The Synergetic Effects of Nonpolar and Polar Protic Solvents on the Properties of Felodipine and Soluplus in Solutions,Casting Films,and Spray-Dried Solid Dispersions

The aim was to explore the effects of nonpolar and polar protic solvents composed of dichloromethane (DCM) and ethanol (EtOH) on the properties of felodipine (FLDP) and Soluplus in solutions, casting films, and spray-dried drug-rich or polymer-rich solid dispersions (SDs). Measurement of intrinsic viscosity and solubility indicated that FLDP and Soluplus were miscible. EtOH-DCM ranging from 20:80 to 50:50 induced the strongest molecular interactions for FLDP-Soluplus-solvents systems. Accordingly, the casting films and spray-dried powders of FLDP and Soluplus were prepared using pure EtOH or DCM and their mixtures as solvents. Polarized light microscopy, differential scanning calorimetry, Fourier transform infrared spectroscopy, in vitro dissolution tests, and stability have been conducted to characterize these films or spray-dried powders. EtOH-DCM (50:50) showed δ_H 2-3 MPa^1/2 higher than FLDP and Soluplus. It exhibited stronger inhibitory effects on phase separation and recrystallization of amorphous FLDP than pure DCM or EtOH in the drug-rich casting films, spray drying process, and spray-dried SDs exposure to 40°C/RH75% for 1 month. Higher ratio of Soluplus may offset the effects of solvents on the dissolution and stability of polymer-rich SDs. In conclusion, combination of nonpolar and polar protic solvents is of high potential for spray drying to optimize drug-rich SDs.     

Acute inhalation co‐exposure to 1,2‐dichloropropane and dichloromethane cause liver damage by inhibiting mitochondrial respiration and defense ability in mice

1,2‐Dichloropropane (1,2‐DCP) is used as an industrial solvent, insecticide fumigant and household dry cleaning product. Carcinogenicity caused by long‐term exposure to 1,2‐DCP is well established. However, the possible liver damage and related toxic mechanisms associated with acute inhalation exposure to 1,2‐DCP are rarely reported. In this study, we investigated the effects of individual and combined exposure to 1,2‐DCP and dichloromethane (DCM) on mice liver. The results showed that 1,2‐DCP significantly caused liver necrosis, possibly due to 1,2‐DCP‐induced inhibition of the mitochondrial respiratory chain complex I‐IV activities, resulting in mitochondrial dysfunction and extreme ATP consumption. Moreover, 1,2‐DCP also decreased mitochondrial defense ability by inhibiting the mitochondrial glutathione S‐transferase 1 (MGST1) activity, further aggravating liver damage. Additionally, we found that DCM co‐exposure potentially enhanced 1,2‐DCP toxicity. Our findings suggest that inhibition of mitochondrial function and MGST1 activity play critical roles in modulating 1,2‐DCP‐induced liver damage. Furthermore, our results contribute to study the new mechanism of mitochondria‐dominated signaling pathways underlying liver injury induced by 1,2‐DCP and DCM.     

GC测定盐酸氟西汀中二氯甲烷残留量

目的采用气相色谱法检测盐酸氟西汀中的二氯甲烷残留量。方法色谱柱:DB-624毛细管柱(30 m×0.53 mm);载气:高纯氮气,0.05 MPa;检测器:ECD;进样口温度:150℃;检测器温度:300℃;柱温为程序升温;进样量:1μL;分流比:1∶20。结果二氯甲烷在5.96～71.55μg.mL 1内,峰面积和浓度之间呈良好的线性关系(r=0.999 6),3批样品中的二氯甲烷残留量均符合规定(<0.06%)。结论该方法操作简便,精密度好,准确性高,可用于检测盐酸氟西汀中二氯甲烷残留量。     

Antitumor Activity of Dichloromethane Extract from Salvia plebeia and Induction of Apoptosis on K562 Cells

Objective To study the antitumor activity of extract from Salvia plebeia and investigate whether the extract induce apoptosis of K562 cells. Methods The aqueous, petroleum ether, dichloromethane (CH2Cl2), ethyl acetate, and butanol extracts were prepared from the aerial parts of S. plebeia. Taking fluorouracil as reference, the cytotoxic activities of these extracts on HeLa, A549, SGC-7901, HCT-116, K562, LoVo, DU-145, and HepG2 cells were evaluated. To clarify the apoptosis of K562 cells induced by CH2Cl2 extract, the methods of Hoechst 33258 staining, flow cytometry assay, and DNA ladder assay were investigated. Results The CH2Cl2 extract showed the most potent cytotoxic effect against K562 cells, with an IC50 < 15 μg/mL for 3 d treatment. The characteristic apoptotic symptoms such as DNA fragmentation and chromatin condensation were also observed in the K562 cells. Conclusion The CH2Cl2 extract from S. plebeia may inhibit the cancer cell proliferation by inducing cell apoptosis.     

