雷公藤甲素对生殖系统毒性的研究进展

雷公藤甲素为雷公藤的主要活性成分之一,也是雷公藤片、雷公藤多苷片等制剂的主要有效成分。它具有抗炎、抗肿瘤、免疫调节等药理作用,是热点研究的天然活性化合物。但是,雷公藤甲素的副作用在很大程度上影响了其在临床上的应用,其中对生殖系统的毒性及抗生育作用尤为明显,特别是对雄性生殖系统的影响。综述了雷公藤甲素对男性睾丸、附睾和精子等,以及对女性生殖系统的损害及作用机制,并建议系统开展配伍减毒增效的研究,实现对配伍雷公藤甲素安全窗口的拓宽优化,为安全有效地应用于临床提供有力依据。     

雷公藤甲素生殖毒性及其防治策略研究进展

雷公藤甲素是传统中药雷公藤中最主要的生物活性成分,具有抗癌、抗炎和免疫抑制等功效,临床上用于治疗肿瘤,类风湿性关节炎和系统性红斑狼疮等自身免疫疾病.然而,雷公藤甲素具有严重的生殖毒性,会造成精子数量减少和活力下降,直接损伤睾丸、卵巢和子宫等,其毒性机制主要与氧化应激、线粒体损伤,及乳腺癌耐药蛋白、过氧化物酶体增殖物激活...     

雷公藤甲素及其纳米制剂抗肿瘤作用研究进展

雷公藤甲素是从卫茅科雷公藤根部提取的一种环氧二萜内酯化合物，已经证实具有抗炎、抗病毒、免疫调节、抗生育等多种药理活性，近年来，尤其在抗肿瘤方面显示出巨大潜力。雷公藤甲素对多种肿瘤细胞具有显著抑制作用，其作用机制包括抑制肿瘤细胞增殖与迁移、诱导肿瘤细胞凋亡、诱导肿瘤细胞自噬、诱导肿瘤细胞周期阻滞等。但其水溶性差、生物利用度低及不良反应严重等缺陷限制其临床应用，目前通过纳米制剂手段如脂质纳米粒、聚乳酸纳米粒、聚合物胶束、外泌体等，可将药物精准递送到肿瘤部位，提高药物疗效，降低毒性等，其展现出良好的应用前景。本文通过对近年来国内外雷公藤甲素的抗肿瘤活性、作用机制及其纳米制剂抗肿瘤应用的研究进行归纳总结，以期为雷公藤甲素及其纳米制剂在抗肿瘤方面的进一步开发应用提供指导。     

雷公藤甲素脂质体制备及体内抗肿瘤实验研究

目的注入法制备雷公藤甲素脂质体,观察其形态特征和包封率,并对其体内抗H22疗效进行初步研究。方法用注入法制备雷公藤甲素脂质体,通过普通光学显微镜和动态光散色粒度分析仪测定其形态、粒径,用HPLC测定其包封率;并建立H22荷瘤模型观察其抗肿瘤活性。结果该法所得脂质体形态规则、粒度均匀,平均直径约为45.6 nm,但包封率不是很高约为46.7%;体内抗肿瘤实验结果表明,雷公藤甲素脂质体具有较强的抗H22活性,且与浓度呈正相关,而且相对“游离”雷公藤甲素毒性较小。结论雷公藤甲素脂质体具有较强的抗肿瘤活性,且不良反应较小。     

雷公藤甲素脂质体制备及体内抗肿瘤实验研究

目的注入法制备雷公藤甲素脂质体,观察其形态特征和包封率,并对其体内抗H22疗效进行初步研究。方法用注入法制备雷公藤甲素脂质体,通过普通光学显微镜和动态光散色粒度分析仪测定其形态、粒径,用HPLC测定其包封率;并建立H22荷瘤模型观察其抗肿瘤活性。结果该法所得脂质体形态规则、粒度均匀,平均直径约为45.6 nm,但包封率不是很高约为46.7%;体内抗肿瘤实验结果表明,雷公藤甲素脂质体具有较强的抗H22活性,且与浓度呈正相关,而且相对"游离"雷公藤甲素毒性较小。结论雷公藤甲素脂质体具有较强的抗肿瘤活性,且不良反应较小。     

