Pseudolaric acid B

432.46

432.46

White to off-white powder or crystals|Solid

29329990

116.20000

2.78

white to off-white

1.3±0.1 g/cm3

143-144 °C

613.8±55.0 °C at 760 mmHg

208.8±25.0 °C

1.565

methanol: soluble1mg/mL, clear, colorless

2-8°C

2.0X10-11 mm Hg at 25 °C (est)

pKa = 4.14 (est)

UN 2811 6.1 / PGIII

3

25-62

36/37-45-24/25

T

P281-P301 + P310

H301-H361

SRP: Criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.|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.

Safety glasses, compatible chemical-resistant gloves.|Eye wash station in work area; safety shower in work area.|NIOSH approved respirator, as conditions warrant.|Use process enclosures, local exhaust ventilation, or other engineering controls to control airborne levels below recommended exposure limits.

Suitable Extinguishing Media: Use alcohol-resistant foam, carbon dioxide, water, or dry chemical spray. Use water spray to cool fire-exposed containers.|Unsuitable Extinguishing Media: A solid water stream may be inefficient.|As in any fire, wear self-contained breathing apparatus pressure-demand (NIOSH approved or equivalent), and full protective gear to prevent contact with skin and eyes.

Released or Spilled: Avoid raising and breathing dust, and provide adequate ventilation. As conditions warrant, wear a NIOSH approved self-contained breathing apparatus, or respirator, and appropriate personal protection (rubber boots, safety goggles, and heavy rubber gloves). Transfer to proper chemical waste container for disposal.

SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. The completeness of the cleaning procedures should be considered before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at the end of shift, but should remain at employee's place of work for cleaning.|Lab coat|Wash thoroughly after handling.|Avoid breathing (dust, vapor, mist, gas). Avoid prolonged or repeated exposure.|Avoid contact with skin and eyes.

Pseudolaric acid B is isolated from the extract of the root bark of Pseudolarix kaempferi Gordon (Golden Larch)(1).

Pseudolaric acid B's production and use as an antifungal medication(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 9500(SRC), determined from a structure estimation method(2), indicates that pseudolaric acid B is expected to be immobile in soil(SRC). The pKa of pseudolaric acid B is estimated as 4.14(3), indicating that this compound will exist almost entirely in anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of pseudolaric acid B from moist soil surfaces is not expected to be an important fate process(SRC) given its pKa(3). Pseudolaric acid B is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.0X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Biodegradation data in soil were not available(SRC, 2013).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 9500(SRC), determined from a structure estimation method(2), indicates that pseudolaric acid B is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 4.14(3) indicates pseudolaric acid B will exist almost entirely in the anion form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 3(SRC), from an estimated log Kow of 3.06(5) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). A base-catalyzed second-order hydrolysis rate constant of 2.1X10-3 L/mole-sec(SRC) was estimated using a structure estimation method(7); this corresponds to half-lives of 110 and 11 years at pH values of 7 and 8, respectively(7). Biodegradation data in water were not available(2013, SRC).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), pseudolaric acid B, which has an estimated vapor pressure of 2.0X10-11 mm Hg at 24 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase. Particulate-phase pseudolaric acid B may be removed from the air by wet or dry deposition(SRC). Pseudolaric acid B contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

A base-catalyzed second-order hydrolysis rate constant of 2.1X10-3 L/mole-sec(SRC) was estimated using a structure estimation method(1); this corresponds to half-lives of 110 and 11 years at pH values of 7 and 8, respectively(1). Pseudolaric acid B contains chromophores that absorb at wavelengths >290 nm(2) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 3 was calculated in fish for pseudolaric acid B(SRC), using an estimated log Kow of 3.06(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of pseudolaric acid B can be estimated to be 9500(SRC). According to a classification scheme(2), this estimated Koc value suggests that pseudolaric acid B is expected to be immobile in soil. The pKa of pseudolaric acid B is estimated as 4.14(3), indicating that this compound will exist almost entirely in anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

An estimated pKa of 4.14(1) indicates pseudolaric acid B will exist almost entirely in the anion form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). Pseudolaric acid B is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.0X10-11 mm Hg(SRC), determined from a fragment constant method(2).

