Toxicologic evaluation of modified gum acacia: mutagenicity, acute and subchronic toxicity.

Modified gum acacia, produced from acacia gum by a process analogous to the production of modified food starch, was tested for mutagenicity in the microbial reverse mutation assay. The assay employed a wide range of dose levels, both with and without metabolic activation. Test results gave no indication that modified gum acacia possessed any mutagenic potential. The acute oral toxicity of modified gum acacia was determined in two studies employing Sprague-Dawley rats, and the LD50 values were found to be >2000 mg/kg. The primary dermal irritation potential of modified gum acacia was evaluated in rabbits by the Draize method. Test results indicated that modified gum acacia was slightly irritating by the Environmental Protection Agency (EPA) classification but not a primary irritant by Consumer Product Safety Commission (CPSC) guidelines. The subchronic toxicity of modified gum acacia was examined in Sprague-Dawley rats fed diets containing 0%, 1%, 2.5%, and 5% modified gum acacia for 13 weeks. No dose-related effects on survival, growth, hematology, blood chemistry, organ weights, or pathologic lesions were observed. Results of these studies indicate that modified gum acacia does not possess mutagenic potential and that animals are not adversely affected by acute or subchronic exposure to modified gum acacia.     

Ⅱ型糖尿病患者脂质代谢指标的观察

检测144例II型糖尿病各项脂质代谢指标，其中糖尿病合并冠心病32例，伴高血压41例，伴脑梗塞38例，将无上述疾病史者69例为对照。结果结示，CHOL/HDLC在各组比较中H值和U值高于单项血脂代谢指标。认为CHOL/HDLC是筛选II型糖尿病伴冠心病患者的敏感指标，并可作为判断糖尿病治疗过程中脂质代谢纠正程度的一个有用指标。     

Construction of nanoscale multicompartment liposomes for combinatory drug delivery

Liposomes are clinically used delivery systems for chemotherapeutic agents, biological macromolecules and diagnostics. Due to their flexibility in size and composition, different types of liposomes have been developed varying in surface and structural characteristics. Multicompartment liposomes constitute an attractive drug carrier system offering advantages in terms of inner vesicle protection, sustained drug release and possibility for combinatory (cocktail) therapies using a single delivery system. However, all previously described methodologies for multicompartment or multivesicular liposomes resulted in micrometer-sized vesicles limiting most pharmaceutical applications. In this work we report formulation of nanoscale multicompartment liposomes which maybe applicable for systemic administration. A small unilamellar vesicle (SUV) aqueous dispersion (DOPC:DOPG:CHOL) was used to hydrate a dried film of different lipid contents (DMPC:CHOL), followed by extrusion. The system was characterised by techniques such as photon correlation spectroscopy (PCS), zeta potential measurement, transmission electron microscopy (TEM) and laser scanning confocal microscopy (LSCM). We observed a single, multicompartment vesicle population composed of the two different bilayer types of approximately 200 nm in mean diameter rather than a mixture of two independent vesicle populations. In the case of tumour therapy, such multicompartment liposome systems can offer a single carrier for the delivery of two different modalities.     

Quantitative and ultrastructural studies on the uptake of drug loaded liposomes by mononuclear phagocytes infected with Leishmania donovani

This study compared splenic and hepatic uptake of free and liposome-entrapped sodium antimony gluconate after i.v. administration to mice infected with Leishmania donovani. It was demonstrated that entrapment within liposomes greatly altered the kinetics of uptake of the drug. We were also able to show that liposomes composed of sphingomyelin, stearylamine and cholesterol were marginally better than any other preparation in delivering entrapped drug to liver and spleen. X-ray microanalytical studies on the uptake of liposomes by Kupffer cells infected with L. donovani have indicated that internalised liposomes probably fuse with parasitophorous vacuoles, transferring their contents into the immediate locality of the leishmanial parasites. It is proposed that this is the way in which liposome entrapped antileishmanial agents have an enhanced therapeutic effect over free drug therapy.     

