Tip-loaded dissolving microneedles for transdermal delivery of donepezil hydrochloride for treatment of Alzheimer's disease.

Donepezil hydrochloride (DPH) is often used in the treatment of Alzheimer's disease. A new treatment method was developed by encapsulating high DPH content in the tips of dissolving microneedles for rapid, transdermal delivery of a predetermined dose of DPH. The microneedles were prepared by a micromolding method using a hydroxy-propyl-methyl-cellulose (HPMC)-ethanol/water mixture (80:20, v/v) for the tips and carboxy-methyl cellulose (CMC)-water for the base of the needles. The micromolding method involved centrifuging a DPH-HPMC-ethanol/water mixture at 10°C to obtain tips with sufficient mechanical strength. To test their mechanical strength, microneedles with different DPH content were inserted into porcine skin. Then the amount of DPH encapsulated in the microneedles was measured using high-performance liquid chromatography. The efficiency of administering DPH tip-loaded microneedles was investigated using four administrations of a pharmacokinetic test: (1) two oral administration groups (283µg/kg and 692µg/kg) and (2) two microneedle administration groups (283µg/kg and 692µg/kg). High DPH content (up to 78%, w/w) was encapsulated in the microneedle tips without serious loss of mechanical strength by using a mixture of hydroxy-propyl-methyl-cellulose (HPMC) and ethanol/water mixture (80:20, v/v). Because of the distribution of DPH in the tips, 95% of the DPH was delivered into porcine skin after 5min of insertion. As measured by Cmax and AUC, transdermal delivery of DPH tip-loaded microneedles was more effective compared to oral administration of the same dose of DPH. Transdermal delivery could replace oral administration of DPH.

Correlation between midthigh low-density muscle and insulin resistance in obese nondiabetic patients in Korea.

OBJECTIVE: We investigated the link between lipid-rich skeletal muscle, namely low-density muscle, and insulin resistance in Korea. RESEARCH DESIGN AND METHODS: Abdominal adipose tissue areas and midthigh skeletal muscle areas of 75 obese nondiabetic subjects (23 men, 52 women; mean age +/- SD, 41.9 +/- 14.1 years) were measured by computed tomography (CT). The midthigh skeletal muscle areas were subdivided into low-density muscle (0 to +30 Hounsfield units) and normal-density muscle (+31 to +100 Hounsfield units). The homeostasis model assessment (HOMA) score was calculated to assess whole-body insulin sensitivity. RESULTS: The abdominal visceral fat area and the midthigh low-density muscle area were found to be well correlated with the HOMA score (r = 0.471, P < 0.01 and r = 0.513, P < 0.01, respectively). The correlation between low-density muscle area and insulin resistance persisted after adjusting for BMI or total body fat mass (r = 0.451, P < 0.01 and r = 0.522, P < 0.01, respectively) and even after adjusting for abdominal visceral fat area (r = 0.399, P < 0.01). CONCLUSIONS: The midthigh low-density muscle area seems to be a reliable determinant of insulin resistance in Korean obese nondiabetic patients.

Inhibitory action of minocycline on lipopolysaccharide-induced release of nitric oxide and prostaglandin E2 in BV2 microglial cells.

Microglia are the major inflammatory cells in the central nervous system and become activated in response to brain injuries such as ischemia, trauma, and neurodegenerative diseases including Alzheimer's disease (AD). Moreover, activated microglia are known to release a variety of proinflammatory cytokines and oxidants such as nitric oxide (NO). Minocycline is a semisynthetic second-generation tetracycline that exerts anti-inflammatory effects that are completely distinct form its antimicrobial action. In this study, the inhibitory effects of minocycline on NO and prostaglandin E2 (PGE2) release was examined in lipopolysaccharides (LPS)-challenged BV2 murine microglial cells. Further, effects of minocycline on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression levels were also determined. The results showed that minocycline significantly inhibited NO and PGE2 production and iNOS and COX-2 expression in BV2 microglial cells. These findings suggest that minocycline should be evaluated as potential therapeutic agent for various pathological conditions due to the excessive activation of microglia.