Occupational exposure to pseudolaric acid B may occur through dermal contact with this compound at workplaces where pseudolaric acid B is extracted or used. The general population may be exposed to pseudolaric acid B via ingestion as a medication. (SRC)

Drugs, Chinese Herbal|EXPL THER Candida albicans is the most common fungal pathogen in humans. The emergence of resistance to azole antifungals has raised the issue of using such antifungals in combination to optimise therapeutic outcome. The objective of this study was to evaluate in vitro synergy of pseudolaric acid B (PAB) and fluconazole (FLC) against clinical isolates of C. albicans. The in vitro antifungal activity of PAB, a diterpene acid from Pseudolarix kaempferi Gordon, was evaluated alone and in combination with FLC against 22 FLC-resistant (FLC-R) and 12 FLC-susceptible (FLC-S) C. albicans using the chequerboard microdilution method and time-killing test assays. Synergism was observed in all 22 (100%) FLC-R strains tested as determined by both fractional inhibitory concentration index (FICI) with values ranging from 0.02 to 0.13 and bliss independence (BI) models. Synergism was observed in two of 12 (17%) FLC-S strains as determined by FICI model with values ranging from 0.25 to 0.5 and in three of 12 (18%) FLC-S strains as determined by BI model. For FLC-R strains, the drug concentrations of FLC and PAB, where synergistic interactions were found, ranged from 0.06 to 4 ug mL(-1) and 0.5 to 4 ug mL(-1) respectively. For FLC-S strains, the drug concentrations of FLC and PAB were 1-8 ug mL(-1) and 0.5-4 ug mL(-1) respectively. The BI model gave results consistent with FICI, but no antagonistic activity was observed in any of the strains tested. These interactions between PAB and FLC were confirmed using the time-killing test for the selected strains. Fluconazole and PAB exhibited a good synergism against azole-R isolates of C. albicans.|EXPL THER As an opportunistic infection, candidiasis is common among individuals infected with HIV. About 90% of patients develop oral and/or oropharyngeal candidiasis in various stages of AIDS. Triazole antifungal agents, such as fluconazole and itraconazole, are considered to be first-choice agents for treatment and prevention because of their relatively low side effects and high effectiveness on mucosal infections. However, with prolonged exposure to azoles, drug resistance becomes a challenge for clinicians and patients alike. In traditional Chinese medicine, more than 300 herbs have been discovered to have "pesticidal" activities, and some of these have been used as antifungal agents in clinical practice for many years. Crude extracts from a number of medicinal herbs have been shown to exhibit antifungal activities in vitro. These include cortex moutan, cortex pseudolaricis, rhizoma alpiniae officinarum, rhizoma coptidis, clove and cinnamon, anemarrhena cortex phellodendri, ramulus cinnamomi, and Chinese gall. The effective anti-Candida principals were identified to be berberine, palmatine, allincin, pseudolaric acid A and B, magnolol, honokiol, and galangin. Thus, traditional Chinese medicinal herbs provide abundant choices for the treatment of refractory candidiasis commonly seen in HIV/AIDS patients. However, there remains a need for further screening of effective extracts and for study of the antifungal mechanisms involved. Importantly, ahead of clinical application, the safety of these compounds must be firmly established.