雷公藤的毒理作用及增效减毒配伍的研究进展

祛风湿类中药雷公藤具有抗炎、免疫抑制作用，临床广泛用于治疗自身免疫系统疾病，如类风湿性关节炎、系统性红斑狼疮、银屑病、器官移植后免疫排斥等，效果显著。自1958年有关雷公藤中毒的研究被报道至今，其毒性受到越来越多人的重视。雷公藤的治疗窗较窄，长期用药毒性易蓄积，致生殖器官、肝、肾等脏器不可逆病变。目前，对雷公藤的毒理研究主要集中于雷公藤有效部位提取物雷公藤多苷和雷公藤有效成分雷公藤甲素（TP）。临床报道的雷公藤不良反应主要源自服用主含雷公藤多苷的制剂，     

凤尾草对雷公藤甲素的减毒作用

目的:研究凤尾草对雷公藤甲素的减毒作用以及免疫抑制和抗炎镇痛活性的影响。方法:通过比较雷公藤甲素单用及与凤尾草联用对小鼠急性毒性、肝组织形态和大鼠肝功能的影响来评价凤尾草对雷公藤甲素的减毒作用;采用噻唑兰(MTT)法测定雷公藤甲素单用及与凤尾草联用对小鼠T、B淋巴细胞增殖的影响;采用二甲苯致小鼠耳廓肿胀实验研究凤尾草对雷公藤甲素抗炎作用的影响;采用热板法和扭体法研究凤尾草对雷公藤甲素镇痛作用的影响。结果:雷公藤甲素联用凤尾草后LD50增大了约1倍,肝细胞损伤明显减轻,ALT和AST明显降低;雷公藤甲素单用及与凤尾草联用均能显著抑制小鼠T、B淋巴细胞的增殖和二甲苯致小鼠耳廓肿胀,并均有明显的镇痛作用,但两者作用效果差异无显著性。结论:联合运用凤尾草可降低雷公藤甲素毒性并基本保持其免疫抑制和抗炎镇痛活性。     

雷公藤甲素抗肿瘤药理作用的研究进展

雷公藤甲素是从中药雷公藤中提取的一种具有多种生物活性的天然产物,是雷公藤片、雷公藤多甙片等制剂的主要有效成分,临床多用于抗炎及免疫抑制。药理研究表明雷公藤甲素还具有广谱、高效的抗肿瘤活性,作用机制涉及诱导细胞凋亡、阻滞细胞周期、逆转肿瘤细胞多药耐药等多个方面。综述了雷公藤甲素对消化系统、生殖系统、血液系统、呼吸系统肿瘤的抗肿瘤作用及相关机制的研究进展,为加速其抗肿瘤新药研发提供理论依据。     

雷公藤甲素药理作用及分子水平机制研究进展

雷公藤甲素为雷公藤二萜类成分,具有较高的药理活性,广泛应用于类风湿关节炎、各种原发性及继发性肾病、结缔组织病等,近期在抗肿瘤、抗器官移植排斥反应、脑神经元及心肌保护等方面的作用也受到广泛关注.近5年来,我国学者通过大量的实验研究,从细胞、分子、基因等水平揭示了其药理机制,为临床应用提供了理论依据和思路参考,有广阔的发展空间.但对神经元保护及心肌保护方面的研较少,进展较为缓慢.此外雷公藤甲素的毒性作用大大影响了其开发利用,如何保持其生物活性,降低其不良反应,使其能够更广泛应用于临床显得更为迫切.     

雷公藤甲素提取分离工艺研究现状

雷公藤甲素属二萜类化合物,是雷公藤中具有抗炎、抗肿瘤和免疫抑制活性的有效部位。1972年文献首次报道雷公藤甲素、雷公藤乙素和雷公藤内酯酮具有明显抑制白血病瘤株L1210,P388的效果,此后国内外形成一股雷公藤甲素药理学、毒理学研究的高潮。但雷公藤甲素在雷公藤植物中的含量不高,传统的提取工艺比较复杂,因此对雷公藤甲素进行提取、分离、富集、精制的系统研究显得很有必要。本文对近年来较新的几种制备雷公藤甲素的方法进行了介绍,包括醇提氯仿萃取法、醇提氯仿萃取法、醇提乙酸乙酯萃取法、英国专利提取法等,希望通过对这些方法的研究获得好的思路,为雷公藤甲素的工业化生产提供简单、重复性好、可靠性高的最佳提取工艺。     

Cyclophosphamide toxicity. Characterising and avoiding the problem.

