Action of 5-HT3 receptor antagonists and dexamethasone to modify cisplatin-induced emesis in Suncus murinus (house musk shrew)

Ondansetron (1-3 mg/kg), granisetron (0.3-1 mg/kg) and dexamethasone (0.3-1 mg/kg), administered at 12-h intervals, were investigated for their potential to prevent cisplatin (30 mg/kg, i.p.)-induced emesis during a 72-h observation period. Ondansetron appeared more active than granisetron to antagonise the emetic response occurring in the first 4-h (P<0.05) period, but none of the regimens significantly antagonised emesis during the 0-24- and 24-72-h periods (P>0.05). However, ondansetron was more active to antagonise emesis on day 1 using a more frequent drug administration, whereas bilateral vagotomy only reduced emesis for 2 h, and 5-HT, 2-methyl-5-HT and 1-m-chloro-phenylbiguanide (up to 20-30 mg/kg, i.p.) were not emetic. The combination of ondansetron 1 mg/kg and dexamethasone 1 mg/kg, both administered every 12 h, significantly delayed the onset of emesis (P<0.05) but failed to reduce the total numbers of retches+vomits over the 3-day period (P>0.05). Results are discussed in relation to the clinical situation.     

Breast milk dioxins in Hong Kong and Pearl River Delta

There are no previous reports from South China on chemically determined polychlorinated dibenzo-para-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (PCBs) in human breast milk expressed as World Health Organization (WHO) toxic equivalents (TEQs). In a 2002-2003 WHO exposure study, 13 pools of breast milk comprising samples from 316 primiparous women in Hong Kong in 2002 were analyzed by gas chromatography/mass spectrometry for 29 PCDD/F and dioxin-like PCB congeners. Total WHO-TEQs ranged from 8.97 to 16.7 pg/g fat (weighted mean, 12.9 pg; weighted median, 13.4 pg). Variations in TEQs included positive associations with age (R2 = 0.73, p < 0.0005), higher consumption of dairy products and seafood, and lower TEQs in overseas mothers and ever-smokers. Congener profiles indicated geographic specificity of exposure in Hong Kong, mainland China, and overseas Asian countries, including higher proportions of PCB-TEQs (overseas) and PCDF-TEQs (mainland China). The median TEQs of PCDD/Fs (8.69 pg/g fat) and PCBs (4.73 pg/g fat) in Hong Kong were highest among the five Asian Pacific countries but lower than the levels for at least half of the European countries that participated in the WHO study. However, future international studies should incorporate mother's age in the design of the pooling strategy to allow standardization by other exposure factors and valid comparisons among different countries. The findings allow support for the WHO breast-feeding advisory. Trends in human dioxin levels in the region cannot yet be determined, and rigorous controls are needed to reduce emissions of dioxins and human exposure in mainland China.     

Emetic action of the prostanoid TP receptor agonist, U46619, in Suncus murinus (house musk shrew)

The emetic action of the prostanoid TP receptor agonist, 11alpha,9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619; 300 microg/kg, i.p.), was investigated in Suncus murinus. The emetic response was reduced by 76% following bilateral abdominal vagotomy (P<0.001) and by reserpine (5 mg/kg, i.p., 24 h pretreatment; P<0.05) but U46619 administered i.c.v. (30-300 ng) was not emetic, suggesting a peripheral mechanism involving monoamines. However, fenfluramine (5 mg/kg, repeated treatment) and para-chlorophenylalanine (100-400 mg/kg) and ondansetron (0.3-3 mg/kg) were inactive (P>0.05) to reduce U46619-induced emesis precluding a role of 5-HT and 5-HT(3) receptors in the mechanism. Similarly, phentolamine (0.3-3 mg/kg), propranolol (3 mg/kg), and their combination, and metoclopramide (0.3-3 mg/kg), domperidone (0.3-3 mg/kg), droperidol (0.3-3 mg/kg), scopolamine (0.3-3 mg/kg) and promethazine (0.3-3 mg/kg) were inactive (P>0.05) to reduce the retching and vomiting response. However, the tachykinin NK(1) receptor antagonist, (+)-2S,3S(-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine) (CP-122,721; 1-10 mg/kg) antagonized emesis (P<0.01). In conclusion, U46619-induced emesis appears to be mediated via a predominant peripheral mechanism sensitive to reserpine and is not likely to involve adrenoceptors, dopamine, 5-HT(3), muscarinic or histamine (H(1)) receptors. The action of CP-122,721 to reduce U46619-induced emesis extends the spectrum of anti-emetic action tachykinin NK(1) receptor antagonists to mechanisms involving TP receptors.     