The aim of this study was to investigate the mechanism of pseudolaric acid B (PLAB)-induced cell cycle arrest in human melanoma SK-28 cells. Cell growth inhibition was detected by MTT assay, the cell cycle was analyzed by flow cytometry, and protein expression was examined by Western blot analysis. PLAB inhibited the growth of human melanoma cells and induced G(2)/M arrest in SK-28 cells, accompanied by an up-regulation of Cdc2 phosphorylation and a subsequent down-regulation of Cdc2 expression. Furthermore, PLAB decreased the expression of Cdc25C phosphatase and increased the expression of Wee1 kinase. Meanwhile, a reduction in Cdc2 activity was partly due to induction of the expression of p21(waf1/cip1) in a p53-dependent manner. In addition, PLAB activated the checkpoint kinase, Chk2, and increased the expression of p53, two major targets of ATM kinase. These effects were inhibited by caffeine, an ATM kinase inhibitor. We also found that PLAB significantly enhanced ATM kinase activity. Taken together, these results suggest that PLAB induced G(2)/M arrest in human melanoma cells via a mechanism involving the activation of ATM, and the effect of PLAB on Cdc2 activity was mediated via interactions with the Chk2-Cdc25C and p53 signalling pathways, two distinct downstream pathways of ATM. PLAB may be a promising chemopreventive agent for treating human melanoma.|Pseudolaric acid B (PAB) is the primary biologically active compound isolated from the root bark of P. kaempferi Gordon. Previous studies have demonstrated that PAB arrests cells in G2/M phase in several cancer cell lines without significantly perturbing the G2/M transition-associated proteins. CylinB1, a marker for mitotic phase arrest, was up-regulated in cells treated with PAB. Therefore, /the researchers/ investigated whether PAB affects cell cycle progression at the mitotic phase. The mitotic index increased during a 24 hr treatment with PAB, suggesting that PAB arrested cell cycle progression at mitosis. In addition, after a prolonged mitotic arrest, the cells underwent mitotic catastrophe. After an extended treatment with PAB (longer than 24 hr), the protein levels of cylinB1 and cdc2 significantly decreased in both nuclear and cytosolic extracts. According to these results, /the investigators/ concluded that mitotic slippage could be due to the inactivation of the cylinB1-cdc2 complex resulting from prolonged treatment with PAB. The cells undergoing mitotic catastrophe died via apoptosis.|Pseudolaric acid B (PAB) is the major bioactive constituent in the root bark of Pseudolarix kaempferi that has been used as an antifungal remedy in traditional Chinese medicine. Previous studies showed that PAB exhibited substantial cytotoxicity. The aims of this study were to elucidate the molecular target of PAB, to examine its mechanism of action, and to evaluate the efficacy of this compound in vivo. The effect of PAB on cell growth inhibition toward a panel of cancer cell lines was assayed. Cell cycle analysis, Western blotting, immunocytochemistry, and apoptosis analysis were carried out to examine the mechanism of action. Tubulin polymerization assays were conducted to examine the interaction between PAB and tubulin. A P-glycoprotein-overexpressing cell line was used to evaluate the efficacy of PAB toward multidrug-resistant phenotypes. In vivo efficacy of PAB was evaluated by the murine xenograft model. PAB induces cell cycle arrest at G2-M transition, leading to apoptosis. The drug disrupts cellular microtubule networks and inhibits the formation of mitotic spindles. Polymerization of purified bovine brain tubulin was dose-dependently inhibited by PAB. Furthermore, PAB circumvents the multidrug resistance mechanism, displaying notable potency also in P-glycoprotein-overexpressing cells. Finally, /the investigators/ showed that PAB is effective in inhibiting tumor growth in vivo. We identified the microtubules as the molecular target of PAB. Furthermore, we showed that PAB circumvents P-glycoprotein overexpression-induced drug resistance and is effective in inhibiting tumor growth in vivo. ...

