Toxicity of CI-949, a Novel Anti-allergy Agent

The toxicity of CI-949, an effective inhibitor of allergic mediatorrelease in pharmacology models, was evaluated in rodents anddogs. Median lethal doses at 24-hr postdose ranged from 343to 453 mg/kg in mice and 806 to 2058 mg/kg in rats. Delayedtoxicity was observed at 300 mg/kg and greater in mice and at500 mg/kg and greater in rats. Mortality and clinical intoleranceoccurred in rats at 200 and 400 mg/kg in the subacute studies,and at 100 and 150 mg/kg in the 13-week study. In rats, dose-dependentlymphoid tissue atrophy and depletion or necrosis of lymphocytesin lymphoid tissues were seen in deaths and moribund terminations.Although doses up to 60 mg/kg administered for 2 weeks to dogswere well tolerated, 60 and 120 mg/kg in the 13-week dog studywere poorly tolerated. Cutaneous sores, mucocutaneous purulentdischarge, emesis, diarrhea, and weight loss were identifiedat these lethal doses. Histopathologic changes in dogs includedmyocardial, vascular and soft tissue inflammation, and gastriculceration at 60 and 120 mg/kg, and thymic atrophy at 20 mg/kgand greater. Doses of 10 and 50 mg/kg were no-effect doses in13-week repeated dose studies in dogs and rats, respectively.These results were used to support initial human clinical trialsof CI-949.     

A phase II trial of CI-921 in advanced malignancies

CI-921, (9-[[2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino]-N,5-dimethyl-4-acridinecarboxamide 2-hydroxyethanesulfonate (11)), an anilinoacridine derivative with activity in experimental solid tumors was studied in a multicenter phase II trial in patients with solid tumors. Eligible tumor types included cancers of the breast, stomach, pancreas, nonsmall cell lung, small cell lung, colon, head and neck area, and melanoma. Prestudy requirements included an ECOG performance status of 2, no CNS metastases, and measurable disease. CI-921 was administered intravenously over 1–2 hours on days 1,8, and 15 of a 35-day course at an initial dose of 270 mg/M², with modification in subsequent courses based upon tolerance. Principal toxicities included leukopenia, marked phlebitis, and mild nausea and vomiting. One hundred fifty patients were entered of whom 132 were evaluable for response. There was one complete and one partial response among 19 patients with breast cancer, and two partial responses, one each among 14 head and neck and 36 nonsmall cell lung cancer patients.     

Solid-State Phase Transitions of AG337, an Antitumor Agent

The object of this investigation was to perform detailed solid-state characterization studies on the different solid forms of AG337 and to determine the conditions of their interconversions. Solid-state characterization was done using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot stage microscopy, Karl Fischer titrimetry, ambient and variable temperature X-ray powder diffractometry (XRD) and TGA coupled with FTIR (TGA/FTIR). In addition to five polymorphic forms of the anhydrate (I_αto I_ε), a hemihydrate (C₁₄H₁₂N₄OS· 2HCl · 0.5H₂O, II), a monohydrate (C₁₄H₁₂N₄OS · 2HCl · H₂O; III), as well as a dihydrate (C₁₄H₁₂N₄OS · 2HCl · 2H₂O; IV) were identified. The ‘as is’ anhydrate, Iα, resisted water uptake until stored at 98% RH (room temperature), where it transformed directly to IV. II and III transformed to IV at RH values ≥ 7.6 and 84% respectively. Heating II and III to 130°C in the variable temperature XRD resulted in the formation of I_β and I_γ respectively. On the other hand, I_δ and I_ε were obtained when II and III were respectively stored at 60°C under vacuum. Variable temperature XRD, by providing information about the solid-state as a function of temperature, assisted in the interpretation of the DSC and TGA results. TGA/FTIR provided direct evidence that the thermal events observed in the temperature ranges of 25–150°C and 200–250°C were due to loss of water and loss of hydrogen chloride respectively. In addition to the conventional analytical techniques such as XRD, DSC, TGA and KFT, two other techniques, (variable temperature XRD and TGA/FTIR), were very useful in these solid-state characterization studies.     

