Polymorphisms of IL–13 and IL–4–IL–13–SNPs in patients with penicillins allergy

Objective: Although IL–4 and IL–13 share many biologic activities, IL–13manifests some unique activities. We genotype the IL–13 and IL–4–IL–13–SNPs genes for polymorphisms that could then be used to determine associations with IgE regulation as well as levels of IL–4 and IL–13. Methods: Eight kinds of specific IgE to penicillins were determined with radioallergosobent test (RAST) in the sera of 158 patients with penicillins allergy and 89 healthy subjects. Serum levels of IL–4 and IL–13 were measured by using enzyme-linked immunosorbent assay (ELISA). The IL–13Arg130Gln, IL–4–IL–13–SNP3 and IL–4–IL13–SNP4 genotyping were carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Results: Among patients with positive specific IgE, significant differences of IL–4–IL–13–SNP3 and IL–4–IL–13–SNP4 genotypes were observed between patients with positive BPA and control group (P<0.05, P<0.05). Additionally, we also found significant difference in IL–4–IL–13–SNP4 genotype between positive and negative BPA–IgE patients (P<0.05). However, we found no significant differences in the prevalence of these polymorphisms between any group studied (IR and NIR, shock and urticaria, etc.) and control group. The same was true between levels of IL–4 and IL–13, and any of genotypes. Conclusion: These data suggests that IL–4–IL–13–SNP genes between IL–4 and IL–13 play a role in regulation of specific IgE levels in patients with penicillins allergy.     

Antinociceptive activity and chemical composition of Wei–Chang–An–Wan extracts

Abstract

Context: Currently, famous traditional Chinese medicine formulas have undergone re-evaluation and development in China. Wei–Chang–An–Wan (WCAW) as one of them has been used for treating various gastrointestinal diseases for several decades. The secondary development of WCAW is in progress so as to interpret the effective material basis or find new pharmacological activity.

Objective: To evaluate the antinociceptive effect of methanol extract of WCAW (ME) as well as four fractions (P.E., EtOAc, n-BuOH, H₂O) and obtain information on the correlation between the contents of the fractions and antinociceptive effect.

Materials and methods: ME was divided into four parts extracted by petroleum ether, ethyl acetate and n-butanol. Antinociceptive activity was evaluated by three models of acetic acid–induced writhing, formalin and hot-plate test in mice after repetitive administration of ME at 200, 400 or 800?mg/kg, P.E. 132?mg/kg, EtOAc 106?mg/kg, n-BuOH 176?mg/kg and H₂O 176?mg/kg for six days. The chemical compounds were analyzed by HPLC-ESI-MS.

Results: ME at 800?mg/kg inhibited acid-induced writhing by 84.69%, and reduced the licking time of second phase in formalin test by 53.23%. The inhibition rates in acid-induced writhing of P.E., EtOAc, n-BuOH and H₂O were 27.79, 33.85, 38.97 and 37.69%, respectively, and in formalin test about 50%. They had no effect on the hot-plate test. HPLC-ESI-MS analysis showed that 68 chemical compounds were detected and 41 compounds were identified from ME.

Discussion and conclusion: The results obtained herein indicate that WCAW possesses the antinociceptive activity that provides a new aspect in clinical application.     

Thermosensitive PEG–PCL–PEG Hydrogel Controlled Drug Delivery System: Sol–Gel–Sol Transition and In Vitro Drug Release Study

In this article, biodegradable and low molecular weight poly(ethylene glycol)–poly(ε-caprolactone)–poly(ethylene glycol) (PEG–PCL–PEG, PECE) triblock copolymers were successfully synthesized. Aqueous solution of the obtained PECE copolymers underwent sol–gel–sol transition as temperature increased which was flowing sol at room temperature and then turned into nonflowing gel at body temperature. Sol–gel–sol phase transition behaviors of aqueous PECE solutions were studied using rheometry and test tube-inverting method, which were affected by many factors, including the heating/cooling procedure and different additives in copolymers aqueous solution. In vitro drug release behavior was studied using bovine serum albumin (BSA) and Vitamin B₁₂ (VB₁₂) as model drugs, and the PECE hydrogel could protect BSA from acidic degradation for 1 week at least. Therefore, PECE hydrogel is believed to be promising for injectable in situ gel-forming controlled drug delivery system due to their great thermosensitivity and biodegradability. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3707–3717, 2009     

Preparation and characterization of HA–PEG–PCL intelligent core–corona nanoparticles for delivery of doxorubicin