Peripheral site ligand conjugation to a non-quaternary oxime enhances reactivation of nerve agent-inhibited human acetylcholinesterase

Commonly employed pyridinium-oxime (charged) reactivators of nerve agent inhibited acetylcholinesterase (AChE) do not readily pass the blood brain barrier (BBB) because of the presence of charge(s). Conversely, non-ionic oxime reactivators often suffer from a lack of reactivating potency due to a low affinity for the active site of AChE. It was therefore hypothesized that an extra contribution in affinity may be achieved by covalently connecting a peripheral site ligand (PSL) to a non-ionic reactivator, which may result in a higher reactivation potency of the total construct. This validity of this approach, which proved successful for charged pyridinium oximes in earlier work, is now further exemplified with the covalent linkage of a neutral PSL via a spacer to a non-ionic and otherwise almost non-reactivating α-ketoaldoxime. It is demonstrated that the linkage of the PSL resulted in a remarkable increase in reactivation potency of the hybrid compounds. Although the molecules reported here are still inefficient reactivators compared to the current pyridinium oximes, the presented approach holds promise for the future design and synthesis of non-ionic oxime reactivators with improved BBB penetration and may be suited as well for non-oxime reactivators thus further widening the scope in the ongoing search for broad-spectrum reactivators.     

KS900: A hypoxia-directed, reductively activated methylating antitumor prodrug that selectively ablates O-alkylguanine-DNA alkyltransferase in neoplastic cells

To most effectively treat cancer it may be necessary to preferentially destroy tumor tissue while sparing normal tissues. One strategy to accomplish this is to selectively cripple the involved tumor resistance mechanisms, thereby allowing the affected anticancer drugs to gain therapeutic efficacy. Such an approach is exemplified by our design and synthesis of the intracellular hypoxic cell activated methylating agent, 1,2-bis(methylsulfonyl)-1-methyl-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS900) that targets the O-6 position of guanine in DNA. KS900 is markedly more cytotoxic in clonogenic experiments under conditions of oxygen deficiency than the non-intracellularly activated agents KS90, and 90M, when tested in O⁶-alkylguanine-DNA alkyltransferase (AGT) non-expressing cells (EMT6 mouse mammary carcinoma, CHO/AA8 hamster ovary, and U251 human glioma), and than temozolomide when tested in AGT expressing cells (DU145 human prostate carcinoma). Furthermore, KS900 more efficiently ablates AGT in HL-60 human leukemia and DU145 cells than the spontaneous globally activated methylating agent KS90, with an IC₅₀ value over 9-fold lower than KS90. Finally, KS900 under oxygen-deficient conditions selectively sensitizes DU145 cells to the chloroethylating agent, onrigin, through the ablation of the resistance protein AGT. Thus, under hypoxia, KS900 is more cytotoxic at substantially lower concentrations than methylating agents such as temozolomide that are not preferentially activated in neoplastic cells by intracellular reductase catalysts. The necessity for intracellular activation of KS900 permits substantially greater cytotoxic activity against cells containing the resistance protein O⁶-alkylguanine-DNA alkyltransferase (AGT) than agents such as temozolomide. Furthermore, the hypoxia-directed intracellular activation of KS900 allows it to preferentially ablate AGT pools under the oxygen-deficient conditions that are present in malignant tissue.     