Thiolytic cleavage and binding of the antitumour agent CI-921 in blood

The antitumour agent 9-[[2-methoxy-4-[methylsulphonylamino]-phenyl]amino]-N,5-dimethyl- 4-acridinecarboxamide (CI-921; NSC 343499) is currently undergoing clinical evaluation. The plasma disposition of this compound together with its ability to bind to plasma proteins has been investigated in the mouse. Five minutes after intravenous administration of [acridinyl-G-3H]-CI-921 (57.7 mol/kg) to male BDF1 mice, plasma samples were taken and precipitated with acetonitrile. 17% of the total plasma radioactivity was found to be bound to plasma proteins, increasing to 31% by 30 min. To ascertain the mechanism of binding, [acridinyl-G-3H]-CI-921 was incubated at 37 degrees C in mouse blood or plasma and the radioactivity analysed after precipitation with acetonitrile. CI-921 and the cleavage product 4-amino-3-methoxy-methanesulphonanilide (MSA) were detected in the acetonitrile supernatants by HPLC using electrochemical and ultraviolet detection. After incubation for 1 h with blood, extensive association of radioactivity (80% of total) with plasma proteins, together with a rapid decrease in CI-921 concentration and a concomitant increase in MSA concentration, was observed. In blood samples from mice given CI-921, low concentrations (1 to 2 mumol/l) of MSA were detected up to 1 h after injection. The results suggest that in vivo at least part of the covalent binding in blood arises from the nucleophilic attack by protein thiols at the C-9 position of the acridine ring resulting in covalent protein adducts and release of MSA.     

Pharmacokinetics and Pharmacodynamics of an Investigational Antipsychotic Agent,CI-1007, in Rats and Monkeys

Purpose. To study the pharmacokinetics (PK) and pharmacodynamics (PD) of an investigational antipsychotic agent, CI-1007, in rats and monkeys. Methods. CI-1007 and a pharmacologically active metabolite, PD 147693 (Ml), were evaluated in animal antipsychotic tests (inhibition of dopamine neuron firing and spontaneous locomotor activity in rats, and inhibition of continuous avoidance in monkeys). Plasma concentrations of CI-1007 and Ml were determined using validated HPLC assays. Log-linear and link models were used for PK/PD analysis. Results. CI-1007 and Ml have shown similar effects on dopamine neuron firing (2.5 mg/kg i.p.), and produced dose-related effects on spontaneous locomotor activity in rats (0.3–30 mg/kg, p.o.) and on continuous avoidance in monkeys (0.6–1.2 mg/kg p.o.). After pharmacologically active CI-1007 doses, mean plasma CI-1007 C_max increased from 19 to 200 ng/ml in Sprague-Dawley rats at doses of 3–30 mg/ kg, and from 8.1 to 34 ng/ml in squirrel monkeys at doses of 0.6–1.2 mg/kg, but corresponding plasma M1 C_max values were near or below the limit of quantitation (5 ng/ml). CI-1007 EC50 was 31.1 ng/ml in rats, calculated from a log-linear regression. In monkeys, CI-1007 EC_e50, , and K_eo at 0.6 and 1.2 mg/kg were 4.8 and 4.5 ng/ml, 1.9 and 2.0, and 0.47 and 0.48 hr^–1, respectively, calculated by the link model. Conclusions. CI-1007 has shown dose-related pharmacokinetics and pharmacodynamics in rats and monkeys. Although Ml produces anti-psychotic-like effects similar to CI-1007, the contribution of Ml to the activity of the parent drug may not be significant in rats and monkeys as based on plasma levels. CI-1007 plasma concentration correlates log-linearly with inhibition effect from the rat locomotor study. The counter-clockwise hysteresis relationship of CI-1007 plasma concentration and inhibition effect from the monkey avoidance test was described by a link model, and the resulting C_e (concentration in effect compartment) versus effect profile exhibits a sigmoidal curve.     

CI-921: An analog of amsacrine with experimental activity against solid tumors

Summary CI-921, a 4,5-disubstituted analog of amsacrine, has been selected for clinical testing because of its experimental activity in vitro and in vivo against solid tumors as well as leukemias. In studies conducted by Baguley and co-workers, CI-921 demonstrated activity against Lewis lung carcinoma in vivo, producing marked increases in life span and a high proportion of 60-day survivors. An intermittent schedule of administration was more effective than a daily × 5 or daily × 9 schedule. In pharmacokinetic studies in dogs, CI-921 achieved higher plasma concentrations and was cleared more slowly than amsacrine. CI-921 is readily soluble in water and may have antitumor activity when administered orally. Animal toxicology studies indicate that dose-related, reversible leukopenia and thrombocytopenia occur, as well as gastrointestinal toxicity, elevation of alkaline phosphatase and generalized lymphoid depletion. Phase I clinical testing of a parenteral formulation is in progress.     

