A Randomized,Placebo-Controlled Study to Investigate the Safety,Tolerability, and Pharmacokinetics of 3 Weeks of Orally Administered Gefapixant in Healthy Younger and Older Adults

Purpose

Patients with chronic cough are typically female and have a mean age of?~?60 years. However, initial pharmacokinetic (PK) characterization of the P2X3-receptor antagonist gefapixant, developed to treat refractory or unexplained chronic cough, was performed in healthy participants who were predominantly younger adult males. The objective of this Phase 1 study was to assess the safety, tolerability, and PK of gefapixant in younger (18–55 years) and older (65–80 years) males and females.

Methods

A randomized, double-blind, placebo-controlled study was conducted. Healthy adult participants were stratified into 4 cohorts by age and sex (younger males/females and older males/females) and randomized 4:1 (younger adults) or 3:1 (older adults) to receive gefapixant 300 mg twice daily (BID) for 1 week, followed by gefapixant 600 mg BID for 2 weeks or placebo. Safety, tolerability, and PK were assessed.

Results

Of 36 randomized and treated participants, 28 (100%) receiving gefapixant and 6 (75%) receiving placebo reported?≥?1 adverse event (AE). The most common treatment-related AEs in the gefapixant group were taste related. Predefined renal/urologic AEs were reported by 7 (25%) participants receiving gefapixant (all mild to moderate in severity). Gefapixant exposure was generally lower in younger males compared with younger females and older adults; however, differences may have been due to estimated glomerular filtration rate.

Conclusion

The safety profile of gefapixant 300–600 mg BID was generally consistent with previous studies. Additional characterization of gefapixant PK as a function of age and sex using population PK modeling is warranted.

     

Rod-Cone Dystrophy with Initially Preserved Visual Acuity Despite Early Macular Involvement Suggests Recessive CERKL Mutations

Purpose: To highlight that recessive CERKL mutations cause an early-onset rod-cone dystrophy with initially preserved visual acuity despite early macular involvement, an unusual and distinct initial phenotypic presentation.

Methods: A retrospective case series.

Results: Two young Saudi Arabian adults complained of worsening night blindness over the preceding few years, one of whom had been symptomatic since early childhood. Both had retinal pigment epithelium (RPE) mottling/granularity, vascular attenuation, few bone spicules, and frank macular RPE atrophic changes despite relatively preserved visual acuity. Electroretinography was non-recordable, and ocular coherence tomography confirmed retinal thinning, particularly of the outer nuclear layer in the fovea. Each patient harbored a different homozygous CERKL mutation (p.L245P, p.C333*). The few prior reports that detail the presenting phenotype of CERKL mutations describe children or young adults with the similar unusual presenting constellation of findings: rod-cone dystrophy and frank macular atrophy but relatively preserved visual acuity. With time, central vision is affected.

Conclusions: The initial presenting features of CERKL-related retinopathy are distinct and unusual. Recognition of this initial presenting phenotype can facilitate earlier molecular diagnosis and genetic counseling.     

Management of moderate and severe corneal astigmatism with AcrySof? toric intraocular lens implantation – Our experience

Purpose

Visual performance following toric intraocular lens implantation for cataract with moderate and severe astigmatism.

Setting

Cataract services, Shroff Eye Centre, New Delhi, India.

Design

Case series.

Method

This prospective study included 64 eyes of 40 patients with more than 1.50 dioptre (D) of pre-existing corneal astigmatism undergoing phacoemulsification with implantation of the AcrySof® toric IntraOcular Lens (IOL). The unaided visual acuity (UCVA), best corrected visual acuity (BCVA), residual refractive sphere and refractive cylinders were evaluated. Toric IOL axis and alignment error was measured by slit lamp method and Adobe Photoshop (version 7) method. Patient satisfaction was evaluated using a satisfaction questionnaire at 3 months.

Results

The mean residual refractive astigmatism was 0.57 D at the final follow-up of 3 months. Mean alignment error was 3.44 degrees (SD = 2.60) by slit lamp method and 3.88 degrees (SD = 2.86) by Photoshop method. Forty-six (71.9%) eyes showed misalignment of 5 degrees or less, and 60 (93.8%) eyes showed misalignment of 10 degrees or less. The mean log MAR UCVA at 1st post-op day was 0.172 (SD = 0.02), on 7th post-op day was 0.138 (SD = 0.11), and on 30th post-op day was 0.081 (SD = 0.11). The mean log MAR BCVA at three months was −0.04 (SD = 0.76).

Conclusion

We believe that implantation of AcrySof® toric IOL is an effective, safe and predictable method to correct high amounts of corneal astigmatism during cataract surgery.     

