Diclofenac Enables Unprecedented Week-Long Microneedle-Enhanced Delivery of a Skin Impermeable Medication in Humans

Purpose

Microneedles applied to the skin create micropores, allowing transdermal drug delivery of skin-impermeable compounds. The first human study with this technique demonstrated delivery of naltrexone (an opioid antagonist) for two to three days. Rapid micropore closure, however, blunts the delivery window. Application of diclofenac (an anti-inflammatory) allows seven days of naltrexone delivery in animals. The purpose of the current work was to demonstrate delivery of naltrexone for seven days following one microneedle treatment in humans.

Methods

Human subjects were treated with microneedles, diclofenac (or placebo), and naltrexone. Impedance measurements were used as a surrogate marker to measure micropore formation, and plasma naltrexone concentrations were measured for seven days post-microneedle application.

Results

Impedance dropped significantly from baseline to post-microneedle treatment, confirming micropore formation. Naltrexone was detected for seven days in Group 1 (diclofenac + naltrexone, n?=?6), vs. 72 h in Group 2 (placebo + naltrexone, n?=?2). At study completion, a significant difference in impedance was observed between intact and microneedle-treated skin in Group 1 (confirming the presence of micropores).

Conclusion

This is the first study demonstrating week-long drug delivery after one microneedle application, which would increase patient compliance and allow delivery of therapies for chronic diseases.     

The Effect of an Animal-Assisted Reading Program on the Reading Rate,Accuracy and Comprehension of Grade 3 Students: A Randomized Control Study

Background

Animal-assisted therapy has been widely used with students. This study is the first known investigation into the impact of an animal-assisted reading program on reading skills, employing an experimental pre-test/post-test control group design and controlling for the effects of extra attention to student’s reading.

Objective

The purpose of the study was to evaluate the effects of an animal-assisted reading program on the reading rate, accuracy and comprehension of grade 3 students.

Method

Students identified by the ESSI Reading Test as poor readers (N = 102) were randomly assigned to three experimental groups and one control group. Twenty-seven students read to a dog in the presence of a Pets as Therapy volunteer, 24 students read directly to an adult, while 26 students read to a teddy bear in the presence of an adult. Students in the control group (n = 25) were not part of the program and continued with their normal school activities. Data collection took place before the start of the program (Time 1), directly after completion of the 10-week reading program (Time 2), and again 8 weeks after the completion of the program (Time 3).

Results

Mixed method analysis of variance revealed significant interaction between group and time on the Neale reading comprehension scores with the “dog group” scoring higher than the three other groups.

Conclusion

The animal-assisted reading program had an impact on some of the reading skills of the students who read to a dog. The program is flexible and can be applied in a variety of settings.     

Adolescence as a Critical Stage in the MCH Life Course Model: Commentary for the Leadership Education in Adolescent Health (LEAH) Interdisciplinary Training Program Projects

The Life Course Perspective (LCP), or Model, is now a guiding framework in Maternal and Child Health (MCH) activities, including training, supported by the Health Resources and Services Administration’s Maternal and Child Health Bureau. As generally applied, the LCP tends to focus on pre- through post-natal stages, infancy and early childhood, with less attention paid to adolescents as either the “maternal” or “child” elements of MCH discourse. Adolescence is a distinct developmental period with unique opportunities for the development of health, competence and capacity and not merely a transitional phase between childhood and adulthood. Adequately addressing adolescents’ emergent and ongoing health needs requires well-trained and specialized professionals who recognize the unique role of this developmental period in the LCP.     

Rare Norovirus GIV Foodborne Outbreak,Wisconsin, USA

We report a norovirus GIV outbreak in the United States, 15 years after the last reported outbreak. During May 2016 in Wisconsin, 53 persons, including 4 food handlers, reported being ill. The outbreak was linked to individually prepared fruit consumed as a fruit salad. The virus was phylogenetically classified as a novel GIV genotype.     

Analyzing Potential Intestinal Transporter Drug-Drug Interactions: Reevaluating Ticagrelor Interaction Studies

Pharmaceutical Research - Previous studies evaluating ticagrelor drug-drug interactions have not differentiated intestinal versus systemic mechanisms, which we do here. Using recently published...     

