Impact of new cyclooxygenase 2 inhibitors on human cytomegalovirus replication in vitro.

BACKGROUND: Human cytomegalovirus (HCMV) is involved in complications on immunocompromised patients. Current therapeutics are associated with several drawbacks, such as nephrotoxicity. PURPOSE: As HCMV infection affects inflammation pathways, especially prostaglandin E2 (PGE2) production via cyclooxygenase 2 enzyme (COX-2), we designed 2'-hydroxychalcone compounds to inhibit human cytomegalovirus. STUDY DESIGN: We first selected the most efficient new synthetic chalcones for their effect against COX-2-catalyzed PGE2. STUDY SAMPLE: Among the selected compounds, we assessed the antiviral efficacy against different HCMV strains, such as the laboratory strain AD169 and clinical strains (naïve or multi-resistant to conventional drugs) and toxicity on human cells. RESULTS: The most efficient and less toxic compound (chalcone 7) was tested against HCMV in combination with other antiviral molecules: artesunate (ART), baicalein (BAI), maribavir (MBV), ganciclovir (GCV), and quercetin (QUER) using Compusyn software. Association of chalcone 7 with MBV and BAI is synergistic, antagonistic with QUER, and additive with GCV and ART. CONCLUSION: These results provide a promising search path for potential bitherapies against HCMV.

Quality assurance of medicines supplied to low-income and middle-income countries: poor products in shiny boxes?

OBJECTIVE: In today's context of globalisation of pharmaceutical production and distribution, international and national procurement agencies play a de facto key role in defining the quality of medicines available in sub-Saharan Africa. We evaluated the compliance of a sample of pharmaceutical distributors active in sub-Saharan Africa with the standards of the WHO guideline 'Model Quality Assurance System (WHO MQAS) for procurement agencies', and we investigated factors favouring or hindering the adequate implementation of the guideline. METHODS: We used mixed-methods methodology to analyse quantitative and qualitative data. The quantitative study consisted of a retrospective secondary analysis of data collected by QUAMED (Quality Medicines for all), a partnership that pleads for universal access to quality-assured medicines. The qualitative survey consisted of formal and informal interviews with key informants. We adopted an embedded multiple-case study design. FINDINGS: Our analysis suggests that international distributors based in Europe perform, on average, better than sub-Saharan African distributors. However, some weaknesses are ubiquitous and concern critical processes, such as the initial selection of the products and the ongoing reassessment of their quality. This is due to several different factors: weak regulatory oversight, insufficient human/financial resources, weak negotiating power, limited judicial autonomy and/or lack of institutional commitment to quality. CONCLUSIONS: Our findings suggest that pharmaceutical distributors active in sub-Saharan Africa generally do not apply stringent criteria for selecting products and suppliers. Therefore, product quality is not consistently assured but depends on the requirements of purchasers. While long-term solutions are awaited, the WHO MQAS guideline should be used as an evaluation and training tool to upgrade current standards.

Short communication: performance of a blocking antibody ELISA bulk-tank milk test for detection of dairy sheep flocks exposed to border disease virus.

The aim of this study was to investigate the test characteristics of a blocking antibody ELISA applied to bulk-tank milk (BTM) samples for the detection of dairy sheep flocks positive for antibodies to border disease virus. In 161 flocks recruited in 2009 and 2010, the antibody inhibition percentage (AIP) in BTM was compared with the prevalence estimate of antibody-positive ewes obtained from an age-representative sample of 45 milking ewes. A strong negative exponential relationship (R(2)=0.89) was found between AIP in BTM and seroprevalence level. Using receiver operating characteristic analysis, the best AIP decision threshold in BTM to discriminate between low (<10%) and high (≥10%) antibody-positive flocks was 65%. Diagnostic performance estimates based on observed seroprevalence levels and Monte Carlo simulations showed that this threshold value was associated with high sensitivity and specificity (91.9±5.5% and 95.9±1.6%, respectively), whereas the 80% decision threshold recommended in dairy cows yielded lower specificity (83.6±2.0%). Results obtained from the same flocks during 2 subsequent milking campaigns showed that the 65% AIP cut-off value was associated with fewer false-positive results and is preferred. Testing of BTM samples could be a powerful tool in inferring border disease virus seroprevalence in a flock and in Pestivirus control schemes in dairy sheep flocks.

Sclerotomal origin of vascular smooth muscle cells and pericytes in the embryo.

We previously demonstrated that progenitors of both endothelium and smooth muscle cells in the aortic wall originated from the somite in the trunk of the embryo. However whether the contribution to vascular Smooth Muscle Cells (vSMC) is restricted to the aorta or encompasses other vessels of the trunk is not known. Moreover, the somitic compartment that gives rise to vSMC is yet to be defined. Quail-chick orthotopic transplantations of either the segmental plate or the dorsal or ventral halves from single somites demonstrate that 1 degrees vSMC of the body wall including those of the limbs originate from the somite. 2 degrees Like vSMC, aortic pericytes originate from the somite. 3 degrees The sclerotome is the somite compartment that gives rise to vSMC and pericytes. PAX1 and FOXC2, two molecular markers of the sclerotomal compartment, are expressed by vSMC and pericytes during the earliest phases of vascular wall formation. Later on, PDGFR-beta and MYOCARDIN are also expressed by these cells. In contrast, the dermomyotome gives rise to endothelium but never to cells in the vascular wall. Taken together, out data point out to the critical role of the somite in vessel formation and demonstrate that vSMC and endothelial cells originate from two independent somitic compartments.

