Synthesis and biological evaluation of some N 4-aryl-substituted 5-fluoroisatin-3-thiosemicarbazones

A series of N ⁴-aryl-substituted 5-fluoroisatin-3-thiosemicarbazones 3a–3l was synthesized and evaluated for selected biological activities. The brine shrimp lethality bioassay was carried out to study their in vitro cytotoxicity potential and besides, their antifungal, phytotoxic and urease inhibitory effects were also investigated. Seven compounds i.e. 3a, 3d, 3f, 3g, 3h, 3j and 3k proved to be active in the brine shrimp assay, displaying promising cytotoxicity (LD₅₀ = 6.89 × 10^?5–2.79 × 10^?4 M). Amongst these, 3a and 3h were found to be the most active ones (LD₅₀ = 6.89 × 10^?5 and 9.79 × 10^?5 M, respectively). Compounds 3i, 3j and 3 k displayed moderate (40 %) antifungal activity against one or two fungal strains i.e. A. flavus and/or M. canis. In phytotoxicity assay, all the synthesized compounds, including the reference point 2m showed weak-to-moderate (15–70 %) activity at the highest tested concentration (500 μg/mL). In urease inhibition assay, compounds 3f, 3g and 3j proved to be the most potent inhibitors, demonstrating relatively a higher degree of enzymatic inhibition with IC₅₀ values ranging from 37.7 to 47.3 μM.     

Acid-catalyzed hydrolysis of BMS-582664: degradation product identification and mechanism elucidation

BMS-582664 is an investigational drug intended for cancer treatment through oral administration. The preformulation studies revealed two unexpected degradation products under acidic conditions by reversed-phase high-performance liquid chromatography with ultraviolet detection. Additional liquid chromatography-mass spectrometry results suggested that these were cleavage (hydrolysis) products of a diaryl ether. To further understand the degradation mechanism, the reaction was carried out in (18) O-labeled water. The (18) O was found to be incorporated in only one of the two hydrolysis products. The results suggest that the corresponding α carbon in the heterocycle was unusually eletrophilic in acidic conditions probably because of the protonation of the neighboring nitrogen. This led to the selective attack by water and the consequent hydrolysis products. The study provides a new example of hydrolytic degradation of pharmaceutical compounds, and the reaction center is an aromatic heterocyclic carbon with an aryloxy substitution.     

AN INSTRUMENT FOR MEASURING THE SOCIAL WILLINGNESS TO PAY FOR HEALTH STATE IMPROVEMENT

This paper describes an instrument for measuring the social value of changes in health status, the Relative Social Willingness to Pay. It is a unique combination of measurement attributes designed to minimise cognitive complexity and provide an additional option for measuring ‘social value’. Similar to the person trade‐off (PTO), it adopts a social perspective and asks respondents to evaluate programmes on behalf of society. Unlike the PTO, trade‐offs between the options use dollars, not numbers of patients. Respondents are not, however, asked for their personal willingness to pay. Rather, the opportunity cost of funds spent on one service is as an offsetting reduction in funds for a second service. The amount spent on each service therefore indicates relative, not absolute, value. However, the two services combine to produce one Quality adjusted life year which allows the calculation of a Quality adjusted life year‐like unit of social value on a 0–1 scale. A three‐stage survey was used to test the instrument's reliability, validity and sensitivity to the framing of the main question. Results indicate that the Relative Social Willingness to Pay produces values similar to but less than the PTO and time trade‐off techniques. Copyright © 2013 John Wiley & Sons, Ltd.     