Cyclophosphamide, an orally active alkylating agent, is widely used to treat a variety of malignant and nonmalignant disorders. Although it has some tumour selectivity, it also possesses a wide spectrum of toxicities. The requirement of metabolic activation before cyclophosphamide exerts either its therapeutic or toxic effects is well established, but has not led to effective counter-measures. Clinically, damage to the bladder (haemorrhagic cystitis), immunosuppression (when not desired) and alopecia are the most significant toxicities associated with cyclophosphamide. Cardiotoxicity is also a possibility when very high doses are given. Preventing these toxicities has focused on modifications of the treatment regimens and, in the case of haemorrhagic cystitis, the administration of a drug which is excreted in the urine where it inactivates the bladder-toxic species. As treatment regimens for cancer become more effective in prolonging a patient's life, and as cyclophosphamide receives increasing use for nonmalignant disorders, the potential for cyclophosphamide-induced cancers, particularly in the bladder, must be recognised. Although the toxicities associated with cyclophosphamide are serious, this agent remains a highly effective drug in many situations. Research on the pathways which play an important role in activating this drug may improve our ability to target particular diseases and decrease unwanted side effects.     

The impact of exposure route for class-based compounds: a comparative approach of lethal toxicity data in rodent models

Relationships of toxicities from intravenous (i.v.), intraperitoneal (i.p.), subcutaneous (s.c.) and intragastric (i.g.) exposure routes to mice were investigated. Regression analysis showed that the toxicities from i.v. route is strongly correlated with i.p. and s.c. routes, but poorly with i.g. route. Close toxicities from different routes for some compounds indicate that distribution rate is the determining step and dictates chemical concentration at the target site(s). On the other hand, the absorption rate is the determining step for many compounds, which lead to different toxicities between exposure routes. The classified compounds characterized as having either absorption or distribution rate determining step were based upon the comparison of toxicities from the different routes. We found that some aliphatic acids and benzoic acids have lower toxicity values from i.g. route compared to an i.v. route because of poor absorption. Many compounds show low toxic effects from i.g. route than those from other routes because of the first-pass metabolism in the gastrointestinal tract, resulting in the poor relationship for toxicities between i.g. and i.v. or other routes. Stepwise regression analysis showed that physicochemical properties of a compound, such as molecular volume, polarizability and hydrophobicity, significantly affect adsorption rate, which leads to different toxicities based upon exposure routes. Comparison of the toxicities between mice and rats indicate that toxic effect and the toxicokinetic processes in mice are very similar to that in rats. A universal correlation equation has been developed for the toxicities between rats and mice from different exposure routes, which can be applied to predict toxicities across species.     

Toxicity patterns of cytotoxic drugs

Toxicity is a major concern for anticancer drugs. These compounds present a narrow therapeutic index, with a small difference between the dose required for an antitumor effect and that responsible for unacceptable toxicity. Their recommended doses are determined according to the toxicity endpoint. Moreover, toxicity is observed earlier than the therapeutic effect, so, toxic effects represent a major endpoint for pharmacodynamic studies of cytotoxic drugs. Knowledge of toxicity patterns and main factors of toxicity of anticancer drugs is required before modeling data of these studies. Hematological toxicities represent the main toxicity of the cytotoxic. However, non-hematological toxicities have become more important than hematological toxicities as pharmacodynamic endpoints in some circumstances such as high-dose chemotherapy associated with bone marrow transplantation. This paper will describe the main toxicity of the cytotoxic drugs, and its factors of both inter- and intra-patient variability. The toxicity pattern of topotecan will be examined as an example. Knowledge of the toxicity pattern of a drug constitutes a prerequirement before modeling its pharmacodynamics.     

Farnesyl transferase inhibitors in clinical development

Farnesyl transferase (FT) inhibitors block the main post-translational modification of the Ras protein, thus interfering with its localisation to the inner surface of the plasma membrane and subsequent activation of downstream effectors. Although initially developed as a strategy to target Ras in cancer, FT inhibitors have subsequently been acknowledged as acting by additional and more complex mechanisms that may extend beyond Ras, involving RhoB, centromere-binding proteins and probably other farnesylated proteins. SCH66336 (lonafarnib, Sarasar?, Schering-Plough), a tricyclic orally active FT inhibitor, was the first of these compounds to undergo clinical development. Gastrointestinal tract toxicities and fatigue have qualified as dose-limiting toxicities in all Phase I/II studies. Evidence of clinical activity has been reported. Lonafarnib combination studies with both gemcitabine and paclitaxel have been carried out. No unexpected toxicities were observed in these Phase I studies, while encouraging clinical activity was observed mainly in pancreatic cancer and non-small cell lung cancer. Further combination studies are ongoing. R115777 (Zarnestra?, Janssen Pharmaceutica) is another orally active FT competitive inhibitor in clinical development. Single-agent Phase I/II studies have shown that myelotoxicity and neurotoxicity are dose-limiting toxicities; intermittent schedule is probably better tolerated; antitumour activity is observed particularly in breast cancer and haematological malignancies. A number of combination studies with R115777 have been carried out. A recently completed, large Phase III trial comparing gemcitabine plus R115777 versus gemcitabine plus placebo in advanced pancreatic cancer has failed to demonstrate any survival benefit in the R115777 arm. BMS-214662 is the third FT inhibitor in clinical development. It has the main advantage of being cytotoxic in nature, rather than cytostatic, and potent in vivo antitumour activity has been reported. A major drawback for BMS-214662 is its severe gastrointestinal and liver toxicities, which prevent the achievement of adequate systemic exposures following the oral route. Alternative ways of interference with the ras oncogene pathway, in particular inhibition of ras downstream effectors, are discussed and early clinical data are presented.     