抗肿瘤药L in ifan ib

血管生成是毛细血管从已存在的血管网络中生长出来的生理过程,可满足组织生成时的营养供给,对于肿瘤的维持或生长至关重要,因此,血管生成抑制剂被认为是癌症治疗的有效手段。     

抗肿瘤药 Brostallicin Hydrochloride

抗肿瘤药brostalliein盐酸盐（PNU-166196A）为一种合成的第二代DNA小沟结合剂（minor groove binder,MGB）,其结构是在偏端霉素A（distamyein A）的主链上共价结合了α-溴代丙烯酰基。Bmstalliein在高浓度谷胱甘肽和（或）谷胱甘肽S-转移酶（GST）存在的条件下具有活性,不受DNA错配修复影响,对一些罕见的、对目前标准化疗耐药的软组织肉瘤（softtissuesarcomas,STS）具有一定疗效。     

抗癌药ABT-263

ABT-263是由雅培制药（AbboaLaboratories）开发的一种可诱导细胞凋亡的小分子Bel-2抑制剂。药理学研究显示,本品对小细胞肺癌（SCLC）和急性成淋巴细胞性白血病（ALL）小鼠的总有效率（overall response rate,ORR）为100％;在接种了Bcl-2依赖的SCLC细胞系NCL—H146的小鼠中,本品（剂量等于或高于100mg·kg^-1·d-1）的疗效明显高于紫杉醇、长春新碱、卡铂、顺铂、环磷酰胺和依托泊苷等药。     

Involvement of glutathione in the metabolism of the anilinoacridine antitumour agents CI-921 and amsacrine

4'-(9-Acridinylamino)methanesulphon-m-anisidide (amsacrine) and CI-921, the 4-methyl-5-(N-methyl-carboxamide) derivative of amsacrine, are two anilinoacridine antitumour agents in clinical use or trial. The elimination of these agents has been investigated in male BDF1 mice. 74% and 86% of the dose of [acridinyl-G-3H]-amsacrine and -CI-921, respectively, was excreted in the faeces of mice by 72 hr after i.v. injection. Administration of both compounds also resulted in significant depletion of glutathione (GSH) in mouse liver, although the effect of CI-921 was delayed and reduced compared with amsacrine. In mouse bile, radiolabelled products which cochromatographed with amsacrine GSH conjugates at both the 5'- and 6'-positions of the anilino ring were present in similar amounts and constituted approximately 70% of the excreted radioactivity, the balance being minor, more polar metabolites. With hepatic microsomal fractions, both conjugates of amsacrine were formed but only the 6'- and not the 5'-conjugate was increased in the presence of cytosol. Preliminary evidence indicates the presence in mouse bile of at least the 5'-GSH conjugate of CI-921, and several other GSH derived products not seen with amsacrine. It is concluded that the elimination of CI-921 occurs by a mechanism similar to that of amsacrine. Further, the possible involvement of GSH transferase in the conjugation of amsacrine may have consequences for the hepatotoxicity of this agent.     

抗肿瘤药Pomalidomide的合成

N-(叔丁氧羰基)-L-谷氨酰胺(2)经闭环、脱保护制得3-氨基-2,6-哌啶二酮三氟乙酸盐(4).另用3-硝基邻苯二甲酸(5)脱水制得3-硝基邻苯二甲酸酐(6).4和6经缩合、铁粉/浓盐酸还原制得免疫调节剂类抗肿瘤药3-氨基-N-(2,6-二氧代-3-哌啶基)-邻苯二甲酰亚胺,以5计总收率约35%.     

抗肿瘤药伏立诺他的合成

目的伏立诺他的合成方法。方法以辛二酸为原料,通过连续两步混合酸酐法制得抗肿瘤药伏立诺他。结果合成的目标化合物经核磁共振氢谱、核磁共振碳谱、质谱及红外光谱确证。结论本合成通过两步得到目标化合物,收率约为41%。     

抗肿瘤药Vorinostat的合成

以辛二酸为原料,通过连续两步混合酸酐法制得抗肿瘤药vorinostat,总收率约62%.     