Evaluation of the antibacterial and antidiarrhoeal activities of heeria insignis o. Ktze

Heeria insignis O. Ktze (Anacardiaceae) is an indigenous African shrub used in treatment of diarrhea, venereal diseases, tapeworm, hookworm, schistosomiasis, kidney trouble and for increasing lactation in women after childbirth. The methanol and dichloromethane extracts of the leaves were evaluated for antibacterial activity (using agar-diffusion method) and antidairrheal activity (using isolated rabbit jejunum and castor-oil induced diarrhea in mice). The methanol extract gave higher antibacterial activity than dichloromethane. The order of susceptibility of test microorganisms to methanol extract were Salmonella typhi>Pseudomous aeruginosa> Staphylococcus aureus>Bacillus subtilis>Escherichia coli which were comparable to standard. The minimum inhibitory concentration of the methanol extract for these microorganisms was also determined. The minimum inhibitory concentration (mg/ml) of methanol extract against microorganisms is; B. subtilis (3.9), S. aureus (1.95), E. coli (62.5), Ps. aeruginosa (3.9) and S. typhi (1.95). On the isolated rabbit jejunum evaluation, both extracts produced concentration-dependent relation of isolated rabbit jejunum that was not blocked by phentolamine, suggesting that extracts act via mechanisms other than alpha-adrenergic receptor. In the castor oil-induced diarrheoeal test, each extract gave 80% protection at 200 mg/kg, which is comparable to loperamide 2 mg/kg with 80% protection. This finding may explain the use of the plant in diarrhea and bacterial diseases.     

小叶锦鸡儿二氯甲烷萃取物的化学成分

[目的]研究小叶锦鸡儿二氯甲烷萃取物的化学成分.[方法]用超声提取,色谱法分离纯化化合物,根据理化性质和光谱分析鉴定结构.[结果]从小叶锦鸡儿二氯甲烷萃取物中分离得到3个单体化合物,分别鉴定为对羟基苯甲酸、阿魏酸二十五烷酯及羽扇豆醇.[结论]化合物对羟基苯甲酸及羽扇豆醇首次从小叶锦鸡儿中分离得到.     

Comparative effects of dimethylsulfoxide on metabolism and toxicity of carbon tetrachloride and dichloromethane

The effects of dimethylsulfoxide (DMSO) on the metabolism and toxicity of chlorinated methanes were examined. Male mice were treated with DMSO (1, 2.5 or 5 ml kg(-1), i.p.) prior to challenge with dichloromethane (CH(2)Cl(2)) or carbon tetrachloride (CCl(4)). Blood carboxyhemoglobin elevation resulting from metabolic conversion of CH(2)Cl(2) to carbon monoxide was inhibited dose-dependently by DMSO pretreatment. The elevation of serum aspartate aminotransferase, alanine aminotransferase and sorbitol dehydrogenase activities induced by CCl(4) (0.1 mmol kg(-1)) was not changed in mice pretreated with DMSO at 1 ml kg(-1), but depressed significantly at a greater dose of DMSO. However, DMSO failed to alter the hepatotoxicity of CCl(4) injected at a dose of 0.2 mmol kg(-1). DMSO induced the microsomal p-nitrophenol hydroxylase and p-nitroanisole O-demethylase activities as early as 2 h following the treatment. Microsomal disposition of CH(2)Cl(2) and CCl(4) was measured using a vial equilibration technique. The disappearance of CH(2)Cl(2) was inhibited competitively by addition of DMSO. But DMSO did not affect the metabolic degradation of CCl(4). The results indicate that DMSO has multiple effects on metabolism and toxicity of xenobiotics. DMSO induces the hepatic metabolizing activity mediated by CYP2E1, but the presence of this solvent in the enzyme site may inhibit directly the enzymatic interaction with a substrate. The toxicological significance of DMSO-induced effects on such an interaction may be variable depending on the properties of each substrate. The invulnerability of CCl(4) metabolism to the effects of DMSO appears to be related to its high affinity for the lipophilic CYP enzyme site.     

毛细管气相色谱法测定哌拉西林中残留溶剂

目的 建立气相色谱法分离测定哌拉西林中残留溶剂二氯甲烷、丙酮与乙酸乙酯.方法 以HP-624毛细管柱为色谱柱(30 m×0.53 mm×3.00 μm),载气为氮气,采用氢火焰离子化检测器,进样口温度为140℃,检测器温度为250℃,采用程序升温(60℃,保持12 min,以20℃·min-1升至240℃),采用顶空进样法,进样量1.0 ml.结果 在本色谱系统中,二氯甲烷、丙酮与乙酸乙酯互不干扰,分离度及检出灵敏度均符合要求,最小检出浓度分别为1.43,0.20,0.20 mg·L-1.结论 本方法可测定哌拉西林中残留溶剂量,方法简单、准确.