Fatty acid-based solid lipid nanoparticles and their effects on metabolism and permeability of drugs

Conclusions from previously reported studies have revealed that many commonly used pharmaceutical excipients, known to be pharmacologically inert, show effects on drug transporters and/or metabolic enzymes. Thus, the pharmacokinetics (absorption, distribution, metabolism, and elimination) of active pharmaceutical ingredients are possibly altered because of their transport and metabolism modulation from the incorporated excipients. Excipients such as surfactants, polymers, fatty acids, and solvents have been reported previously as CYP450 inhibitors. Based on all the stated outcomes, the most potent inhibitors were found to be surfactants and the least effective were organic solvents. However, there are many factors that can influence the inhibition of CYP450, for instance type of excipient, concentration of excipient, type of CYP450 isoenzyme, incubation condition, etc. Such evidence will be very useful in dosage form design, so that the right formulation can be designed to maximize drug availability, especially for poorly bioavailable drugs. The aim of this study is to identify the most potent fatty acids that can inhibit CYP450 enzymes and produce solid-lipid nanoparticles (SLNs) to minimize metabolism and increase drug permeability without harmful side effects. The high-performance Liquid Chromatography-Mass Spectrometric (LCMS) methods were developed for (i) simultaneous quantification of omeprazole, dextromethorphan, verapamil, and propranolol (IS) (ii) individual quantification of testosterone. The separation for both methods were achieved on Poroshell 120 EC-C18 (150 x 4.6 mm) using gradient and isocratic approaches. These analytical methods were successfully used for screening of fatty acids, pre-formulation, and formulation studies. Microsomal assay with rat-liver microsomes was used for screening of fatty acids based on their inhibitory effect on various CYP450s. The most potent inhibitor (stearic acid) was then incorporated in three different solid-lipid nanoparticles formulations (SLNs). The pre-formulation and formulation studies were systematically optimized to produce SLNs. These SLNs were characterized by SEM, zetasizer, DSC, dialysis membrane, and HPLC. Moreover, metabolic assay, permeability assay and cytotoxicity were also studied to investigate the effect of stearic acid, present in SLNs, on CYP450s enzymes and caco-2 cell permeability. The results of the LCMS method validation revealed that the coefficient of determination (R2) values for all probe drugs were greater than 0.99. Furthermore, all the analytes showed highest recovery and lowest interday/intraday values. The effect of fatty acids on CYP450s activity was evaluated using rat-liver microsomes. The percentage of probe drugs recovered in the presence of heptadecanoic acid, myristic acid, pentadecanoic acid, and stearic acid were found to be higher than the control study. Stearic acid was the most potent inhibitor out of all the excipients with an IC50 value ³ 30 µM for CYP3A4, 3A5, 2C8, 2C19, and 2D6. At approximately 200 µM of stearic acid, nearly 100% of the compounds were recovered. Based on the screening phase data, three solid-lipid nanoparticles formulations were produced using stearic acid as an oil phase. Results indicated that testosterone loaded SLNs were spherical in shape with an average particle of 278.29 nm diameter with 55% entrapment efficiency. Moreover, microsomal and permeability assays revealed that the presence of stearic acid in testosterone decreased metabolism by CYP450s and increased permeability via caco-2 layer. Approximately, 54% of testosterone was recovered from the metabolic assay with CLint of 0.04 µL/min/mg and apparent permeability was successfully improved with Papp value of 1.53x10-6 cm/sec. On the other hand, verapamil loaded SLNs were spherical in shape with an average particle size of 300.30 nm but with a better entrapment efficiency of 77%. The formulation demonstrated burst release with nearly 20% drug release in under 0.5 hours, followed by sustained release for 23.5. In contrast to testosterone, metabolic assay revealed poor inhibition for CYPs with net recovery of 2.53% and CLint of 0.014 µL/min/mg for verapamil. However, there was significant improvement in the apparent permeability of verapamil (Papp = 2.39x10-6 cm/sec) when compared to control (Papp = 9.00 x10-6 cm/sec). The third formulation, dextromethorphan loaded SLNs was unsuccessful because of its chemical nature and water solubility. Several strategies were used to prepare dextromethorphan-SLNs such as double emulsion, solvent evaporation, and convention hot emulsion method. The affinity of lipophilic drugs for lipids makes them simple to integrate into SLN. While hydrophilic drugs (such as dextromethorphan) are more readily partitioned in the water phase during the production process, they are more difficult to incorporate into the hydrophobic matrix and therefore, further investigation is required for this formulation. The cell cytotoxicity study further confirms the safety of all the ingredients at different concentrations present in various formulations. Thus, stearic acid based SLNs are a potential formulation approach which can inhibit CYP450 enzymes and improve intestinal permeability of various drugs and therefore, requires further investigation to improve the formulation with various approaches