New Business Structures Creating Organizational Opportunities and Challenges for Work Disability Prevention

Purpose Flexible work arrangements are growing in order to develop resource-efficient production and because of advanced technologies, new societal values, changing demographics, and globalization. The article aims to illustrate the emerging challenges and opportunities for work disability prevention efforts among workers in alternate work arrangements. Methods The authors participated in a year-long collaboration that ultimately led to an invited 3-day conference, “Improving Research of Employer Practices to Prevent Disability,” held October 14–16, 2015, in Hopkinton, Massachusetts, USA. The collaboration included a topical review of the literature, group conference calls to identify key areas and challenges, drafting of initial documents, review of industry publications, and a conference presentation that included feedback from peer researchers and a roundtable discussion with experts having direct employer experience. Results Both worker and employer perspectives were considered, and four common alternate work arrangements were identified: (a) temporary and contingent employment; (b) small workplaces; (c) virtual work/telework; and (d) lone workers. There was sparse available research of return-to-work (RTW) and workplace disability management strategies with regard to alternate work patterns. Limited research findings and a review of the grey literature suggested that regulations and guidelines concerning disabled workers are often ambiguous, leading to unsatisfactory protection. At the workplace level, there was a lack of research evidence on how flexible work arrangements could be handled or leveraged to support RTW and prevent disability. Potential negative consequences of this lack of organizational guidance and information are higher costs for employers and insurers and feelings of job insecurity, lack of social support and integration, or work intensification for disabled workers. Conclusions Future studies of RTW and workplace disability prevention strategies should be designed to reflect the multiple work patterns that currently exist across many working populations, and in particular, flexible work arrangements should be explored in more detail as a possible mechanism for preventing disability. Labor laws and policies need to be developed to fit flexible work arrangements.     

Reported paediatric adverse drug reactions in the UK 2000-2009

AIMS

The UK Medicines and Healthcare products Regulatory Agency (MHRA) runs a national spontaneous reporting system (Yellow Card Scheme) to collect ‘suspected’ adverse drug reaction (ADR) data. MHRA advice is to report all suspected ADRs in paediatric (<17 years) patients.

METHODS

Data on all ADRs reported to the MHRA in patients <17 years from the years 2000–9 were supplied in two datasets, inclusive and exclusive of vaccines.

RESULTS

Of 222 755 ADR reports received by the MHRA from 2000–9, 31 726 (14.2%) were in children <17 years. The number of reports in 2000 was greater than in subsequent years (12 035) due to a national vaccination programme (Meningococcal Serogroup C conjugate vaccine). The median number of ADR reports per annum (2001–2009) for children was 2146 (95% CI 1801, 2575). Vaccines were included in 22 102 (66.5%) paediatric ADR reports, with Meningococcal Serogroup C conjugate vaccine reported most frequently (12 106 reports) and headache the commonest symptom (3163). Excluding vaccines, methylphenidate (653 reports) and atomoxetine (491) were the most commonly reported medications, and the most commonly reported symptom was vomiting (374). Reporting by nurses increased from 396 in 2001 to 1295 in 2009 (41.8% of all reports); reporting by doctors stayed constant. Reports from patients, parents or carers more than doubled but remained infrequent (1.5% in 2005, 4.0% in 2009).

CONCLUSIONS

Although under-reporting is probably common, the Yellow Card Scheme in the UK receives more than 2000 reports per year on patients <17 years. Nurses now report more suspected ADRs in children than any other healthcare professional.     

The population pharmacokinetics of R- and S-warfarin: effect of genetic and clinical factors

BACKGROUND

Warfarin is a drug with a narrow therapeutic index and large interindividual variability in daily dosing requirements. Patients commencing warfarin treatment are at risk of bleeding due to excessive anticoagulation caused by overdosing. The interindividual variability in dose requirements is influenced by a number of factors, including polymorphisms in genes mediating warfarin pharmacology, co-medication, age, sex, body size and diet.

AIMS

To develop population pharmacokinetic models of both R- and S-warfarin using clinical and genetic factors and to identify the covariates which influence the interindividual variability in the pharmacokinetic parameters of clearance and volume of distribution in patients on long-term warfarin therapy.