KPC and NDM-1 Genes in Related Enterobacteriaceae Strains and Plasmids from Pakistan and the United States

To characterize the genomic context of New Delhi metallo-β-lactamase-1 (NDM-1) and Klebsiella pneumoniae carbapenemase (KPC), we sequenced 78 Enterobacteriaceae isolates from Pakistan and the United States encoding KPC, NDM-1, or no carbapenemase. High similarities of the results indicate rapid spread of carbapenem resistance between strains, including globally disseminated pathogens.     

Analysis of misoprostol and chlorhexidine policy gains in Pakistan: the advocacy experience of Mercy Corps Pakistan

While Pakistan has made progress toward achieving Millennium Development Goal 5 for maternal health, it is unlikely to achieve the target; further, it is also not on track for Millennium Development Goal 4 regarding child health. Two low-cost, temperature stable and life-saving drugs, misoprostol and chlorhexidine, can respectively avert maternal and newborn deaths, and are particularly pertinent for poor and marginalized areas which bear the brunt of maternal and newborn deaths in Pakistan. In response, Mercy Corps led focused advocacy efforts to promote changes in policies, protocols, and regulatory environments for misoprostol (2012–2014) and for chlorhexidine (2014). These short-duration advocacy projects facilitated significant policy gains, such as inclusion of misoprostol and chlorhexidine into province-specific essential drug lists, development and endorsement of clinical protocols for the two drugs by provincial health departments, inclusion of misoprostol into pre-service training curriculum for several health cadres, and application for registration of chlorhexidine (at the concentration required for newborn care) by two pharmaceutical companies. These results were achieved by a consultative and evidence-based process which generated feedback from community members, program implementers, and policymakers, and ultimately put the government in the driver’s seat to facilitate change. Community Action Dialogue forums were linked with provincial-level Technical Working Groups and Provincial Steering Committees, who passed on endorsed recommendations to the Health Secretary. The key factors which facilitated change were the identification of champions within the provincial health departments, prioritization of relationship building and follow-up, focus on concrete advocacy aims rather than broad objectives, and the use of multi-stakeholder forums to secure an enabling environment for the policy changes to take root. While these advocacy initiatives resulted in significant policy changes in Pakistan’s devolved health system, to ensure these policy changes have an impact on health outcomes, Pakistan should focus on the scale-up of appropriate use of chlorhexidine and misoprostol. Further, future policy initiatives in Pakistan should make use of similar multi-stakeholder policy forums, while ensuring a third party to facilitate the process so that civil society and community voices are not lost in the policy development discussion.     

Decoupling the Contribution of Surface Energy and Surface Area on the Cohesion of Pharmaceutical Powders

Pharmaceutical Research - Surface area and surface energy of pharmaceutical powders are affected by milling and may influence formulation, performance and handling. This study aims to decouple the...     

Novel Z Scores to Correct Biases Due to Ventricular Volume Indexing to Body Surface Area in Adolescents and Young Adults

BackgroundReference values for cardiac magnetic resonance imaging (cMRI) in children and young adults are scarce. This leads to risk stratification of patients with congenital heart diseases being based on volumes indexed to body surface area (BSA). We aimed to produce cMRI Z score equations for ventricular volumes in children and young adults and to test whether indexing to BSA resulted in an incorrect assessment of ventricular dilation according to sex, body composition, and growth.MethodsWe retrospectively included 372 subjects aged < 26 years with either normal hearts or conditions with no impact on ventricular volumes (reference group), and 205 subjects with repaired tetralogy of Fallot (TOF) aged < 26 years. We generated Z score equations by means of multivariable regression modelling. Right ventricular dilation was assessed with the use of Z scores and compared with indexing to BSA in TOF subjects.ResultsVentricular volume Z scores were independent from age, sex, and anthropometric measurements, although volumes indexed to BSA showed significant residual association with sex and body size. In TOF subjects, indexing overestimated dilation in growing children and underestimated dilation in female compared with male subjects, and in overweight compared with lean subjects.ConclusionsIndexed ventricular volumes measured with cMRI did not completely adjust for body size and resulted in a differential error in the assessment of ventricular dilation according to sex and body size. Our proposed Z score equations solved this problem. Future studies should evaluate if ventricular volumes expressed as Z scores have a better prognostic value than volumes indexed to BSA.     

Molecular basis of non-alcoholic fatty liver disease and metabolic syndrome in a subset of South Asians

International Journal of Diabetes in Developing Countries - Metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD) are emerging threats in Pakistan. The prevalence of MetS is...