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/ALTERNATIVE and IN VITRO TESTS/ Pseudolaric acid B (PAB), the naturally occurring diterpenoid isolated from the root bark of Pseudolarix kaempferi Gordon tree (Pinaceae), possesses potent antifungal and pregnancy-terminating effects that may be tightly associated with angiogenesis. This study was to examine its angiogenic inhibition, impact on vascular endothelial growth factor (VEGF) secretion from tumor cells and the possible mechanism of action. Angiogenesis inhibition was assessed by the human umbilical vascular endothelial cell proliferation, migration, and tube-formation assays, as well as the chorioallantoic membrane assay. ELISA, reverse transcription-PCR, and Western blotting analyses were performed to examine VEGF protein secretion, mRNA expression, and the possible mechanism in hypoxic MDA-MB-468 cells. PAB displayed potent in vitro antiangiogenic activity shown by inhibiting VEGF-stimulated proliferation and migration and fetal bovine serum-stimulated tube formation of human umbilical vascular endothelial cells in a concentration-dependent manner. Moreover, PAB (10 nmol per egg) significantly suppressed in vivo angiogenesis in the chorioallantoic membrane assay. On the other hand, PAB abrogated hypoxia-induced VEGF secretion from MDA-MB-468 cells via reducing HIF-1alpha protein. Additional analyses using LY294002 and U0126 indicated that the increase in hypoxia-inducible factor 1 (HIF-1)alpha protein level was highly dependent on phosphatidylinositol 3'-kinase and p42/p44 mitogen-activated protein kinase activities in hypoxic MDA-MB-468 cells. However, PAB treatment did not affect the active (phosphorylated) forms of Akt and Erk. Interestingly, the selective proteasome inhibitor MG-132 completely reversed the reduction of HIF-1alpha protein in the PAB-treated MDA-MB-468 cells. PAB displays the dual antiangiogenic activities of directly inhibiting endothelial cells and abrogating paracrine stimulation of VEGF from tumor cells due to reducing HIF-1alpha protein by promoting its proteasome-mediated degradation in MDA-MB-468 cells, which has potential clinical relevance.|/ALTERNATIVE and IN VITRO TESTS/ The aim of the present study was to investigate the inhibitory effect of pseudolaric acid B (PAB) on human breast cancer MCF-7 cells. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, morphological changes, acridine orange staining, and agarose gel electrophoresis were applied to detect apoptosis. The percentage of apoptotic and necrotic cells was calculated by the lactate dehydrogenase activity-based cytotoxicity assay; senescence associated (SA)-beta-galactosidase activity was detected to evaluate senescence; flow cytometric analysis of propidium iodide staining was carried out to investigate the distribution of cell cycle, and the protein expression was examined by Western blot analysis. During apoptosis, the half maximal inhibitory concentration IC(50)was 3.4 and 1.35 umol/L at 36 and 48 hr after PAB treatment, respectively. The MCF-7 cells exposed to PAB showed typical characteristics of apoptosis, including the morphological changes and DNA fragmentation. The MCF-7 cells treated with 4 umol/L PAB for 36 hr underwent apoptosis, but not necrosis. The apoptosis induced by PAB was independent of the death receptor pathway. The senescent cells became larger and flatter, and the SA-beta-galactosidase staining was positive. PAB induced obvious mitotic arrest and it preceded apoptosis and senescence. The expressions of p21 and p53 was upregulated with PAB treatment, and cyclin B1 was upregulated and transported from the cytoplasm to nuclei, and sustained stable levels. PAB induced mitotic arrest in the MCF-7 cells and inhibited proliferation through apoptosis and senescence. The apoptosis was independent of the death receptor pathway.|/ALTERNATIVE and IN VITRO TESTS/ The leukemias account for the largest number of cases of childhood cancer and remain the primary cause of cancer-related mortality among children in the United States. There is a need for novel antileukemia agents due to toxicity and resistant to existing chemotherapeutic agents. In this study, the effects of pseudolaric acid B (PAB) on three human leukemia cell lines, acute promyelocytic leukemia HL-60 cells, acute lymphoblastic leukemia CCRF-CEM cells, and human chronic myeloid leukemia blast-phase K562 cells were investigated in vitro, compared to normal human peripheral blood mononuclear cells (PBMC). Cell viability was determined using CellTiter-Glo luminescent reagent. Colony formation was assessed by Microtitration cloning assay. Cell cycle analysis was carried out by flow cytometry. Tubulin polymerization was measured by recording the increase in absorbance. Inhibition of topoisomerase I (topo I) and topoisomerase II (topo II) enzyme activities was measured by DNA relaxation assay using topo I and II drug screening kit. Apoptosis was observed by DAPI staining assay and Caspase3/7 activities was measured using Caspase-Glo((R)) 3/7 assay kit. Pseudolaric acid B selectively inhibited the growth of human leukemia HL-60, CCRF-CEM and K562 cells, but not normal PBMC. PAB suppressed colony formation in HL-60 cells. Cell cycle analysis showed that PAB blocked the cell cycle at G(2)/M phase in HL-60 cells, suggesting that it suppresses mitosis. DNA topo I and topo II were not inhibited, but tubulin polymerization was inhibited. PAB-induced apoptosis and activated caspase-3/7 activity.This study indicates that PAB has a potential for use against leukemia and its effects might be mediated by inhibiting tubulin polymerization, preventing cell division and activating caspase-3, which leads to apoptosis.|/ALTERNATIVE and IN VITRO TESTS/ Two novel diterpendoids, pseudolaric acids A and B (PA, PB) first isolated from the root of Pseudolarix kaempferi Gorden in China, have been reported to possess significant antifertile activities in rats, hamsters, rabbits, and dogs. The present study demonstrated that neither PA nor PB had estrogenic and antiestrogenic activities, they also did not inhibit deciduous formation. ... The human uterus was used as the experimental material in vitro. PA and PB 200 ug.mL-1 cultural medium (McCoy's 5a medium) damaged only a part of the decidual and trophoblast cells. ...|For more Human Toxicity Excerpts (Complete) data for Pseudolaric Acid B (6 total), please visit the HSDB record page.

pseudolaric acid B

Pseudolaric acid B, a natural diterpenoid compound, is isolated from Pseudolarix kaempferi. It has shown antifungal, antifertility, and antiangiogenic properties. It also may exhibit anticancer and anti-inflammatory properties.