Pharmacokinetics of etoricoxib in patients with renal impairment

The effect of renal insufficiency on the pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, was examined in 23 patients with varying degrees of renal impairment (12 moderate [creatinine clearance between 30 and 50 mL/min/1.73 m2], 5 severe [creatinine clearance below 30 mL/min/1.73 m2], and 6 with end-stage renal disease requiring hemodialysis) following administration of single 120-mg oral doses of etoricoxib. Even the most severe renal impairment was found to have little effect on etoricoxib pharmacokinetics. The low recovery of etoricoxib in dialysate (less than 6% of the dose) supports that hemodialysis also has little effect on etoricoxib pharmacokinetics, and binding of etoricoxib to plasma proteins was generally unaffected by renal disease. Single doses of etoricoxib were generally well tolerated by patients with renal impairment. Based on pharmacokinetic considerations, dosing adjustments are not necessary for patients with any degree of renal impairment. However, because patients with advanced renal disease (creatinine clearance below 30 mL/min/1.73 m2) are likely to be very sensitive to any further compromise of renal function, and there is no long-term clinical experience in these patients, the use of etoricoxib is not recommended in patients with advanced renal disease.     

Effects of Formulation and Food on the Absorption of Hydrochlorothiazide and Triamterene or Amiloride from Combination Diuretic Products

The absorption of three combination formulations of hydrochlorothiazide and either triamterene or amiloride was studied over a 5-year period in seven separate investigations under varying conditions of food and fasting. The most widely prescribed combination, containing 25 mg of hydrochlorothiazide and 50 mg of triamterene, demonstrated impaired absorption in the fasting state that was partially corrected by the addition of a breakfast high in fat. The increase in the fat content of the food appeared to correlate directly with the amount of both drugs absorbed from this formulation. The second formulation studied, a new combination formulation of 50 mg of hydrochlorothiazide and 75 mg of triamterene, demonstrated acceptable absorption in the fasting state that was not altered by the concurrent administration of a high-fat breakfast. The absorption of the third formulation, a combination of 50 mg hydrochlorothiazide and 5 mg amiloride, was acceptable in the fasting state and demonstrated a slight reduction in the absorption of the amiloride component when administered concurrently with a high-fat meal. The clinical and biopharmaceutic implications of these observations are discussed.     

Nonpeptide luteinizing hormone-releasing hormone antagonists derived from erythromycin A: design, synthesis, and biological activity of cladinose replacement analogues

The design and synthesis of a series of 11,12-cyclic carbamate derivatives of 6-O-methylerythromycin A that are novel, nonpeptide LHRH antagonists, is described. The macrolide antagonist 1, discovered during a screen of our chemical repository, was compared to a macrocyclic peptide antagonist 2 using molecular modeling, thus providing a model for the design of more potent antagonists. Medicinal chemistry efforts to find a replacement for cladinose at position 3 of the erythronolide core provided a series of oxazolidinone carbamates that were equally as active as the cladinose-containing parent macrolides. The descladinose LHRH antagonist 14 has 1-2 nM affinity for both rat and human LHRH receptors and is a potent inhibitor of LH release (pA2 = 8.76) in vitro. In vivo, 14 was found to produce a dose-dependent suppression of LH in male castrate rats via both i.v. and p.o. dosing.     

Quantitative gene expression analysis in a nonhuman primate model of antibiotic-induced nephrotoxicity

Gene expression patterns using microarrays have been described for rodent models of nephrotoxicity. To determine if significant gene expression changes previously identified have application across multiple species, we studied quantitative gene expression changes in the kidneys of female cynomolgus monkeys after exposure to two nephrotoxicants. Animals were dosed with the aminoglycoside gentamicin (10 mg/kg), the experimental oligosaccharide antibiotic everninomicin (30 or 60 mg/kg), or a combination of gentamicin (10 mg/kg) and everninomicin (30 mg/kg) for 7 days. Monkeys receiving these drugs in combination developed renal lesions as early as Day 1. By Day 7, monkeys dosed with 60 mg/kg everninomicin alone also developed renal lesions, while the group exposed to both compounds had more extensive renal damage. The modulation of several genes previously reported to be associated with nephrotoxicity in rodent models was confirmed using quantitative real-time PCR. Among these, waf-1, matrix metalloproteinase-9, and vimentin exhibited changes consistent with the definition of a genomic indicator of toxicity. In addition, we identified three early gene biomarkers that may be predictive of drug-induced nephrotoxicity: clusterin, osteopontin, and hepatitis A virus cellular receptor-1. Logistic regression demonstrated a high degree of correlation between changes in gene expression and the probability of the development of histopathologic lesions. These results are the first confirming rodent gene expression changes associated with nephrotoxicity in a nonhuman primate model and provide preliminary evidence for identifying early gene expression changes predicting the onset of drug-induced renal tubular damage in cynomolgus monkeys.