Investigation of melt agglomeration process with a hydrophobic binder in combination with sucrose stearate

The melt agglomeration process of lactose powder with hydrogenated cottonseed oil (HCO) as the hydrophobic meltable binder was investigated by studying the physicochemical properties of molten HCO modified by sucrose stearates S170, S770 and S1570. The size, size distribution, micromeritic and adhesion properties of agglomerates as well as surface tension, contact angle, viscosity and specific volume of molten HCO, with and without sucrose stearates, were examined. The viscosity, specific volume and surface tension of molten HCO were found to be modified to varying extents by sucrose stearates which are available in different HLB values and melt properties. The growth of melt agglomerates was promoted predominantly by an increase in viscosity, an increase in specific volume or a decrease in surface tension of the molten binding liquid. The agglomerate growth propensity was higher with an increase in inter-particulate binding strength, agglomerate surface wetness and extent of agglomerate consolidation which enhanced the liquid migration from agglomerate core to periphery leading to an increased surface plasticity for coalescence. The inclusion of high concentrations of completely meltable sucrose stearate S170 greatly induced the growth of agglomerates through increased specific volume and viscosity of the molten binding liquid. On the other hand, the inclusion of incompletely meltable sucrose stearates S770 and S1570 promoted the agglomeration mainly via the reduction in surface tension of the molten binding liquid with declining agglomerate growth propensity at high sucrose stearate concentrations. In addition to being an agglomeration modifier, sucrose stearate demonstrated anti-adherent property in melt agglomeration process. The properties of molten HCO and melt agglomerates were dependent on the type and concentration of sucrose stearate added.     

Presynaptic modulation by L-glutamate and GABA of sympathetic co-transmission in rat isolated vas deferens.

1. The modulatory effects of L-glutamate and its structural analogues, and of gamma-aminobutyric acid (GABA), on sympathetic co-transmission were studied in the rat isolated vas deferens exposed to electrical field stimulation (EFS). 2. Application of exogenous L-glutamate caused a concentration-dependent (1 microM-3 mM) inhibition of the rapid twitch component of the biphasic EFS contraction. However, L-glutamate (1 microM-3 mM) had a minimal effect on the phasic contraction induced by exogenous adenosine 5'-triphosphate (ATP, 150 microM) and noradrenaline (50 microM). Unlike L-glutamate, D-glutamate had no effect on the EFS contraction. 3. The L-glutamate-induced inhibition of the EFS contractions was significantly attenuated by the glutamate decarboxylase (GAD) inhibitor 3-mercapto-propionic acid (150 microM) and was abolished in the presence of the GABA transaminase (GABA-T) inhibitor, 2-aminoethyl hydrogen sulphate (500 microM). 4. The L-glutamate-induced inhibition of the electrically evoked contraction was not affected by the adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX)(30 nM), reactive blue 2 (30 microM) or the GABAA receptor antagonist bicuculline (50 microM). However, the GABAB receptor antagonist 2-hydroxysaclofen (50 microM) significantly inhibited the L-glutamate effect. 5. Similar to L-glutamate, GABA also caused a concentration-dependent (0.1-100 microM) inhibition of the EFS contractions. This GABA-induced inhibition was not affected by either the GABAA receptor antagonist bicuculline (50 microM) or reactive blue 2 (30 microM). However, a significant attenuation of the GABA-mediated effect was recorded with the GABAB receptor antagonist 2-hydroxysaclofen (50 microM). Contractions of the vas deferens induced by exogenous ATP and noradrenaline were not affected by GABA (0.1-100 microM). 6. The L-glutamate analogues, N-methyl-D-aspartate (NMDA) (1 microM-1 mM) and quisqualate (Quis 0.1 microM-0.3 mM) had no effect, whilst kainate (Kain, 1 microM-1 mM) caused an inhibition of the EFS-induced contractions. Effects of Kain could be abolished by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dioxine (CNQX, 10 microM). NMDA, Quis and Kain had no effect on the exogenous ATP- or noradrenaline-induced contractions. 7. It is concluded that the excitatory amino acid L-glutamate modulates the electrically evoked vas deferens contraction through conversion to the inhibitory amino acid GABA by a specific GABA transaminase. The GABA formed may then act on GABAB receptors and cause inhibition of the contraction through a presynaptic mechanism.     