Influence of process parameters on pellets elaborated in a Mi-pro high-shear granulator.

The aim of the study was to prepare porous pellets several hundred micrometers in diameter into or onto which drug substances could be embedded. Wet granulation was carried out on a powder mix of alpha-lactose and polyvinylpyrrolidone in a Mi-Pro high-shear granulator. The process parameters were investigated to point out their influence on pellet physical properties. The reference conditions of granulation that gave the most satisfactory pellets in size and shape were determined by adjusting the volume and the distribution rate of water. Increasing impeller speed resulted in an increase in granule size and granulation yield and in a decrease in proportion of fines. The granules showed easy flowing for all granulation conditions. Adjusting process parameters enabled control of size, shape, surface area, and porosity of the granules and thus the design of ready to use granules to which drug substances could be associated by deposition or inclusion.

Expression of Notch genes and their ligands during gastrulation in the chicken embryo.

Notch signalling is an important evolutionary conserved mechanism known to control cell fate choices through local interactions. Here, the patterns of expression of Notch-1 and -2 genes and their ligands Delta-1, Serrate-1 and -2, were established in the early blastodisc of the chicken embryo from the pre-streak to the first somite stages. Delta-1 was detected as early as the pre-streak stage in the posterior part of the embryo shortly followed in the same region by Notch-1 at the initial streak stage. Thereafter both were strongly expressed in the posterior part of the primitive streak until HH4. Notch-2 was also found at the level of the streak although at low levels. Notch-1 was homogeneously expressed by the epiblast and by mesodermal cells ingressing at the level of the streak whereas Delta-1 expression formed a 'salt and pepper' pattern. The difference between the two was clearly detected by double in situ hybridisation. From the mid-streak to the first somite stages, Notch-1 and Delta-1 expressions appeared in the anterior part of the embryo. Serrate-1 and -2 were not detected at these stages. Taken together, these results constitute a framework for analysing the role(s) for Notch signalling during gastrulation.

Lignans and neolignans from Myristica argentea Warb.

The petrol extract from mace of Myristica argentea Warb. afforded six phenylpropenes, three lignans, three neolignans and a dilignan, bis erythro-argenteane (4) or rel-(8R,8'S,8"S,8"'R)-5',5"'-bis(7-(3,4-methylenedioxyphenyl)-7'-(4'-hydroxy-3'-methoxyphenyl)-8.8'-lignane]. The last-named compound is a new natural product.

Flavonoids: structural requirements for antiproliferative activity on breast cancer cells.

Several classes of flavonoids (flavones, flavanones, 2'-hydroxychalcones and flavan-4-ols) having a variety of substituents on A ring were investigated for their antiproliferative activity against MCF-7 human breast cancer cells. Structure-activity relationships of these compounds were discussed. 2'-hydroxychalcones and methoxylated flavanones were found to be potent inhibitors of MCF-7 cells growth whereas flavones and flavan-4-ols appeared to be weak inhibitory agents except 7,8-dihydroxyflavone.

Chalcones are potent inhibitors of aromatase and 17beta-hydroxysteroid dehydrogenase activities.

Chalcones were tested for estimating anti-aromatase, anti-3beta-hydroxysteroid dehydrogenase delta5/delta4 isomerase (3beta-HSD) and anti-17beta-hydroxysteroid dehydrogenase (17beta-HSD) activities in human placental microsomes. In the present study, we have demonstrated for the first time that chalcones are potent inhibitors of aromatase and 17beta-hydroxysteroid dehydrogenase activities: these enzymes being considered as important targets in the metabolic pathways of human mammary hormone-dependent cells. Our results showed that naringenin chalcone and 4-hydroxychalcone were the most effective aromatase and 17beta-hydroxysteroid dehydrogenase inhibitors with IC50 values of 2.6 and 16 microM respectively. In addition, inhibitory effects of some flavones and flavanones were compared to those of the corresponding chalcones. A structure-activity relationship was established and regions or/and substituents essential for these inhibitory activities were determined.

Chalcones: structural requirements for antioxidant, estrogenic and antiproliferative activities.

Flavonoids are largely studied for their biological properties and particularly for their scavenging and antioxidant activities. In the present study, we first evaluated the antioxidant and the estrogenic actions of chalcones, then we tested their effects on MCF-7 cell proliferation. Chalcones are unique in the flavonoids family in lacking a heterocyclic C ring. We tested substituted chalcones with different numbers and different positions of the hydroxy groups: 2'-hydroxychalcone, 4'-hydroxychalcone, 4-hydroxychalcone, 2',4-dihydroxychalcone, isoliquiritigenin, 2',4'-dihydroxychalcone, phloretin and naringenin chalcone. For the antioxidant tests we established the importance of the alpha-beta double bond and the 6'-hydroxy group. The establishment of the structure-activity relationship for the estrogenic properties showed a correlation between the antioxidant and the estrogenic properties. The importance of conformation and hydroxy group positions observed for chalcones, having antioxidant and estrogenic properties, was also observed on MCF-7 cell growth with the same structure-activity relationship. The role of electron and hydrogen transfer in the correlation between these three biological activities was discussed.