Evaluation of 5-(Trifluoromethyl)-1,2,4-oxadiazole-Based Class IIa HDAC Inhibitors for Huntington’s Disease

Using an iterative structure–activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12) with a pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class IIa HDAC substrates, we developed a surrogate readout to measure compound effects in vivo, by exploiting the >100-fold selectivity compound 12 exhibits over class I/IIb HDACs. We achieved adequate brain exposure with compound 12 in mice to estimate a class I/IIb deacetylation EC₅₀, using class I substrate H4K12 acetylation and global acetylation levels as a pharmacodynamic readout. We observed excellent correlation between the compound 12 in vivo pharmacodynamic response and in vitro class I/IIb cellular activity. Applying the same relationship to class IIa HDAC inhibition, we estimated the compound 12 dose required to inhibit class IIa HDAC activity, for use in preclinical models of Huntington’s disease.     

Prospective evaluation of a prostacyclin-sparing aspiring formulation and heparin/warfarin in aspirin users with unstable angina or non-Q wave myocardial infarction at rest

The aim of this trial was to compare the efficacy of combinationantithrombotic therapy with a prostacyclin-sparing aspirin plusanticoagulation versus conventional aspirin plus anticoagulation,when added to antianginal therapy, in patients with unstableangina or non-Q wave myocardial infarction already being treatedwith aspirin. In a double-blind (for the aspirin) study, 144prior aspirin users were randomized; 72 patients received controiled-release,prostacyclin-sparing aspirin 75 mg daily plus anticoagulation(intravenous heparin followed by warfarin to maintain the internationalnormalized ratio at 2–3), and 72 patients received conventionalaspirin 75 mg daily plus the same anticoagulation. Controlled-releaseaspirin was formulated to preserve endothelial cell prostacyclinsynthesis. Trial therapy was begun by 13.2 ± 12.3 h ofqualifying pain, and continued for 12 weeks. The frequency of recurrent angina with electrocardiographicchanges, myocardial infarction, or death, was analysed by intentionto treat. At 12 weeks, events were     

Who is excluded and how? An analysis of community spaces for maternal and child health in Pakistan

Background

The maternal, newborn, and child health (MNCH) indicators of Pakistan depict the deplorable state of the poor and rural women and children. Many MNCH programmes stress the need to engage the poor in community spaces. However, caste and class based hierarchies and gendered social norms exclude the lower caste poor women from accessing healthcare. To find pathways for improving the lives of the excluded, this study considers the social system as a whole and describes the mechanisms of exclusion in the externally created formal community spaces and their interaction with the indigenous informal spaces.

Methods

The study used a qualitative case study design to identify the formal and informal community spaces in three purposively selected villages of Thatta, Rajanpur, and Ghizer districts. Community perspectives were gathered by conducting 37 focus group discussions, based on participatory rural appraisal tools, with separate groups of women and men. Relevant documents of six MNCH programmes were reviewed and 25 key informant interviews were conducted with programme staff.

Results

We found that lower caste poor tenants and nomadic peasants were excluded from formal and informal spaces. The formal community spaces formed by MNCH programmes across Pakistan included fixed, small transitory, large transitory, and emerging institutional spaces. Programme guidelines mandated selection of community notables in groups/committees and used criteria that prevented registration of nomadic groups as eligible clients. The selection criteria and adverse attitude of healthcare workers, along with inadequacy of programmatic resources to sustain outreach activities also contributed to exclusion of the lower caste poor women from formal spaces. The informal community spaces were mostly gender segregated. Infrequently, MNCH information trickled down from the better-off to the lower caste poor women through transitory interactions in the informal domestic sphere.

Conclusion

A revision of the purpose and implementation mechanisms for MNCH programmes is mandated to transform formal health spaces into sites of equitable healthcare.

     

Alcohol-based pressurised metered-dose inhalers for use in asthma: a descriptive study.

BACKGROUND: Chlorofluorocarbons (CFCs) have historically served as the propellants of choice in pressurised metered-dose asthma inhalers, but concern has been raised in recent decades regarding their damaging effect on the ozone layer. Among the alternative propellants being considered is alcohol, which can be used as a co-solvent in asthma inhalers. Healthcare professionals need to be aware of alcohol-containing inhalers, since certain populations may have religious and/or cultural concerns regarding the use of such preparations. OBJECTIVES: To identify pressurised metered-dose asthma inhalers which contain alcohol-based propellants. METHODS: We searched the British National Formulary to identify companies that manufacture asthma treatments and wrote to them to enquire about which of their products contained alcohol and if so in what percentage. These direct contacts were supplemented by searching medical databases and the Internet for additional information. RESULTS: We identified 11 manufacturers of asthma inhalers, seven of which produced pressurised metered-dose inhalers; of these, six were willing to disclose the requested information, and information on the seventh product was obtained from an alternative valid source of information. Most CFC preparations contain alcohol, but CFC- and alcohol-free preparations do exist. CONCLUSIONS: Clinicians need to be aware that the majority of CFC-free inhalers contain alcohol. Alcohol-free, and CFC- and alcohol-free, preparations are available for the delivery of both rescue and preventative treatment and these should be considered for use in those patients who may have concern about alcohol-based treatments.     

Embracing Technology for Capacity Building in Mental Health: New Path,Newer Challenges

Psychiatric Quarterly - Technology driven capacity building initiatives are the way to break the barrier of shortage of mental health human resources in India. This new path, while is a welcome...