Anti‐inflammatory Activities of an Active Fraction Isolated from the root of Astragalus membranaceus in RAW 264.7 Macrophages

The root of Astragalus membranaceus (AR), which has been widely used in Traditional Chinese herbal formulae for treating foot ulcer, was found to exhibit anti‐inflammatory property, but its molecular mechanism still remains unknown. We previously identified the anti‐inflammatory sub‐fraction using bioassay‐guided fractionation. The objective of the present study was to investigate the anti‐inflammatory mechanism of the major active fraction (MAF) (0.039 to 0.156 mg/mL) using lipopolysaccharide (LPS)‐stimulated mouse macrophage RAW 264.7 cells. MAF was shown to inhibit LPS‐induced mRNA and protein expression of inducible nitric oxide synthase by 54.7% and 65.1%, respectively. Additionally, MAF down‐regulated the protein expression of cyclooxygenase‐2 and MAPK regulator by 45.0% to 74.6%, as well as the reduction of DNA binding activity of nuclear factor kappa B (NFκB) by 66.5%. It also attenuated the production of prostaglandin E₂, interleukin‐1 beta (IL‐1β), IL‐6 and tumor necrosis factor alpha by 21.2% to 86.2%. Furthermore, the chemical constituents of MAF were identified. A total of 13 known chemical compounds were found in MAF, including five isoflavonoids and eight saponins. In conclusion, a bioactive fraction of AR was identified which possessed anti‐inflammatory property by reducing the release of inflammatory mediators and inactivation of NFκB through MAPK signalling pathway. Copyright © 2013 John Wiley & Sons, Ltd.     

Regulatory properties of polysaccharopeptide derived from Coriolus versicolor and its combined effect with ciclosporin on the homeostasis of human lymphocytes

Objectives Lymphocyte homoeostasis is essential in inflammatory and autoimmune diseases. In search of natural fungal metabolites with effects on lymphocyte homoeostasis, we recently reported that polysaccharopeptide (PSP) from Coriolus versicolor exhibited ciclosporin‐like activity in controlling aberrant lymphocyte activation. This object of this study was to investigate its effect on lymphocyte homoeostasis. This was done by investigating the mechanistic actions of PSP in relation to ciclosporin by performing cell cycle and cell death analysis of human lymphocytes in vitro. Methods We investigated the effect of PSP in the presence and absence of ciclosporin on cell proliferation, cell cycle, cell death, immunophenotype and cell cycle regulatory proteins in human lymphocytes. Key findings The data showed that PSP exhibited homoeostatic activity by promoting and inhibiting the proliferation of resting and phytohaemagglutinin (PHA)‐stimulated lymphocytes, respectively. PHA‐stimulated lymphocytes exhibited G0/G1 cell cycle arrest that was accompanied by a reduction of cyclin E expression with PSP treatment. Both PSP and ciclosporin blocked the reduction of the CD4/CD8 ratio in stimulated lymphocytes. PSP did not induce cell death in human lymphocytes, but the suppression of the Fasreceptor suggested a protective role of PSP against extrinsic cell death signals. These homoeostatic effects were more potent with combined PSP and ciclosporin treatment than with either fungal metabolite alone. Conclusions Collectively, the results reveal certain novel effects of PSP in lymphocyte homoeostasis and suggest potential as a specific immunomodulatory adjuvant for clinical applications in the treatment of autoimmune diseases.     