The objective of the present study was to synthesize core–corona nanoparticles of doxorubicin (DOX) using hyaluronic acid–polyethyleneglycol–polycaprolactone (HA–PEG–PCL) copolymer for tumor targeting. Targeting efficiency of HA–PEG–PCL nanoparticles was compared with non-HA-containing nanoparticles (methoxy poly ethylene glycol (MPEG)–PCL). The copolymers were chemically synthesized and characterized by IR and NMR spectroscopies. The nanoparticles were characterized for shape and morphology by transmission electron microscopy, particle size, percentage of drug entrapment, and in vitro drug release profile. Differential scanning calorimetry and X-ray diffraction studies were also performed to appraise the crystalline or amorphous nature of DOX inside the polymer matrix. Formulations were prepared using different DOX:polymer ratios (1:1–1:3 w/w) and the optimum formulation with the drug:polymer ratio of 1:1 showed the mean particle size of 95 ± 5 nm and entrapment efficiency of 95.56% in the case of HA–PEG–PCL nanoparticles, while the values were 115 nm and 95.50%, respectively, in the case of MPEG–PCL nanoparticles. The HA–PEG–PCL nanoparticles could release DOX for up to 17 days, whereas the MPEG–PCL nanoparticles could release it for up to 14 days. The hemolytic toxicity and hematological studies confirmed that both DOX-loaded HA–PEG–PCL and MPEG–PCL nanoparticles were safe and suitable for sustained and targeted drug delivery. The tissue distribution study and tumor growth inhibition were performed after intravenous injection of nanoparticles in Ehrlich ascites tumor (EAT)-bearing mice. The nanoparticles of HA–PEG–PCL copolymer accomplishes efficient delivery of DOX in EAT tumor when compared with the MPEG–PCL nanoparticles by the process of receptor-mediated endocytosis, as well as enhanced permeability and retention effect.     

Simultaneous analysis of bioactive metabolites from Ziziphus jujuba by HPLC–DAD–ELSD–MS/MS

A high-performance liquid chromatography (HPLC) with diode array detector (DAD), evaporative light scattering detector (ELSD) and electrospray ionization mass spectrometry (ESI-MS) was established for the simultaneous determination of nine representative metabolites of the alkaloid, flavonoid and triterpenoid classes from Ziziphus jujuba var. spinosa. The optimal chromatographic conditions were obtained on an ODS column and the mobile phase was composed of water and methanol with 0.1% formic acid using a gradient elution system. Using the developed methods, all of the validation parameters were successfully obtained. In addition, effectiveness of diverse extraction methods was compared to each other for the development of standard analytic method. The verified method was successfully applied to the quantitative determination of representative metabolites in commercial samples of Z. jujuba and Z. mauritiana from different markets in Korea, China and Myanmar. The analytical results showed that the contents of the nine analytes vary significantly with sources and species, thus demonstrating its potential for the detection of this plant.     

Wilcoxon–Mann–Whitney Test: Stratify or Not?

The Wilcoxon–Mann–Whitney (WMW) test is the most commonly used nonparametric method to compare two treatments when the underlying distribution of the outcome variable is not normally distributed. In the presence of stratum effects, the van Elteren (vE) test, a stratified WMW test, can be used to adjust for the stratum effect. We provide guidance on how to choose between the two tests in the design phase of clinical trials and in the analysis of clinical data. We show by simulations that both tests preserve the type I error rate regardless of the presence of the stratum effects. Therefore, the test with greater power is preferred. In comparing powers, we found that the WMW test is better when the stratum effects are small, whereas the vE test is better when the stratum effects are large. Finally, when the stratum effects are moderate, the decision depends on the shape of the distribution and the ratio of the number of strata and the number of subjects. In this case, results presented in this article or from similar simulations may be used to determine which test is better.     

Drug–phytochemical interactions

Changes in dietary habits favouring diets rich in fruits and vegetables, and a meteoric rise in the consumption of dietary supplements and herbal products have substantially increased human exposure to phytochemicals. It is, therefore, not surprising that diet and herbal remedies can modulate drug-metabolising enzyme systems, such as cytochromes P450, leading to clinically relevant drug-phytochemical interactions. Phytochemicals have the potential to both elevate and suppress cytochrome P450 activity. Such effects are more likely to occur in the intestine, where high concentrations of phytochemicals may be achieved, and alteration in cytochrome P450 activity will influence, in particular, the fate of drugs that are subject to extensive first-pass metabolism as a result of intestinal cytochrome P450-mediated biotransformation. Moreover, it is becoming increasingly apparent that phytochemicals can also influence the pharmacological activity of drugs by modifying their absorption characteristics through interaction with drug transporters. Clearly, phytochemicals have the potential to alter the effectiveness of drugs, either impairing or exaggerating their pharmacological activity.     

