Linagliptin loaded Solid-SMEEDS for enhanced solubility and dissolution: Formulation development and optimization by D-optimal design

The aim of the present investigation was to formulate and evaluate solid self-micro emulsifying drug-delivery systems (S-SMEDDS) to improve solubility and dissolution profile of Linagliptin. Solubility of Linagliptin in different oils, surfactants and co-surfactants was assessed and optimizations of pseudo-ternary plots were also carried out for preparation of liquid SMEDDS. D-optimal design mixture was used in the optimization of Linagliptin loaded liquid SMEEDS. The optimized SMEEDS were characterized for globule size, zeta potential, dilution stability, transmittance, pH and in-vitro release profile. The morphology of the Linagliptin SMEEDS was observed by Transmission Electron Microscopy (TEM). Among the different silicates, Nusillin US2 was used as the solid carrier/absorbent to formulate S-SMEEDS of Linagliptin. Improved in-vitro dissolution profile of optimized formulation was observed, resulting in multifold improvement in the absorption profile of Linagliptin as compared with pure drug. In a nutshell, this optimized S-SMEDD formulation holds great promise for enhancement of its physiochemical and biological attributes. Keywords: Linagliptin, Solid Self-micro Emulsifying Drug Delivery Systems, D-optimal design, Zeta-potential, Transmission Electron Microscop

Cancer Incidence among Pesticide Applicators Exposed to Permethrin in the Agricultural Health Study

BACKGROUND: Permethrin is a synthetic pyrethroid insecticide widely used in agriculture, in public health, and in many U.S. homes and gardens. OBJECTIVE: In this study we evaluated the incidence of cancer among pesticide applicators exposed to permethrin in the Agricultural Health Study (AHS). METHODS: A total of 49,093 pesticide applicators were included in this analysis of the AHS, a prospective cohort study of licensed pesticide applicators in Iowa and North Carolina. Detailed information on pesticide exposure and lifestyle factors was obtained from self-administered questionnaires completed in 1993-1997. Average length of follow-up since applicator enrollment in the cohort was 9.14 years. We used two permethrin exposure metrics: a) lifetime days applicators personally mixed or applied permethrin and b) intensity-weighted lifetime days (lifetime days weighted by estimated intensity of exposure). We used Poisson regression analysis to estimate relative risks (RRs) and 95% confidence intervals (CIs) for malignancies by tertiles of exposure. RESULTS: We found no associations between permethrin and all malignant neoplasms combined, or between permethrin and melanoma, non-Hodgkin lymphoma, leukemia, or cancers of the colon, rectum, lung, or prostate. We found elevated and statistically significant risks for multiple myeloma in the highest tertiles of both lifetime exposure-days (RR = 5.72; 95% CI, 2.76-11.87) and intensity-weighted lifetime exposure-days (RR = 5.01; 95% CI, 2.41-10.42), compared with applicators reporting they never used permethrin; these results are based on only 15 exposed cases. These findings were similar across a variety of alternative exposure metrics, exposure categories, and reference groups. CONCLUSIONS: This study found no association with most cancers analyzed. Although the suggested association with multiple myeloma was based on a small number of cases, it warrants further evaluation

Chlorothalonil exposure and cancer incidence among pesticideapplicator participants in the agricultural health study

Background: Chlorothalonil is a broad spectrum, non-systemic fungicide widely used to control diseases affecting over 50 fruit, vegetable, and agricultural crops. Despite its extensive use for over 30 years, little is known about the potential human carcinogenicity associated with the routine application of chlorothalonil. Rodent studies have shown evidence of renal tubular carcinomas and adenomas. We explored cancer incidence with chlorothalonil exposure using data from the Agricultural Health Study, a prospective cohort of licensed pesticide applicators in Iowa and North Carolina. Methods: Licensed private and commercial pesticide applicators were recruited into this study from 1993 to 1997. Detailed information regarding pesticide use was obtained via self-administered questionnaires. Cancer incidence was followed through December 31, 2004. Chlorothalonil exposure was classified by lifetime exposure days and intensity-weighted lifetime exposure days, and then categorized into tertiles. The intensity-weighted lifetime exposure days metric was calculated based on a complex algorithm which includes pesticide application methods among other factors. This may increase or decrease exposure. Results: Of the 47,625 pesticide applicators included in this analysis, 3657 applicators reported using chlorothalonil with a median of 3.5 application days per year. Chlorothalonil was not associated with overall cancer incidence, nor did we find any association with colon, lung, and prostate cancers—the only cancers for which we had sufficient numbers to explore associations. Conclusion: We did not find any strong evidence for an association between chlorothalonil and the cancers investigated. Although animal studies have suggested renal cancer may be associated with chlorothalonil, we had insufficient data to evaluate this cancer

Transactional access to shared memory in StarSs, a task based programming model

With an increase in the number of processors on a single chip, programming environments which facilitate the exploitation of par- allelism on multicore architectures have become a necessity. StarSs is a task-based programming model that enables a flexible and high level programming. Although task synchronization in StarSs is based on data flow and dependency analysis, some applications (e.g. reductions )require locks to access shared data. Transactional Memory is an alternative to lock-based synchronization for controlling access to shared data. In this paper we explore the idea of integrating a lightweight Software Transactional Memory (STM) library, TinySTM , into an implementation of StarSs (SMPSs). The SMPSs run- time and the compiler have been modified to include and use calls to the STM library. We evaluated this approach on four applications and observe better performance in applications with high lock contention.Peer Reviewe

Transactional access to shared memory in StarSs, a task based programming model

With an increase in the number of processors on a single chip, programming environments which facilitate the exploitation of par- allelism on multicore architectures have become a necessity. StarSs is a task-based programming model that enables a flexible and high level programming. Although task synchronization in StarSs is based on data flow and dependency analysis, some applications (e.g. reductions )require locks to access shared data. Transactional Memory is an alternative to lock-based synchronization for controlling access to shared data. In this paper we explore the idea of integrating a lightweight Software Transactional Memory (STM) library, TinySTM , into an implementation of StarSs (SMPSs). The SMPSs run- time and the compiler have been modified to include and use calls to the STM library. We evaluated this approach on four applications and observe better performance in applications with high lock contention.Peer Reviewe