Engineered peptides for the development of actively tumor targeted liposomal carriers of doxorubicin

Chemotherapy is still the treatment of choice for many types of cancer; but its effectiveness is hampered by dose limiting toxicity. Properly designed delivery systems can overcome this shortcoming by reducing the non-specific distribution and toxicity of chemotherapeutics in healthy organs and at the same time increasing drug concentrations at tumor tissue. In this study, we developed stealth liposomal formulations of doxorubicin (DOX) having a novel stable engineered peptide ligand, namely p18-4, that binds specifically to breast cancer cell line MDA-MB-435 on its surface. The coupling of p18-4 to liposomes was carried out through conventional, post insertion and post conjugation techniques and prepared liposomes were characterized for their size and level of peptide modification. The p18-4 decorated liposomal DOX formulations were then evaluated for their cellular uptake as well as cytotoxicity against the human breast cancer MDA-MB-435 cells. In this context, the effect of coupling technique on the uptake and cytotoxicity of p18-4 liposomal DOX in MDA-MB-435 cells was evaluated. The conventional and post conjugation methods of peptide incorporation were found to be more reliable for the preparation of p18-4 decorated liposomes for active DOX targeting to MDA-MB-435 cells. p18-4 decoration of liposomes by these methods did not have a notable effect on the size of prepared liposomes and DOX release, but increased the uptake and cytotoxicity of encapsulated DOX in MDA-MB-435 cells. The results show a potential for p18-4 decorated liposomes prepared by conventional and post conjugation method for tumor targeted delivery of DOX in breast tumor models.     

Two generation reproduction and teratogenicity studies of feeding cyadox in Wistar rats

To investigate the teratogenic potential and reproductive toxicity of cyadox, a growth promoting agent, Wistar rats (F₀) were fed with diets containing cyadox (0, 50, 150 and 2500 mg/kg) or olaquindox (150 mg/kg), approximately equivalent to cyadox 5, 15, 250 or olaquindox 15 mg/kg b.w./day across two generations. Half of the pregnant rats (F₀, F_1b) were subjected to caesarean section on gestational day 20 for teratogenic examination and the other half produced pups F_1a and F_2a, respectively. At the 250 mg/kg b.w./day cyadox group, body weights of F_1b pregnant rats and F_2a on day 21 after birth decreased; fetal body lengths and tail lengths decreased; the number of fetal resorptions increased significantly; litter weights, number of viable fetuses decreased; number of embryo resorptions increased significantly; number of liveborn F_1a, F_1b and F_2a decreased. No macroscopic or microscopic change of any significance was found in the reproductive organs. Significant increases in the incidence of cervial ribs or lumbar ribs in F_2a pups and significant increases of relative organ weight of testis and epididymis in F_1b were observed at the 250 mg/kg b.w./day cyadox group. The NOAEL for reproduction/development of cyadox for rats was estimated to be 150 mg/kg diet, which was equivalent to approximately 15 mg/kg b.w./day.     

Positron emission tomographic imaging with<Superscript>11</Superscript>C-choline in differential diagnosis of head and neck tumors: comparison with<Superscript>18</Superscript>F-FDG PET