Clinical dose-volume histogram analysis in predicting radiation pneumonitis in Hodgkin's lymphoma

PURPOSE: To quantify the incidence of radiation pneumonitis (RP) in a modern Hodgkin's lymphoma (HL) cohort, and to identify any clinically relevant parameters that may influence the risk of RP. METHODS AND MATERIALS: Between January 2003 and February 2005, 64 consecutive HL patients aged 18 years or older receiving radical mediastinal radiation therapy (RT) were retrospectively reviewed. Symptomatic cases of radiation pneumonitis were identified. Dose-volume histogram parameters, including V(13), V(20), V(30), and mean lung dose (MLD), were quantified. RESULTS: At a median follow-up of 2.1 years, the actuarial survival for all patients was 91% at 3 years. There were 2 (2/64) cases of Radiation Therapy Oncology Group (RTOG) Grade 2 RP (incidence 3.1%). Both index cases with corresponding V(20) values of 47.0% and 40.7% were located in the upper quartile (2/16 cases), defined by a V(20) value of > or =36%, an incidence of 12.5% (p = 0.03). Similarly for total MLD, both index cases with values of 17.6 Gy and 16.4 Gy, respectively, were located in the upper quartile defined by MLD > or =14.2 Gy, an incidence of 11.8% (2/17 cases, p = 0.02). CONCLUSIONS: Despite relatively high V(20) values in this study of HL patients, the incidence of RP was only 3%, lower compared with the lung cancer literature. We suggest the following clinically relevant parameters be considered in treatment plan assessment: a V(20) greater than 36% and an MLD greater than 14 Gy, over and above which the risk of RTOG Grade 2 or greater RP would be considered clinically significant.     

Characterization of infections and hypogammaglobulinemia treated with the combination of pertuzumab and trastuzumab

We update a patient series that reported a high incidence of infection with Gram-positive cocci in women treated with the combination of pertuzumab and trastuzumab and further characterize this clinical problem. Treating physicians and advanced practice partners identified women who developed infections while on treatment with pertuzumab and trastuzumab alone or in combination with chemotherapy and enrolled them onto this registry trial. Between March, 2014 and May, 2017, 48 patients with HER2-positive breast cancers were reported to have 59 individual infections. The median age was 48 years. Twenty-four patients received neoadjuvant therapy, 17 were treated for metastatic disease, and 7 were treated in the adjuvant setting. Pertuzumab and trastuzumab were combined with carboplatin and docetaxel in 24 (49%) patients, docetaxel in 10 (21%), nab-paclitaxel in 12 (24%), and without other agents in 2 (4%). Granulocyte growth factors were administered in 24 (49%) patients and no patients were documented to be neutropenic. Folliculitis developed in 25 (52%) patients and was counted as a single infection. Abscesses developed at a number of sites in 24 (49%) patients, including a septic knee requiring total knee replacement. Paronychia occurred in 7 (15%) patients, and 5 (10%) developed cellulitis. When cultures were obtained, Gram-positive cocci were consistently identified. Hypogammaglobulinemia was documented in 14 (36%) of the 33 patients tested. Our data continue to support an increased risk of infections with Gram-positive cocci as a potentially serious adverse event in women treated with pertuzumab and trastuzumab.