METHODS

Patients commencing warfarin therapy were followed up for 26 weeks. Plasma warfarin enantiomer concentrations were determined in 306 patients for S-warfarin and in 309 patients for R-warfarin at 1, 8 and 26 weeks. Patients were also genotyped for CYP2C9 variants (CYP2C9*1,*2 and *3), two single-nucleotide polymorphisms (SNPs) in CYP1A2, one SNP in CYP3A4 and six SNPs in CYP2C19. A base pharmacokinetic model was developed using NONMEM software to determine the warfarin clearance and volume of distribution. The model was extended to include covariates that influenced the between-subject variability.

RESULTS

Bodyweight, age, sex and CYP2C9 genotype significantly influenced S-warfarin clearance. The S-warfarin clearance was estimated to be 0.144 l h⁻¹ (95% confidence interval 0.131, 0.157) in a 70 kg woman aged 69.8 years with the wild-type CYP2C9 genotype, and the volume of distribution was 16.6 l (95% confidence interval 13.5, 19.7). Bodyweight and age, along with the SNPs rs3814637 (in CYP2C19) and rs2242480 (in CYP3A4), significantly influenced R-warfarin clearance. The R-warfarin clearance was estimated to be 0.125 l h⁻¹ (95% confidence interval 0.115, 0.135) in a 70 kg individual aged 69.8 years with the wild-type CYP2C19 and CYP3A4 genotypes, and the volume of distribution was 10.9 l (95% confidence interval 8.63, 13.2).

CONCLUSIONS

Our analysis, based on exposure rather than dose, provides quantitative estimates of the clinical and genetic factors impacting on the clearance of both the S- and R-enantiomers of warfarin, which can be used in developing improved dosing algorithms.     

Form conversion of anhydrous lactose during wet granulation and its effect on compactibility

The purpose of this study was (a) to evaluate the factors affecting the form conversion of anhydrous lactose to the monohydrate form during wet granulation using water as the granulating agent and (b) study the effect of lactose form conversion on its compaction properties. A two-level full factorial design with two center points was used to evaluate the factors affecting form conversion. The three variables evaluated were percentage of microcrystalline cellulose (low 0 and high 20), water to intragranular solids ratio (low 0.10 and high 0.18) and drying conditions (tray drying and fluid bed drying). The presence of microcrystalline cellulose in the formulation did not provide any benefit in reducing the percent lactose conversion. But, the conversion was significantly reduced by decreasing the amount of water added to the granulation and/or by decreasing the drying time, using a fluid bed dryer compared to a tray dryer. In the second part of the study, complete conversion of the anhydrous lactose to monohydrate was achieved by storing the anhydrous form under 25 °C/97% RH for 4 weeks. Physical characterization (compactibility, surface area and surface morphology) was performed on the form converted material and compared to the as received anhydrous lactose. The physical characterization results indicated that even though anhydrous lactose undergoes complete form conversion to monohydrate form under high humidity and/or during wet granulation, it retains its inherent higher as received material compactibility and the BET surface area and porosity of the form converted material are higher than that of the as received anhydrous lactose.     

Wastewater irrigation and environmental health: implications for water governance and public policy

Climate change is a large-scale and emerging environmental risk. It challenges environmental health and the sustainability of global development. Wastewater irrigation can make a sterling contribution to reducing water demand, recycling nutrients, improving soil health and cutting the amount of pollutants discharged into the waterways. However, the resource must be carefully managed to protect the environment and public health. Actions promoting wastewater reuse are every where, yet the frameworks for the protection of human health and the environment are lacking in most developing countries. Global change drivers including climate change, population growth, urbanization, income growth, improvements in living standard, industrialization, and energy intensive lifestyle will all heighten water management challenges. Slowing productivity growth, falling investment in irrigation, loss of biodiversity, risks to public health, environmental health issues such as soil salinity, land degradation, land cover change and water quality issues add an additional layer of complexity. Against this backdrop, the potential for wastewater irrigation and its benefits and risks are examined. These include crop productivity, aquaculture, soil health, groundwater quality, environmental health, public health, infrastructure constraints, social concerns and risks, property values, social equity, and poverty reduction. It is argued that, wastewater reuse and nutrient capture can contribute towards climate change adaptation and mitigation. Benefits such as avoided freshwater pumping and energy savings, fertilizer savings, phosphorous capture and prevention of mineral fertilizer extraction from mines can reduce carbon footprint and earn carbon credits. Wastewater reuse in agriculture reduces the water footprint of food production on the environment; it also entails activities such as higher crop yields and changes in cropping patterns, which also reduce carbon footprint. However, there is a need to better integrate water reuse into core water governance frameworks in order to effectively address the challenges and harness the potential of this vital resource for environmental health protection. The paper also presents a blueprint for future water governance and public policies for the protection of environmental health.     