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

Strategies for Effective Management of Intellectually Disabled Patients on the Psychiatric Inpatient Unit

The management of aggressive behavior remains a fundamental challenge when working on a psychiatric inpatient service. The task becomes far more daunting when the patient presents not only with mental illness but also has an intellectual disability (ID) or impulse control disorder (IC). Intellectual Disability is defined as “the impairment of general mental abilities that impact adaptive functioning in three domains: conceptual, social and practical.” Impulse control disorder, is defined as “a psychiatric disorder characterized by impulsivity- the failure to resist a temptation, urge or impulse that may harm oneself or others” [1]. Those with ID and or IC may present with varying degrees of impairment and social functioning. Numerous studies have identified an association with ID and psychiatric co-morbidities including: bipolar disorder, impulse control disorder, psychosis and depression. Due to budgetary cuts and the precipitous decline in available residential placements, inpatient psychiatric services are faced with the dilemma of managing these exceptionally complicated patients. While numerous studies have examined the utility of psychotropic medication to aid in the management of these patients, convincing evidence concerning the use of psychiatric medication in the management of this patient population remains elusive [2]. Therefore, this paper aims to explore the treatment strategies available to the multidisciplinary team on the inpatient service. Ultimately, future investigations will be necessary to better understand how to optimize the inpatient management of this complex patient population

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

Utility of point-of-care ultrasound in differentiating causes of shock in resource-limited setup

Background: Delivering early diagnosis of shock in resource-limited setting is challenging, especially with limited availability of point-of-care laboratory and radiological diagnostic facilities. There is growing urgency to provide point-of-care diagnosis and treatment for time-sensitive condition like shock. Aims: We tried to evaluate the application of point-of-care ultrasound (Rapid Ultrasound for Shock and Hypertension [RUSH] protocol) considering different disease cohort and practice realities in our setup. Settings and Design: This study was a single-center prospective diagnostic study to check the diagnostic accuracy of point-of-care ultrasound (RUSH protocol). This study was approved by the ethics committee. Materials and Methods: The study was conducted at the emergency medicine department of a tertiary care government hospital in Central Gujarat from November 16 to October 17. All adult patients with clinical features of shock with systolic blood pressure 1 presenting to emergency department were included as participants. The results of point-of-care ultrasound (RUSH protocol) were compared with the diagnosis given by consultants of respective department as per standard departmental practices. Statistical Analysis and Results: A total of 130 patients were enrolled in this study. Mean time taken to examine by the point-of-care Ultrasound (RUSH protocol) was 12 min (range 11–14 min). Kappa index was 0.860. This protocol was able to correctly diagnose 100% of obstructive shock, 96.3% of cardiogenic shock, 94.4% of hypovolemic shock, 80.9% of mixed type of shock, and 75% of distributive type of shock. Conclusion: This study highlights the role of point-of-care ultrasound (RUSH protocol) for early diagnosis of the shock etiology in emergency medicine department. Diagnosis using point-of-care ultrasound (RUSH protocol) significantly agreed with medical diagnosis. It showed good efficacy of point-of-care ultrasound (RUSH protocol) to differentiate causes of shock with good accuracy except distributive shock