The aim of this study was to evaluate the clinical value of positron emission tomography (PET) with¹¹C-labeled choline (CHOL) for the differential diagnosis of malignant head and neck tumors from benign lesions as compared with¹⁸F-fluorodeoxyglucose PET.Methods: We studied 45 patients (28 males, 17 females, age range, 29-84 years) with suspected lesions in the head and neck region using both CHOL and FDG PET within a 2-week period on each patient. All patients fasted for at least 6 hours for both the CHOL and FDG studies. PET imaging was performed 5 min and 50-60 min after intravenous injection of CHOL and FDG, respectively. After data acquisition, PET images were corrected for attenuation, and the reconstructed images were analyzed by visual interpretation. Then, the standardized uptake value (SUV) was calculated for semiquantitative evaluation of tumor tracer uptake. Finally the results of PET scans were compared with the histological diagnoses from surgical specimens or biopsies.Results: With CHOL PET, malignant tumors were correctly detected in 24 (96%) of 25 patients, and benign lesions in 14 (70%) of 20 patients with an accuracy of 84.4%. With FDG PET, malignancy was correctly diagnosed in 23 (92%) of 25 patients, and benign lesions in 13 (65%) of 20 patients resulting an accuracy of 80%. A significant positive correlation between CHOL and FDG SUVs was found for all lesions (r = 0.677, p = 0.004, n = 45). Malignant tumors showed significantly higher tracer accumulation than the benign lesions in both CHOL and FDG studies (5.69 ± 1.61, n = 25 vs. 2.98 ± 2.13, n = 20, p < 0.0001; 9.21 ± 4.23, n = 25 vs. 3.60 ± 2.57, n = 20, p < 0.0001). The cutoff SUV for differentiating malignant and benign lesions was 3.5 for CHOL and 3.9 for FDG. CHOL showed slightly better differentiation between malignant and benign lesions than FDG although some overlap existed on both studies. But the difference was not statistically significant.Conclusion: The results of this study indicate that CHOL PET may be feasible clinically for head and neck tumor imaging. PET imaging with CHOL seems to be able to detect malignant head and neck tumors as effectively as FDG PET. The advantages of CHOL PET were shorter examination period and low uptake in the muscle. However, both CHOL and FDG have some limitations in the evaluation of salivary gland lesions.     

山茱萸环烯醚萜总苷对2型糖尿病心脏病变大鼠胰岛素抵抗及血脂含量的影响

目的:观察山茱萸环烯醚萜总苷(ICO)对2型糖尿病心脏病变大鼠胰岛素抵抗及血脂含量的影响。方法:大鼠以高脂饲养结合STZ腹腔注射造模,2周后灌胃给予ICO(0.1,0.2g/kg)或氨基胍(AG,0.1g/kg)治疗,连续16周。检测体重、空腹血糖、血清Ins、Ins-Ab、CHOL、TG、HDL-C及LDL-C含量;分离心脏进行形态学观察。结果:模型组大鼠体重、血糖、Ins-Ab、IR、CHOL、TG、LDL-C明显升高,Ins水平显著降低;光镜检查显示心肌肥大伴程度不等的间质水肿和组织细胞增生,心内膜或心包膜有轻度炎症及纤维化。ICO及AG组大鼠体重、血糖、Ins-Ab、IR、CHOL、TG、LDL-C均明显降低,心肌肥大程度减轻。结论:ICO对2型糖尿病心脏病变有一定的保护作用。     

"Sinking" lipoprotein in normal, hyperlipoproteinaemic and atherosclerotic patients.

The presence of a "sinking" lipoprotein (SLP), demonstrated by combining electrophoretic and ultracentrifugal methods, has been recorded in 13.6% of 44 normal subjects, in 62.2% of 37 hyperlipoproteinaemic patients with types IIA, IIB and IV and in 39.8% of 107 atherosclerotic patients. The recorded data suggest that the "sinking" lipoprotein may be related to human atherosclerosis and to hyperipoproteinaemic states. A pre-beta (S band in the fraction with density greater than 1.006 appeared in 2 out of 20 subjects receiving as isocaloric hyperglucidic diet (CHO, 80; F, 5;P, 15) for 8 days and in 3 out of 10 subjects receiving an acute ethanol oral load. The nature of the nutritionally determined lipoprotein is doubtful. It seems improbable that the newly synthetized lipoprotein is the "true" sinking lipoprotein as this considered to be a genetically determined marker. These data may signify that other "sinking" lipoproteins unrelated to LP-Berg system may exist or may be determined. It is also probable that the new synthetized lipoprotein may have some relationship with the "intermediate" lipoprotein.