己酮可可碱以剂量依赖性方式抑制细胞生长（0.1–50 mM；24-48 小时）[3]。在 MDA-MB-231 细胞中，己酮可可碱（0.5 mM；12-36 小时）可减少自噬并促进细胞凋亡 [3]。在 MDA-MB-231 细胞中，己酮可可碱（0.5 mM；12-36 小时）可促进自噬 [3]。细胞周期的 G0/G1 期被己酮可可碱（0.5 mM；24-48 小时）阻断 [3]。己酮可可碱导致 LC3-II/LC3 比率升高 [3]。

在暴露于短暂性全身缺血的大鼠中，己酮可可碱（200 mg/kg；腹膜内注射）发挥保护作用并减轻认知损伤[4]。

细胞增殖测定[3]
细胞类型： MDA-MB-231 细胞
测试浓度： 0.1 mM、1 mM、5 mM、10 mM、 50 mM
孵育时间：24 小时、48 小时
实验结果：抑制细胞增殖剂量依赖性方式。

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细胞凋亡分析[3]
细胞类型： MDA-MB-231 细胞
测试浓度： 0.5 mM
孵育时间：12 hrs（小时）、24 hrs（小时）、36 hrs（小时）
实验结果：诱导细胞凋亡。

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自噬测定 [3]
细胞类型： MDA-MB-231 细胞
测试浓度： 0.5 mM
孵育持续时间：24 小时、48 小时
实验结果：大约 20-28% 的自噬被诱导。

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细胞周期分析 [3]
细胞类型： MDA-MB-231 细胞
测试浓度： 0.5 mM
孵育持续时间：24 小时、48 小时
实验结果：诱导 G0/G1 期停滞。

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蛋白质印迹分析[3]
细胞类型： MDA-MB-231 细胞
测试浓度： 0.5 mM
孵育持续时间：24小时、48小时
实验结果：诱导高LC3-II/LC3比率。

Animal/Disease Models: Adult male Wistar rats, 12-13 weeks old (250-300 g) [4]
Doses: 200 mg/kg
Route of Administration: intraperitoneal (ip) injection, 1 hour before ischemia and 3 hrs (hrs (hours)) after ischemia.
Experimental Results: Significant Improves spatial memory and memory abilities. The effect was Dramatically different from that of the sham operation group and the vehicle group.

Absorption, Distribution and Excretion
Oral pentoxifylline (PTX) is almost completely absorbed but has low bioavailability of 20-30% due to extensive first-pass metabolism; three of the seven known metabolites, M1, M4, and M5 are present in plasma and appear soon after dosing. Single oral doses of 100, 200, and 400 mg of pentoxifylline in healthy males produced a mean tmax of 0.29-0.41 h, a mean Cmax of 272-1607 ng/mL, and a mean AUC0-∞ of 193-1229 ng\*h/mL; corresponding ranges for metabolites 1, 4, and 5 were 0.72-1.15, 114-2753, and 189-7057. Single administration of a 400 mg extended-release tablet resulted in a heightened tmax of 2.08 ± 1.16 h, lowered Cmax of 55.33 ± 22.04 ng/mL, and a comparable AUC0-t of 516 ± 165 ng\*h/mL; all these parameters were increased in cirrhotic patients. Smoking was associated with a decrease in the Cmax and AUCsteady-state of metabolite M1 but did not dramatically affect the pharmacokinetic parameters of pentoxifylline or other measured metabolites. Renal impairment increases the mean Cmax, AUC, and ratio to parent compound AUC of metabolites M4 and M5, but has no significant effect on PTX or M1 pharmacokinetics. Finally, similar to cirrhotic patients, the Cmax and tmax of PTX and its metabolites are increased in patients with varying degrees of chronic heart failure. Overall, metabolites M1 and M5 exhibit plasma concentrations roughly five and eight times greater than PTX, respectively. PTX and M1 pharmacokinetics are approximately dose-dependent, while those of M5 are not. Food intake before PTX ingestion delays time to peak plasma concentrations but not overall absorption. Extended-release forms of PTX extend the tmax to between two and four hours but also serves to ameliorate peaks and troughs in plasma concentration over time.
Pentoxifylline is eliminated almost entirely in the urine and predominantly as M5, which accounts for between 57 and 65 percent of the administered dose. Smaller amounts of M4 are recovered, while M1 and the parent compound account for less than 1% of the recovered dose. The fecal route accounts for less than 4% of the administered dose.
Pentoxifylline has a volume of distribution of 4.15 ± 0.85 following a single intravenous 100 mg dose in healthy subjects.
Pentoxifylline given as a single 100 mg intravenous infusion has a clearance of 3.62 ± 0.75 L/h/kg in healthy subjects, which decreased to 1.44 ± 0.46 L/h/kg in cirrhotic patients. In another study, the apparent clearance of either 300 or 600 mg of pentoxifylline given intravenously (median and range) was 4.2 (2.8-6.3) and 4.1 (2.3-4.6) L/min, respectively. It is important to note that, due to the reversible extra-hepatic metabolism of the parent compound and metabolite 1, the true clearance of pentoxifylline may be even higher than the measured values.