The safety of bevacizumab

Despite the significant gains made in the treatment of many cancers over the last few decades, further improvements in survival using traditional chemotherapeutic agents have now begun to plateau. The development of bevacizumab, a monoclonal antibody targeted against the vascular endothelial growth factor, has provided promise for continued gains in survival in the therapy of a variety of cancers, including some previously refractory to traditional chemotherapeutic agents. Although its toxicity profile differs from traditional chemotherapeutic drugs, bevacizumab is not completely without side effects. The mechanisms of its unique toxicities have not yet been fully characterised, and at this time it is not possible to predict which toxicities will be experienced by each individual patient or which population.     

Propylene oxide: genotoxicity profile of a rodent nasal carcinogen

Propylene oxide (PO) is a DNA-reactive genotoxic agent; that is, it reacts with DNA to produce lesions in the genetic material. PO also induces tumors in rodents, although only at high concentrations and at portals of entry. This review of PO's genotoxicity profile is organized according to endpoints measured, that is, nonmutational or mutational endpoints, and as to whether the results were from in vitro or in vivo studies. In addition to results of experimental studies, PO's genotoxicity for humans is assessed by reviewing results of published biomarker studies. The weight of evidence indicates that although it is genotoxic, PO's potency as a DNA-reactive mutagen is weak. Other aspects of PO's overall tissue toxicities are also reviewed, with attention to glutathione (GSH) depletion and its consequences, that is, cell proliferation, death, and necrosis. These toxic tissue responses occur in the same anatomical regions in rodents as do the PO-induced tumors. Furthermore, some of these tissue toxicities can produce effects that may either augment PO's DNA-reactive mutagenicity or be genotoxic in themselves, not dependent on PO's DNA reactivity. Although its DNA reactivity may be a necessary component of PO's overall genotoxicity and rodent carcinogenicity, it is likely not sufficient, and the associated tissue toxicities, which are rate-limiting, also seem to be required. This complex mode of action has implications for estimations of PO's cancer potential in humans, especially at low exposure concentrations.     

Synthesis and evaluation of anti-inflammatory, analgesic, ulcerogenicity and nitric oxide-releasing studies of novel ibuprofen analogs as nonulcerogenic derivatives

Since the last 41?years, Ibuprofen has been one of the most widely used Non-Steroidal Anti-Inflammatory Drug (NSAID) due to its anti-inflammatory actions. As all the NSAIDs are suffering from the deadlier GI toxicities, Ibuprofen also is no exception to these toxicities. The free ?CCOOH group is thought to be responsible for the Gastrointestinal (GI) tract toxicity associated with all the traditional NSAIDs. Therefore, the main aim of this study was to develop new chemical entities as potential anti-inflammatory agents with less GI toxicities. In this article, synthesis of a series of Hybrid molecules containing important pharmacophore of Ibuprofen and substituted diaryl rings on 5-membered heterocycle similar to coxibs and Nitric oxide-releasing moiety are described. All the synthesized compounds were tested in vivo for their anti-inflammatory, analgesic, ulcerogenic properties, and histopathological studies and in vitro for their nitric oxide-releasing properties. Out of the six synthesized compounds, four compounds showed significant anti-inflammatory and analgesic activity which was compared with standard. All the synthesized compounds exhibited significant nitric oxide-releasing and reduced GI ulcerogenic activity.     

