (3) or both coronary arteries (2), the RR interval shortened, but non-significantly however, the QT interval (and QTc) and the QTU interval (and QTUc) were significantly prolonged. VTAs developed in four women: torsade de pointes in 3 followed by ventricular fibrillation and ventricular premature beats in 1 patient. After papaverine administration, QTU and QTUc were more prolonged in women than men and in patients with VTAs compared to those without. Just prior to VTAs, giant T-U waves were observed. Intracoronary papaverine was used to determine FFR which may induce VTAs. VTAs developed only in women and they were closely related to prolongation of the QTU intervals with prominent T-U waves./HUMAN EXPOSURE STUDIES/ Fatalities have followed intravenous use. Polymorphous ventricular tachycardia with prolongation of the QT intervalhas followed infusion of 6 to 10 mg into the coronary arteries./HUMAN EXPOSURE STUDIES/ Doses as high as 1 g by mouth produce only minimal side effects. IV doses of 30 and 65 mg produced rapid demise of 2 adults preceded by hyperpnea, tachypnea and eventually apnea. Heart sounds were not audible after onset of respiratory symptoms. Death may have resulted from either cardiac or respiratory disturbance./SIGNS AND SYMPTOMS/ The symptoms of toxicity from papaverine hydrochloride often result from vasomotor instability and include nausea, vomiting, weakness, central nervous system depression, nystagmus, diplopia, diaphoresis, flushing, dizziness, and sinus tachycardia.For more Human Toxicity Excerpts (Complete) data for PAPAVERINE (22 total), please visit the HSDB record page.
Artificial Pollution Sources	Papaverine's production and adminstration as a vasodialator(1) and drug of abuse(2) may result in its release to the environment through various waste streams(SRC).
Drug Induced Liver Injury	Drug-Induced Liver Injury Severity and Toxicity (DILIst)papaverineDILI PositiveIntravenousDOI:10.1016/j.drudis.2019.09.022
Environmental Bioconcentration	An estimated BCF of 41 was calculated in fish for papaverine(SRC), using a log Kow of 2.95(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).
Volatilization from Water/Soil	The Henry's Law constant for papaverine is estimated as 7.5X10-13 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that papaverine is expected to be essentially nonvolatile from water or moist soil surfaces(2). Papaverine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.3X10-8 mm Hg(SRC), determined from a fragment constant method(3).
Non-Human Toxicity Excerpts	/LABORATORY ANIMALS: Acute Exposure/ The aim of this study is to investigate erectile response to intraurethral administration of papaverine in /male Sprague-Dawley/ rats. Under urethane anesthesia, penis was exposed and intracavernous pressure (ICP) was recorded through a 23-gauge needle, which was inserted into right corpus cavernosum. Effects of intraurethral application of incremental doses of 0.2 mL papaverine gel (4-17.5 mg) on intracavernosal pressure were observed and compared with those of 0.4 mg papaverine applied into corpus cavernosum. Mean arterial blood pressure (MABP) and heart rate were also monitored. The mean basal ICP was 8.9 +/- 1.8 mm Hg. Intraurethral administration of papaverine did not increase ICP at any doses used in this study. After intracavernous injection of papaverine (0.4 mg), a significant increase in the ICP occurred from resting (8.9 +/- 1.8 mm Hg) to a peak at 57.5 +/- 9.9 mm Hg and persisted for 22.3 +/- 6.7 minutes (p < 0.05). The latter application significantly decreased MABP (22.3 +/- 3.1 mm Hgp < 0.05). Intraurethral administration of papaverine does not seem to be an alternative to other erectile dysfunction treatment modalities. .../LABORATORY ANIMALS: Acute Exposure/ Arrhythmias and AV heart block are commonly observed in ... animals after iv admin./LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In August 1995, an outbreak of bronchiolitis obliterans was observed in Taiwan. This progressive respiratory distress disease was associated with consumption of the uncooked vegetable, Sauropus androgynus. The vegetable is reportedly high in papaverine, a chemical that affects vasodilatation. This study determined whether Sauropus androgynus and papaverine induce bronchiolitis obliterans in Sprague-Dawley (S/D) rats. ... In part A of the experiment, 30 S/D rats were fed various concentrations of S. androgynus juice for eight weeks. The rats were divided into six groups, including a normal control and study groups with one time (1X), 10 times (10X, leaf only and mixed leaf and stalk) and 30 times (30X, leaf only and mixed leaf and stalk) concentration. In part B, 33 S/D rats were fed different doses of papaverine for 4 weeks. The rats were also divided into six groups, including normal control, oral feeding subgroups (1X, 10X and 20X) and intraperitoneal injection subgroups (5X and 10X). The degree of inflammation was defined semiquantitatively in the bronchioles and pulmonary vessel adventitia as including grade 0 (no inflammation), grade 1 (minimal), grade 2 (mild), grade 3 (moderate) and grade 4 (severe). There was no evidence of bronchiolitis obliterans in either experiment. The histopathologic findings of the lungs revealed normal or only minimal inflammatory changes in the peribronchial and perivascular adventitia in each group of both studies. The mean degree of inflammatory changes in the study groups was no different from that of control group. /The authors/ conclude that ingestion of high-dose S. androgynus and papaverine do not induce injuries to the airways, alveoli or pulmonary vessels in the animal model of S/D rats. The species barrier may be one of the possible reasons./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No teratogenic effects were observed in rats when papaverine hydrochloride was administered subcutaneously as a single agent.For more Non-Human Toxicity Excerpts (Complete) data for PAPAVERINE (11 total), please visit the HSDB record page.
Populations at Special Risk	... Use of papaverine in patients with Parkinson's diease should probably be avoided, particularly if the patients are receiving levodopa.It is not known whether papaverine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Papaverine Hydrochloride should be given to a pregnant woman only if clearly needed.Vasoactive therapy for impotence should not be used in patients who might have conditions predisposing to priapism (e.g., sickle cell anemia or trait, multiple myeloma, leukemia), in those with anatomic deformation of the penis (e.g., angulation, cavernosal fibrosis, Peyronie's disease), or in men for whom sexual activity is inadvisable or contraindicated. In addition, vasoactive therapy should be discontinued in any patient who develops penile angulation, cavernosal fibrosis, or Peyronie's disease during therapy with the drug. ... Patients with penile implants should not be treated with vasoactive therapy for impotence.
수질 위해 등급(WGK)	1
RTECS 번호	NW8575000
운송 번호(UN)	UN 1544 6.1/PG 3
독성	LD50 orl-rat: 325 mg/kg ARZNAD 20,1338,70
위험 문구(R)	22
위험 표시	Xn
안전 문구(S)	22
포장분류	II
위험 등급	6.1(a)
F 고인화성물질	8
유해 물질 데이터	58-74-2(Hazardous Substances Data)

용도

folate metabolic inhibitor, coccidiostat