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Metabolism / Metabolites
Pentoxifylline (PTX) metabolism is incompletely understood. There are seven known metabolites (M1 through M7), although only M1, M4, and M5 are detected in plasma at appreciable levels, following the general pattern M5 > M1 > PTX > M4. As PTX apparent clearance is higher than hepatic blood flow and the AUC ratio of M1 to PTX is not appreciably different in cirrhotic patients, it is clear that erythrocytes are the main site of PTX-M1 interconversion. However, the reaction likely occurs in the liver as well. PTX is reduced in an NADPH-dependent manner by unknown an unidentified carbonyl reductase to form either [lisofylline] (the (R)-M1 enantiomer) or (S)-M1; the reaction is stereoselective, producing (S)-M1 exclusively in liver cytosol, 85% (S)-M1 in liver microsomes, and a ratio of 0.010-0.025 R:S-M1 after IV or oral dosing in humans. Although both (R)- and (S)-M1 can be oxidized back into PTX, (R)-M1 can also give rise to M2 and M3 in liver microsomes. _In vitro_ studies suggest that CYP1A2 is at least partly responsible for the conversion of [lisofylline] ((R)-M1) back into PTX. Unlike the reversible oxidation/reduction of PTX and its M1 metabolites, M4 and M5 are formed via irreversible oxidation of PTX in the liver. Studies in mice recapitulating the PTX-ciprofloxacin drug reaction suggest that CYP1A2 is responsible for the formation of M6 from PTX and of M7 from M1, both through de-methylation at position 7. In general, metabolites M2, M3, and M6 are formed at very low levels in mammals.
Pentoxifylline is a known human metabolite of lisofylline.

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Biological Half-Life
Overall, pentoxifylline has an elimination half-life of between 0.39 and 0.84 hours, while its primary metabolites have elimination half-lives of between 0.96 and 1.61 hours.

Hepatotoxicity
Chronic therapy with pentoxifylline has not been associated with elevations in serum enzyme levels, although the rigor with which liver test abnormalities were sought in patients taking the drug was not always clear. Despite its use for more than 3 decades, pentoxifylline has been linked to only rare and not completely convincing cases of clinically apparent liver injury. Nevertheless, adverse effects of hepatitis, jaundice, cholestasis and increased liver enzymes are listed in product labels for pentoxifylline. In reported cases, the time to onset was 3 to 4 weeks and the pattern of liver enzyme elevations was distinctly cholestatic (Case 1). Autoimmune and immunoallergic features were not present. The injury was self-limited and there have been no reports of acute liver failure, chronic hepatitis or vanishing bile duct syndrome associated with pentoxifylline therapy.
In addition, pentoxifylline has been evaluated as the therapy of several liver diseases including acute alcoholic hepatitis and cirrhosis, nonalcoholic fatty liver disease and autoimmune liver conditions with varying results. In several small controlled trials in severe acute alcoholic hepatitis, pentoxifylline therapy was associated with a significant decrease in short term mortality and in the frequency of the hepatorenal syndrome. However, in large well controlled trials in alcoholic fatty liver, pentoxifylline with or without corticosteroids was found to have no effect on either short- or long-term mortality and minimal or no effect on rates of renal failure. Pentoxifylline has also been reported to improve serum aminotransferase levels and hepatic histology in adult patients with nonalcoholic steatohepatitis (NASH), but these findings have yet to be tested in larger randomized controlled trials. All studies, however, found pentoxifylline well tolerated in patients with liver disease and without evidence of hepatotoxicity.
Likelihood score: D (possible rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited data indicate that pentoxifylline is poorly excreted into breastmilk. It would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Pentoxifylline is approximately 45% bound to erythrocyte membranes.