微管蛋白聚合抑制剂类抗肿瘤药Plinabulin

鉴于血管生成对肿瘤的生长和转移至关重要,因此肿瘤血管系统已成为极具价值的肿瘤治疗靶。目前,靶向肿瘤脉管系统的抗肿瘤药物主要包括抗血管生成剂和血管阻断剂（VDAs）,前者可抑制肿瘤新血管的生长,而后者则是靶向破坏为肿瘤细胞供应氧和营养的已有血管网。肿瘤血管具有与正常血管不同的异常结构,     

Photoinduced Particulate Matter in a Parenteral Formulation for Bisnafide,an Experimental Antitumor Agent

This paper assesses the cause of particulate formation in vials of the experimental antitumor agent bisnafide and investigates pharmaceutical techniques to reduce the number of particulates in the product. Solution preparation and particulate isolation were performed under Class 100 laminar air flow. Reversed-phase HPLC and infrared microscopy were used to characterize drug and isolated particulate matter, whereas a Hiac particle counter was used to quantify the particulate matter. Particulate matter was observed following agitation of the drug solutions and was found to be associated with specific lots of drug substance. HPLC of the isolated particulate matter indicated that the particulates consisted largely of bisnafide and impurities that were identified as the products of photodegradation, confirmed to be the result of the photolytic cleavage of bisnafide to form a poorly soluble aldehyde. The aldehyde may, in turn, interact with bisnafide molecules to form the particulate matter as suggested by the observed pH-dependent reversibility of the particulate phenomenon. The particulate matter could be reduced by protecting solutions of bisnafide from light during chemical synthesis and production of the dosage form and, alternatively, by reducing the solution pH to 3.0 or less, addition of surfactants below their critical micelle concentration, and removal of impurities by froth flotation of the bisnafide solutions.     

抗肿瘤药物NSC-639829的合成

目的合成抗肿瘤药物NSC-639829。方法以4-氨基-2-甲基苯酚为起始原料,经亲核取代、异氰酸酯化合成4-（5-溴-2-嘧啶氧基）-3-甲基苯基异氰酸酯,再与2-二甲氨基苯甲酰胺缩合得目标化合物NSC-639829。结果目标化合物经质谱、核磁共振氢谱和元素分析确证其化学结构,经HPLC分析纯度达99．5％,总收率达40．2％。结论此工艺路线原料易得,产品收率高,操作安全,适用于工业化生产。     

抗肿瘤药物泊马度胺的合成工艺改进

改进抗肿瘤药泊马度胺的合成工艺,以3-硝基邻苯二甲酸为原料,合成3-硝基邻苯二甲酸酐;再与谷氨酰胺反应,经氨解、缩合、还原得到目标产物泊马度胺,反应总收率60.8%。     

Differences in the metabolism of the antitumour agents amsacrine and its derivative CI-921 in rat and mouse.

1. Rats and mice were treated with the antitumour agent CI-921 (I), and parent compound amsacrine, with all biliary metabolites being analysed. 2. In both rat and mouse the major biliary metabolites of amsacrine are the 5'- and 6'-glutathione (GSH) conjugates, with no C9-GSH conjugate being detected. 3. 5'- and 6'-GSH conjugates of I are also formed in both species. However, two additional products were detected and their structures confirmed by liquid secondary ion mass spectrometry and 1H-n.m.r. spectrometry, and by comparison with synthetic standards. 4. Additional metabolites of I are the C9-GSH conjugate and the 4-hydroxymethyl derivative which, either as the aglycone or glucuronide, is the predominant product in rat bile (comprising 56% of the dose eliminated over 3.5 h). 5. Relative amounts of the C9-GSH conjugate to the 5'- and 6'-GSH conjugates to the 4-hydroxymethyl derivatives, were 24:65:10 in mouse bile and 2:8:90 in rat bile. 6. These differences indicate first, likely enzyme involvement in the formation of the C9-GSH conjugate of I, and second, in comparison with amsacrine, alternative pathways which may decrease formation of the reactive quinone diimine intermediate of I and consequent hepatotoxicity.     

