Drug release from HPMC matrices in milk and fat‐rich emulsions

“Biorelevant” media for the fed stomach, including fat emulsions, are routinely used during in vitro testing of solid dosage forms. However, their complexity undoubtedly creates difficulties in identifying factors which affect drug release. Here, we show fats can directly influence drug release from hydroxypropyl methylcellulose (HPMC; Methocel K4M) matrices which are often subjected to biorelevant testing. Model fat systems included milk (0.1%–3.5% fat) and the parenteral emulsion Intralipid® (20%–30% fat). The matrix showed good extended‐release properties for at least 12 h in these media (USP‐1/USP‐4), but at the highest fat concentration, release was retarded and shifted towards zero‐order release. Confocal imaging studies using a water‐soluble (fluorescein) and fat‐soluble (Nile red) fluorophore provided evidence of phase separation of Intralipid® at the surface of the emerging gel. Combined magnetic resonance imaging–USP‐4 drug release testing provided further evidence for deposition of fat on the tablets. We propose that the aqueous portion of the emulsion is removed by the hydrating matrix, causing coalescence and deposition of a fat layer at the surface, and these deposits cause slower drug release by reducing the matrix surface area available for release. Therefore, there is a risk of a direct interaction between fat emulsions and HPMC tablets, with resultant effects on drug release in vitro. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4823–4835, 2011     

Prevention of carcinogenesis and inhibition of breast cancer tumor burden by dietary stearate

Previous studies have shown that stearate (C18:0), a dietary long-chain saturated fatty acid, inhibits breast cancer cell neoplastic progression; however, little is known about the mechanism modulating these processes. We demonstrate that stearate, at physiological concentrations, inhibits cell cycle progression in human breast cancer cells at both the G(1) and G(2) phases. Stearate also increases cell cycle inhibitor p21(CIP1/WAF1) and p27(KIP1) levels and concomitantly decreases cyclin-dependent kinase 2 (Cdk2) phosphorylation. Our data also show that stearate induces Ras- guanosine triphosphate formation and causes increased phosphorylation of extracellular signal-regulated kinase (pERK). The MEK1 inhibitor, PD98059, reversed stearate-induced p21(CIP1/WAF1) upregulation, but only partially restored stearate-induced dephosphorylation of Cdk2. The Ras/mitogen-activated protein kinase/ERK pathway has been linked to cell cycle regulation but generally in a positive way. Interestingly, we found that stearate inhibits both Rho activation and expression in vitro. In addition, constitutively active RhoC reversed stearate-induced upregulation of p27(KIP1), providing further evidence of Rho involvement. To test the effect of stearate in vivo, we used the N-Nitroso-N-methylurea rat breast cancer carcinogen model. We found that dietary stearate reduces the incidence of carcinogen-induced mammary cancer and reduces tumor burden. Importantly, mammary tumor cells from rats on a stearate diet had reduced expression of RhoA and B as well as total Rho compared with a low-fat diet. Overall, these data indicate that stearate inhibits breast cancer cell proliferation by inhibiting key check points in the cell cycle as well as Rho expression in vitro and in vivo and inhibits tumor burden and carcinogen-induced mammary cancer in vivo.     

Presynaptic α₂-adrenoceptors control the inhibitory action of presynaptic CB₁ cannabinoid receptors on prefrontocortical norepinephrine release in the rat

Endocannabinoids play a crucial neuromodulator role in both physiological and pathological states in various brain regions including the prefrontal cortex (PFC). We examined, whether presynaptic cannabinoid receptors are involved in the modulation of basal and electrical field stimulation-evoked [³H]norepinephrine ([³H]NE) release from rat PFC slices. WIN55,212-2, a nonselective CB₁ receptor (CB₁R) agonist, inhibited the electrical stimulation-evoked efflux of [³H]NE in a concentration-dependent fashion, which was antagonized by the CB₁R antagonist/inverse agonist, AM251 (1 μM). Idazoxan, a selective α₂-adrenoceptor antagonist, augmented the evoked [³H]NE release. In the presence of idazoxan, the effect of WIN55,212-2 was exacerbated or attenuated, depending on the applied concentration and stimulation frequency. Moreover their combined, but not individual application elicited a depressive-like phenomenon in the forced-swim test. These data were bolstered with fluorescent and confocal microscopy analysis, which revealed that CB₁R immunoreactivity co-localized with dopamine-β-hydroxylase positive (i.e. noradrenergic) fibers and the inhibitory α_2A adrenergic autoreceptors (α_2AR) in the PFC. Furthermore, idazoxan triggered a decrease in CB₁R density in the PFC, suggesting that high extracellular level of norepinephrine downregulates CB₁Rs.     

Glucocerebrosidase mutations do not cause increased Lewy body pathology in Parkinson's disease

Mutations in the glucocerebrosidase (GBA) gene have been implicated in increased formation of Lewy bodies (LBs) in Parkinson's disease (PD). We found GBA mutation status not to be significantly associated with the density of cortical LBs, after adjusting for sex, age at death, duration of PD and presence of dementia. Comparison of GBA carriers to PD controls found no difference in Alzheimer's disease pathological findings. Our results do not support GBA carriers to have a more advanced neuropathologic disease i.e. increased density of protein aggregates.     

Liraglutide: once-daily GLP-1 agonist for the treatment of type 2 diabetes

What is known and Objective: The prevalence of diabetes is increasing worldwide. Over the recent years, new discoveries have led to the development of new pharmacological agents targeting the incretin hormones gastric inhibitory peptide (GIP) and glucagon‐like peptide‐1 (GLP‐1). These agents, called incretin‐mimetics, are the newest agents added to the diabetes treatment options. The purpose of this article is to review the relevant literature on the chemistry, pharmacology, pharmacokinetics, metabolism, clinical trials, safety, drug interactions and place in therapy of liraglutide in the treatment of type 2 diabetes. Methods: An extensive search of the literature was performed with liraglutide and NN2211 as key terms. This article presents a review of the literature related to the chemistry, pharmacology, pharmacokinetics, drug interactions and safety and efficacy of liraglutide. Results and Discussion: Liraglutide, a subcutaneously administered GLP‐1 agonist, displays phamacodynamic and pharmacokinetic properties that allow for once‐daily administration. The agent has been shown to be efficacious as monotherapy, as well as in combination with glimperide, metformin and/or rosiglitazone, reducing glycoslyated haemoglobin (A1C) between 0·84% and 1·5%. The primary adverse event reported with liraglutide is transient nausea. What is new and conclusion: Liraglutide has been well studied in dual and triple combination therapies with sulfonylureas, metformin and rosiglitazone and appears safe and effective. For patients who cannot tolerate first‐line agents, metformin, insulin and sulfonylureas, liraglutide is a reasonable treatment option.     

Gout diagnosis and management: what NPs need to know

Gout is the result of hyperuricemia, from either the body's overproduction or underexcretion. It can result in joint deterioration and destruction when improperly managed. Because primary care providers diagnose and treat the vast majority of patients with gout, it is important that they understand current guidelines and evidence-based practice.