[1]. Pentoxifylline and its applications in dermatology. Indian Dermatol Online J. 2014 Oct-Dec; 5(4): 510–516.

[2]. Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs. 1987 Jul;34(1):50-97.

[3]. Synergistic promoting effects of pentoxifylline and simvastatin on the apoptosis of triple-negative MDA-MB-231 breast cancer cells. Int J Oncol. 2018 Apr;52(4):1246-1254.

[4]. Effect of Pentoxifylline on Ischemia- induced Brain Damage and Spatial Memory Impairment in Rat. Iran J Basic Med Sci. 2012 Sep-Oct; 15(5): 1083-1090.

Pentoxifylline is an oxopurine.
Pentoxifylline (PTX) is a synthetic dimethylxanthine derivative that modulates the rheological properties of blood and also has both anti-oxidant and anti-inflammatory properties. Although originally developed to treat intermittent claudication, a form of exertion-induced leg pain common in patients with peripheral arterial disease, PTX has been investigated for its possible use in diverse conditions, including osteoradionecrosis, diabetic kidney disease, and generally any condition associated with fibrosis. More recently, PTX has been suggested as a possible treatment for COVID-19-induced pulmonary complications due to its ability to regulate the production of inflammatory cytokines. Pentoxifylline has been marketed in Europe since 1972; PTX extended-release tablets sold under the trade name TRENTAL by US Pharm Holdings were first approved by the FDA on Aug 30, 1984, but have since been discontinued. A branded product, PENTOXIL, marketed by Upsher-Smith Laboratories, and generic forms marketed by Valeant Pharmaceuticals and APOTEX have been available since the late 1990s.
EHT 0202 is developed to treat neurodegenerative disorders by ExonHit Therapeutics.
Pentoxifylline is a Blood Viscosity Reducer. The physiologic effect of pentoxifylline is by means of Hematologic Activity Alteration.
Pentoxifylline is a xanthine derivative that decreases the viscosity of blood and is used to treat symptoms of intermittent claudication due to peripheral vascular disease. Pentoxifylline has not been associated with serum enzyme elevations during therapy, but in several isolated case reports has been linked to clinically apparent liver injury.
Pentoxifylline is a methylxanthine derivative with hemorrheologic and immunomodulating properties. Pentoxifylline inhibits phosphodiesterase, resulting in increased levels of cyclic adenosine monophosphate (cAMP) in erythrocytes, endothelium, and the surrounding tissues. This leads to vasodilation, improves erythrocyte flexibility, and enhances blood flow. In addition, the increased level of cAMP in platelets inhibits platelet aggregation, which may contribute to a reduction in blood viscosity. This agent also inhibits production of tumor necrosis factor-alpha and interferon-gamma, while it induces Th2-like (T-helper 2) cytokine production, thereby inhibiting Th1-mediated (T-helper 1) inflammatory and autoimmune responses.
A METHYLXANTHINE derivative that inhibits phosphodiesterase and affects blood rheology. It improves blood flow by increasing erythrocyte and leukocyte flexibility. It also inhibits platelet aggregation. Pentoxifylline modulates immunologic activity by stimulating cytokine production.
See also: Pentoxifylline; triamcinolone acetonide (component of) ... View More ...

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Drug Indication
Pentoxifylline is indicated for the treatment of intermittent claudication in patients with chronic occlusive arterial disease. Pentoxifylline may improve limb function and reduce symptoms but cannot replace other therapies such as surgical bypass or removal of vascular obstructions.
FDA Label
Investigated for use/treatment in alzheimer's disease and neurologic disorders.