Farnesyl transferase inhibitors in clinical development

Farnesyl transferase (FT) inhibitors block the main post-translational modification of the Ras protein, thus interfering with its localisation to the inner surface of the plasma membrane and subsequent activation of downstream effectors. Although initially developed as a strategy to target Ras in cancer, FT inhibitors have subsequently been acknowledged as acting by additional and more complex mechanisms that may extend beyond Ras, involving RhoB, centromere-binding proteins and probably other farnesylated proteins. SCH66336 (lonafarnib, Sarasar( trade mark ); Schering-Plough), a tricyclic orally active FT inhibitor, was the first of these compounds to undergo clinical development. Gastrointestinal tract toxicities and fatigue have qualified as dose-limiting toxicities in all Phase I/II studies. Evidence of clinical activity has been reported. Lonafarnib combination studies with both gemcitabine and paclitaxel have been carried out. No unexpected toxicities were observed in these Phase I studies, while encouraging clinical activity was observed mainly in pancreatic cancer and non-small cell lung cancer. Further combination studies are ongoing. R115777 (Zarnestra( trade mark ); Janssen Pharmaceutica) is another orally active FT competitive inhibitor in clinical development. Single-agent Phase I/II studies have shown that myelotoxicity and neurotoxicity are dose-limiting toxicities; intermittent schedule is probably better tolerated; antitumour activity is observed particularly in breast cancer and haematological malignancies. A number of combination studies with R115777 have been carried out. A recently completed, large Phase III trial comparing gemcitabine plus R115777 versus gemcitabine plus placebo in advanced pancreatic cancer has failed to demonstrate any survival benefit in the R115777 arm. BMS-214662 is the third FT inhibitor in clinical development. It has the main advantage of being cytotoxic in nature, rather than cytostatic, and potent in vivo antitumour activity has been reported. A major drawback for BMS-214662 is its severe gastrointestinal and liver toxicities, which prevent the achievement of adequate systemic exposures following the oral route. Alternative ways of interference with the ras oncogene pathway, in particular inhibition of ras downstream effectors, are discussed and early clinical data are presented.     

Propylene Oxide: Genotoxicity Profile of a Rodent Nasal Carcinogen

Propylene oxide (PO) is a DNA-reactive genotoxic agent; that is, it reacts with DNA to produce lesions in the genetic material. PO also induces tumors in rodents, although only at high concentrations and at portals of entry. This review of PO's genotoxicity profile is organized according to endpoints measured, that is, nonmutational or mutational endpoints, and as to whether the results were from in vitro or in vivo studies. In addition to results of experimental studies, PO's genotoxicity for humans is assessed by reviewing results of published biomarker studies. The weight of evidence indicates that although it is genotoxic, PO's potency as a DNA-reactive mutagen is weak. Other aspects of PO's overall tissue toxicities are also reviewed, with attention to glutathione (GSH) depletion and its consequences, that is, cell proliferation, death, and necrosis. These toxic tissue responses occur in the same anatomical regions in rodents as do the PO-induced tumors. Furthermore, some of these tissue toxicities can produce effects that may either augment PO's DNA-reactive mutagenicity or be genotoxic in themselves, not dependent on PO's DNA reactivity. Although its DNA reactivity may be a necessary component of PO's overall genotoxicity and rodent carcinogenicity, it is likely not sufficient, and the associated tissue toxicities, which are rate-limiting, also seem to be required. This complex mode of action has implications for estimations of PO's cancer potential in humans, especially at low exposure concentrations.     

Pharmacokinetic drivers of toxicity for basic molecules: Strategy to lower pKa results in decreased tissue exposure and toxicity for a small molecule Met inhibitor

Several toxicities are clearly driven by free drug concentrations in plasma, such as toxicities related to on-target exaggerated pharmacology or off-target pharmacological activity associated with receptors, enzymes or ion channels. However, there are examples in which organ toxicities appear to correlate better with total drug concentrations in the target tissues, rather than with free drug concentrations in plasma. Here we present a case study in which a small molecule Met inhibitor, GEN-203, with significant liver and bone marrow toxicity in preclinical species was modified with the intention of increasing the safety margin. GEN-203 is a lipophilic weak base as demonstrated by its physicochemical and structural properties: high LogD (distribution coefficient) (4.3) and high measured pKa (7.45) due to the basic amine (N-ethyl-3-fluoro-4-aminopiperidine). The physicochemical properties of GEN-203 were hypothesized to drive the high distribution of this compound to tissues as evidenced by a moderately-high volume of distribution (Vd > 3 l/kg) in mouse and subsequent toxicities of the compound. Specifically, the basicity of GEN-203 was decreased through addition of a second fluorine in the 3-position of the aminopiperidine to yield GEN-890 (N-ethyl-3,3-difluoro-4-aminopiperidine), which decreased the volume of distribution of the compound in mouse (Vd = 1.0 l/kg), decreased its tissue drug concentrations and led to decreased toxicity in mice. This strategy suggests that when toxicity is driven by tissue drug concentrations, optimization of the physicochemical parameters that drive tissue distribution can result in decreased drug concentrations in tissues, resulting in lower toxicity and improved safety margins.