Recombinant herpesvirus of turkeys as a vector-based vaccine against highly pathogenic H7N1 avian influenza and Marek's disease

A major challenge for poultry vaccination is the design of vaccines that protect against multiple pathogens via a single protective dose delivered through mass vaccination methods. In this investigation, we examined herpesvirus of turkeys (HVT) as a vaccine vector for delivery of haemagglutinin (HA) antigen of highly pathogenic H7N1 avian influenza virus that can act as a dual vaccine against avian influenza and Marek's disease. The HVT vector was developed using reverse genetics based on an infectious bacterial artificial chromosome (BAC) clone of HVT. The BAC carrying the HVT genome was genetically modified to express the HA gene of a highly pathogenic H7N1 virus. The resultant recombinant BAC construct containing the modified HVT sequence was transfected into chicken embryo fibroblast (CEF) cells, and HVT recombinants (rHVT-H7HA) harbouring the H7N1 HA were recovered. Analysis of cultured CEF cells infected with the rHVT-H7HA showed that HA was expressed and that the rescued rHVT-H7HA stocks were stable during several in vitro passages with no difference in growth kinetics compared with the parent HVT. Immunisation of one-day-old chicks with rHVT-H7HA induced H7-specific antibodies and protected chickens challenged with homologous H7N1 virus against virus shedding, clinical disease and death. This vaccine supports differentiation between infected and vaccinated animals (DIVA) vaccination strategies because no nucleoprotein-(NP) specific antibodies were detected in the rHVT-H7HA vaccinated birds. The rHVT-H7HA not only provided protection against a lethal challenge with highly pathogenic H7N1 virus but also against highly virulent Marek's disease virus and can be used as a DIVA vaccine.     

Degradation of a lyophilized formulation of BMS-204352: identification of degradants and role of elastomeric closures

The purpose of this study was to identify two degradation products formed in the parenteral lyophilized formulation of BMS-204352, investigate the possible role of elastomeric closures in their formation, and develop a strategy to minimize/control their formation. The first degradant was identified as the hydroxymethyl derivative (formaldehyde adduct, BMS-215842) of the drug substance formed by the reaction of BMS-204352 with formaldehyde. Structure confirmation was based on liquid chromatography/mass spectroscopy (LC/MS), nuclear magnetic resonance (NMR), and chromatographic comparison to an authentic sample of the hydroxymethyl degradation product, BMS-215842. To confirm the hypothesis that formaldehyde originated from the rubber closure, migrated into the product, and reacted with BMS-204352 drug substance to form the hydroxymethyl degradant, lyophilized drug product was manufactured, the vials were stoppered with two different rubber closure formulations, and its stability was monitored. The formaldehyde adduct degradant was observed only in the drug product vials stoppered with one of the rubber closures that was evaluated. Although formaldehyde has not been detected historically as leachable and is not an added ingredient in the rubber formulation, information obtained from the stopper manufacturer indicated that the reinforcing agent used in the stopper formulation may be a potential source of formaldehyde. The second degradant was identified as the desfluoro hydroxy analog (BMS-188929) based on LC/MS, NMR, and chromatographic comparison to an authentic sample of the desfluoro hydroxy degradation product.