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Mechanism of Action
Patients with peripheral arterial disease (PAD) may suffer from intermittent claudication, exertional leg pain that resolves upon rest, which is underscored by a complex etiology including vascular dysfunction (reduced limb perfusion, angiogenesis, and microcirculatory flow), systemic inflammation, and skeletal muscle dysfunction. Pentoxifylline (PTX), (3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione) or 1-(5-oxohexyl)-3,7-­dimethylxanthine, is a methyl-xanthine derivative that acts to lower blood viscosity by increasing erythrocyte flexibility, reducing plasma fibrinogen, inhibiting neutrophil activation, and suppressing erythrocyte/platelet aggregation; it also has antioxidant and anti-inflammatory effects. Although the precise mechanism of action has yet to be elucidated, numerous studies have suggested several effects of PTX. The classical interpretation of PTX's broad effects is due to its ability to act, _in vitro_, as a non-specific cyclic-3',5'-phosphodiesterase (PDE) inhibitor at millimolar concentrations; specifically, it has been proposed that inhibition of PDE type III and IV isozymes leads to elevated cyclic adenosine monophosphate (cAMP) levels, which mediate diverse downstream effects. This view has been challenged, specifically by observing those plasma concentrations of PTX in routine clinical use are typically only around 1μM, far lower than those used to inhibit PDEs _in vitro_. Instead, several studies have suggested that PTX can modulate adenosine receptor function, specifically the Gα-coupled A2A receptor (A2AR). Whether PTX acts directly as an A2AR agonist is unclear, although it can clearly increase the response of A2AR to adenosine. A2AR activation activates adenylyl cyclase, which increases intracellular cAMP levels; this observation may explain PTX's ability to increase intracellular cAMP in a PDE-independent fashion. Elevated cAMP levels have numerous downstream effects. cAMP-mediated activation of protein kinase A (PKA) suppresses nuclear translocation of NF-κB, which suppresses transcription of pro-inflammatory cytokines such as tumour necrosis factor (TNF-α), interleukin-1 (IL-1), and IL-6 as well as TNF-induced molecules such as adhesion molecules (ICAM1 and VCAM1) and the C-reactive protein (CRP). PTX has also been shown to prevent the downstream phosphorylation of p38 MAPK and ERK, which are responsible for assembling the NADPH oxidase involved in the neutrophil oxidative burst. This effect is due to a PKA-independent decrease in Akt phosphorylation and a PKA-dependent decrease in phosphorylation of p38 MAPK and ERK. This transcriptional regulation at least partially explains the anti-inflammatory and anti-oxidative properties of PTX. Also, activated PKA can activate the cAMP response element-binding protein (CREB), which itself blocks SMAD-driven gene transcription, effectively disrupting transforming growth factor (TGF-β1) signalling. This results in lower levels of fibrinogenic molecules such as collagens, fibronectin, connective tissue growth factor, and alpha-smooth muscle actin. Hence, disruption of TGF-β1 signalling may explain the anti-fibrotic effects of PTX, including at least some of the decrease in blood viscosity. The picture is complicated by the observation that PTX metabolites M1, M4, and M5 have been shown to inhibit C5 Des Arg- and formyl-methionylleucylphenylalanine-induced superoxide production in neutrophils and M1 and M5 significantly contribute to PTX's observed hemorheological effects. Overall, PTX administration is associated with decreased pro-inflammatory molecules, an increase in anti-inflammatory molecules such as IL-10, and decreased production of fibrinogenic and cellular adhesion molecules.
EHT 0202 was discovered to play a role in protecting neurons in pharmacological models of neuronal cell death. ExonHit identified RNA isoforms produced by alterations of splicing specifically taking place in neurodegenerative disease models. These isoforms were identified using DATAS(TM), ExonHit's proprietary gene profiling technology. DATAS(TM), stands for Differential Analysis of Transcripts with Alternative Splicing.

C13H18N4O3

278.30702

278.137

6493-05-6

Pentoxifylline-d6;1185878-98-1;Pentoxifylline-d5;1185995-18-9

4740

White to off-white solid powder

1.3±0.1 g/cm3

531.3±56.0 °C at 760 mmHg

98-100°C

275.1±31.8 °C

0.0±1.4 mmHg at 25°C

1.621

0.32

78.89

0

4

5

20

426

0

BYPFEZZEUUWMEJ-UHFFFAOYSA-N

InChI=1S/C13H18N4O3/c1-9(18)6-4-5-7-17-12(19)10-11(14-8-15(10)2)16(3)13(17)20/h8H,4-7H2,1-3H3

1,2,3,6-Tetrahydro-3,7-dimethyl-1-(5-oxohexyl)-2,6-purindion

Dimethyloxohexylxanthine; EHT-0202, EHT0202, EHT 0202; BL 191, BL191, BL-191; Oxpentifylline, Pentoxifilina, Theobromine, Trental, Vazofirin, Etazolate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~93.3 mg/mL (~335.24 mM)
DMSO : ≥ 2.8 mg/mL (~10.06 mM)

配方 1 中的溶解度: 110 mg/mL (395.24 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。