Evaluation of the polyethylene glycol–KF–water system in the context of purifying PEG–protein adducts

Covalent binding of PEG to proteins leads to conjugates widely investigated in several biotechnological processes. Their use as pharmaceuticals requires both careful purification and proper characterization. In this context, this paper examines the potentialities offered by hydrophobic interaction chromatography and compares aqueous potassium fluoride and ammonium sulfate as the eluents. Relative contribution of the various forces which dictate the chromatographic behaviour of PEG–protein adducts on Fractogel TSK–Butyl 650 is discussed.     

PEG–lipid–PLGA hybrid nanoparticles loaded with berberine–phospholipid complex to facilitate the oral delivery efficiency

The natural product berberine (BBR), present in various plants, arouses great interests because of its numerous pharmacological effects. However, the further development and application of BBR had been hampered by its poor oral bioavailability. In this work, we report on polymer–lipid hybrid nanoparticles (PEG–lipid–PLGA NPs) loaded with BBR phospholipid complex using a solvent evaporation method for enhancing the oral BBR efficiency. The advantage of this new drug delivery system is that the BBR–soybean phosphatidylcholine complex (BBR–SPC) could be used to enhance the liposolubility of BBR and improve the affinity with the biodegradable polymer to increase the drug-loading capacity and controlled/sustained release. The entrapment efficiency of the PEG–lipid–PLGA NPs/BBR–SPC was observed to approach approximately 89% which is more than 2.4 times compared with that of the PEG–lipid–PLGA NPs/BBR. To the best of our knowledge, this is the first report on using polymer material for effective encapsulation of BBR to improve its oral bioavailability. The prepared BBR delivery systems demonstrated a uniform spherical shape, a well-dispersed core-shell structure and a small particle size (149.6?±?5.1?nm). The crystallographic and thermal analysis has indicated that the BBR dispersed in the PEG–lipid–PLGA NPs matrix is in an amorphous form. More importantly, the enhancement in the oral relative bioavailability of the PEG–lipid–PLGA NPs/BBR–SPC was ～343% compared with that of BBR. These positive results demonstrated that PEG–lipid–PLGA NPs/BBR–SPC may have the potential for facilitating the oral drug delivery of BBR.     

Mother–Daughter and Father–Daughter Attachment of College Student ACOAs

This 2005 study compared parent–child attachment in 89 American female Adult Children of Alcoholics (ACOAs) as compared to 201 non-ACOAs. Women attended a large university in the southeastern United States. Participants categorized as ACOA on the Children of Alcoholics Screen Test (CAST; ) reported significantly more negative affect and less support from their fathers as indicated on the Parental Attachment Questionnaire (). When results were examined by the gender of the alcohol-abusing parent, participants who suspected their fathers were problem drinkers did not differ from non-ACOAs in their attachment to either parent. As compared to non-ACOAs, women who self-identified as daughters of problem-drinking mothers reported poorer attachment both to mothers and fathers.     

Pyrazole–coumarin and pyrazole–quinoline chalcones as potential antitubercular agents

Pyrazole, coumarin, and quinoline are medicinally important moieties. In this study, two series of novel pyrazole–coumarin chalcones and pyrazole–quinoline chalcones were synthesized using multiple-step reactions. All the synthesized compounds were well characterized using different spectroscopic techniques including ¹H and ¹³C nuclear magnetic resonance, high-resolution mass spectroscopy, and electrospray ionization–mass spectrometry. The compounds were evaluated for their antitubercular activity against the Mycobacterium tuberculosis H37Rv strain using the microplate Alamar Blue assay, and the minimal inhibitory concentrations (MIC) of the compounds were determined. Among the 32 tested compounds, compounds 3e , 3u , and 7h showed an MIC value of 3.125 µg/ml, and they were found to be nontoxic. Molecular docking studies of the compounds with the enzyme DprE1 revealed the probable mechanism of action. The chalcone derivatives exhibited binding affinity values between −7.047 and −9.353 kcal/mol. ADME parameters were predicted using the QikProp module of the Schrödinger software, and these compounds exhibited good pharmacological and oral absorption properties.     

Glucan–Resveratrol–Vitamin C Combination Offers Protection against Toxic Agents

Biological immunomodulators are routinely evaluated as a natural source of molecules with profound effects on the immune system. They belong to a group of physiologically active compounds, collectively termed biological response modifiers. Most of the studies were focused on immune system stimulation. Recently, they have become the focus of studies seeking molecules that are able to overcome negative effects of various immunotoxins. This paper concentrates on the effects of a glucan/resveratrol/vitamin C combination on immunosuppressive effects of mercury and perfluorinated hydrocarbons. Effects described in this review have strong clinical potential, as environmental contaminants have adverse effects on all aspects of the immune system and represent a serious threat to the health of both humans and animals.     