Reproductive and Developmental Toxicity of Phthalates

The purposes of this review are to (1) evaluate human and experimental evidence for adverse effects on reproduction and development in humans, produced by exposure to phthalates, and (2) identify knowledge gaps as for future studies. The widespread use of phthalates in consumer products leads to ubiquitous and constant exposure of humans to these chemicals. Phthalates were postulated to produce endocrine-disrupting effects in rodents, where fetal exposure to these compounds was found to induce developmental and reproductive toxicity. The adverse effects observed in rodent models raised concerns as to whether exposure to phthalates represents a potential health risk to humans. At present, di(2-ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DBP), and butyl benzyl phthalate (BBP) have been demonstrated to produce reproductive and developmental toxicity; thus, this review focuses on these chemicals. For the general population, DEHP exposure is predominantly via food. The average concentrations of phthalates are highest in children and decrease with age. At present, DEHP exposures in the general population appear to be close to the tolerable daily intake (TDI), suggesting that at least some individuals exceed the TDI. In addition, specific high-risk groups exist with internal levels that are several orders of magnitude above average. Urinary metabolites used as biomarkers for the internal levels provide additional means to determine more specifically phthalate exposure levels in both general and high-risk populations. However, exposure data are not consistent and there are indications that secondary metabolites may be more accurate indicators of the internal exposure compared to primary metabolites. The present human toxicity data are not sufficient for evaluating the occurrence of reproductive effects following phthalate exposure in humans, based on existing relevant animal data. This is especially the case for data on female reproductive toxicity, which are scarce. Therefore, future research needs to focus on developmental and reproductive endpoints in humans. It should be noted that phthalates occur in mixtures but most toxicological information is based on single compounds. Thus, it is concluded that it is important to improve the knowledge of toxic interactions among the different chemicals and to develop measures for combined exposure to various groups of phthalates.     

Reproductive and Developmental Toxicity of N,N-Diethyl-m-toluamide in Rats

N,N-Diethyl-m-toluamide (mDET, DEET) is widely used as a topicalinsect repellent. It is the active ingredient in many consumerformulations, which usually contain 10–25% mDET in analcohol base. More concentrated consumer products are also available,including some that are pure technical grade mDET. Persons livingor employed in mosquito-infested areas may have very high seasonalexposures to mDET. Because contradictory reports had been publishedon the reproductive and developmental toxicity of mDET, a seriesof studies was conducted in male and female Sprague-Dawley rats.All treatments were administered by daily subcutaneous injectionsof undiluted mDET. A dose finding study was done using 12 time-matedfemales per group treated on Gestational Days (GD) 6–15with 0.50, 0.62, 0.78, 0.92, or 1.2 ml mDET /kg/day. No femalessurvived 10 days of mDET dosing with 1.2 ml/kg/day. Deaths occurredin all other groups except the low dose (0.50 ml/kg/ day). Pregnantfemales treated on GD 6–15 with 0 or 0.30 ml/ kg/day wereused for the teratology study. Half of each group was euthanizedon GD 20: the second half was singly housed in nesting boxesand allowed to deliver litters. Live pups were counted and weighedsoon after birth on Postnatal Day (PD) 0 and again on PD 3,9, and 14. Proven fertile males were treated 5 days/week for9 weeks with 0, 0.30, 0.73, 1.15, or 1.80 ml mDET /kg/day fora male dose-finding study. Each group consisted of 20 males.No males survived the 1.80 ml/kg/day. Deaths occurred in allremaining dose groups except the 0.30 ml/kg/ day and controlgroup. Immediately following the final treatment of the maledose study, 11 males were randomly selected from the 0.30 and0.73 ml/kg/day groups. They were cohabited for 7 days with 4females per male during post-treatment Weeks 1 and 2. Half ofthe females were euthanized 12–14 days after the lastday of cohabitation for a dominant lethal study; the remainingfemales were singly housed in nesting boxes and allowed to deliverlitters. Live pups were counted and weighed on PD 0 and 3. Therewas no evidence of reproductive or developmental toxicity inany of these assays, but there were signs of neuro-toxicityin treated adult male and female rats, which may relate to reportsof neurotoxicity in humans heavily exposed to mDET -containinginsect repellents, o 1992 society of Toxicology.