Antiosteoporotic activity of Du–Zhong–Wan water extract in ovariectomized rats

Context Eucommiae Cortex and Radix Dipsaci, occurring in a ratio of 1:1 in Du-Zhong-Wan (DZW), a Chinese herbal medicine, is available as a water extract followed by ethanol precipitation for the treatment of osteoporosis, fractures and menopausal syndrome.

Objective This study investigates the protective effects of DZW in ovariectomy (OVX)-induced bone loss in a rat osteopenia model.

Materials and methods Sixty Sprague–Dawley rats were randomly divided into the sham-operated group (SHAM) and five OVX subgroups: OVX with vehicle (OVX), 17β-estradiol (E2) and with three graded doses of DZW. Daily oral administration of the different samples started on the fifth week and lasted for 12 weeks, respectively. The body weight, uterus wet weight, serum biochemical parameters, bone mineral density (BMD), bone biomechanical properties, bone microarchitecture and immunohistochemistry were examined.

Results Compared with the SHAM group, the DZW treatment significantly reversed the osteoporotic changes in OVX rats. The DZW-H group showed that serum tartrate-resistant acid phosphatase 5b (TRACP-5b) levels reduced by 152.25% (p?<?0.01) and osteocalein (OCN) levels dose dependently increased by 118.43% (p?<?0.01) as compared with the OVX group. Compared with the OVX group, the DZW at different three dosages of DZW evidently increased the right femur BMD by 112.43, 114.56 and 116.45%, and dramatically promoted bone quality and bone strength (p?<?0.05). Further, immunohistochemical evaluation also showed that DZW administration increased ER expression in uteri (p?<?0.01).

Conclusions DZW exhibits an anti-osteoporotic effect, probably mediated via phyto-estrogenic effects. It might be a potential herbal alternative for the management of postmenopausal osteoporosis.     

Folate-receptor-targeted delivery of docetaxel nanoparticles prepared by PLGA–PEG–folate conjugate

For folate-receptor-targeted anticancer therapy, docetaxel (DTX) nanoparticles (NPs) were produced employing polylactide-co-glycolide–polyethylene glycol–folate (PLGA–PEG–FOL) conjugate. The FOL-conjugated di-block copolymer was synthesized by coupling the PLGA–PEG–NH₂ di-block copolymer with an activated folic acid. It was expected that FOL moieties were exposed on the micellar surface.

The conjugates assisted in the formation of DTX NPs with an average size of 200 nm in diameter through an emulsification/solvent diffusion method. The FOL-targeted NPs showed a greater extent of intracellular uptake in FOL-receptor-positive cancer cells (SKOV3) in comparison with the non-targeted NPs, indicating that the FOL-receptor-mediated endocytosis mechanism could have a role in the cellular uptake of NPs. These results suggested that FOL-targeted DTX NPs could be a potentially useful delivery system for FOL-receptor-positive cancer cells.     

Monoclonal antibody–drug conjugates

This review covers cytotoxic antibody–drug conjugates for use in oncology. The focus is on drug conjugates of current interest, such as those of the taxanes, maytansines, CC-1065 and the duocarmycins, the calicheamicins and other enediynes, and the auristatins. A few classes of drug conjugates from earlier work are also mentioned, such as those of the antifolates, vinca alkaloids, and the anthracyclines. Also covered are some more recent linker systems that are useful for making antibody–drug conjugates. This review does not cover conjugates of plant toxins, other bioactive proteins, enzymes (i.e., antibody-directed enzyme prodrug therapy [ADEPT]), radioisotopes (photodynamic therapy), or conjugates made with secondary carriers for the cytotoxic agent, such as liposomes or polymers.     

Drug metabolism and liver disease: a drug–gene–environment interaction

Despite the central role of the liver in drug metabolism, surprisingly there is lack of certainty in anticipating the extent of modification of the clearance of a given drug in a given patient. The intent of this review is to provide a conceptual framework in considering the impact of liver disease on drug disposition and reciprocally the impact of drug disposition on liver disease. It is proposed that improved understanding of the situation is gained by considering the issue as a special example of a drug–gene–environment interaction. This requires an integration of knowledge of the drug’s properties, knowledge of the gene products involved in its metabolism, and knowledge of the pathophysiology of its disposition. This will enhance the level of predictability of drug disposition and toxicity for a drug of interest in an individual patient. It is our contention that advances in pharmacology, pharmacogenomics, and hepatology, together with concerted interests in the academic, regulatory, and pharmaceutical industry communities provide an ideal immediate environment to move from a qualitative reactive approach to quantitative proactive approach in individualizing patient therapy in liver disease.