A Novel Faster-Acting, Dry Powder-Based, Naloxone Intranasal Formulation for Opioid Overdose.

OBJECTIVE: To examine the pharmacokinetics and safety of FMXIN001, a new intranasal powder-based naloxone formulation, in comparison to Narcan® nasal liquid spray. METHODS: FMXIN001, was developed by blending drug microspheres with larger lactose monohydrate particles, that serve as diluent and carrier, as well as a disaggregating agent. Scanning electron microscopy and X-ray were used to characterize the formulation and in vitro deposition was investigated using a nasal cast. We compared the pharmacokinetics and safety of FMXIN001 versus Narcan® in two clinical trials: a pilot study with 14 healthy adults and a pivotal trial in 42 healthy adults (NCT04713709). The studies were open-label, single-dose, randomized, two-period, two-treatment, two-sequence crossover studies to assess the pharmacokinetics and safety of FMXIN001 versus Narcan® nasal spray. RESULTS: FMXIN001 comprises naloxone microspheres (5-30 µM) and lactose particles (40-240 µM). Upon in vitro testing, naloxone deposits mainly to the middle turbinates region and the upper part of the nasal cavity of a nasal cast. In human subjects, FMXIN001 produced significantly higher exposure at the initial time points of 4, 10, and 30 min, post-administration, compared to Narcan®. Both treatments were safe and well tolerated. FMXIN001, powder-based spray, results in similar overall exposure to Narcan®, but with more rapid absorption in the first 30 min. CONCLUSIONS: FMXIN001 is expected to have a shorter onset of action for a more effective therapeutic intervention to manage opioid overdose. Rapid administration of naloxone in cases of opioid overdose is imperative, given the alarming increase in mortality rates.

Fast Acting, Dry Powder, Needle-Free, Intranasal Epinephrine Spray: A Promising Future Treatment for Anaphylaxis.

BACKGROUND: Epinephrine intramuscular (IM) autoinjector is a life-saving drug for the emergency treatment of immediate-type allergic reactions (type I). Nevertheless, it is sometimes applied incorrectly or underused because of short shelf life, high costs, fear of use, or inconvenience of carrying. FMXIN002, a nasal powder spray of epinephrine, was developed as a needle-free alternative. OBJECTIVE: To compare epinephrine pharmacokinetics, pharmacodynamics, and safety after the administration of the FMXIN002 nasal spray versus autoinjector. METHODS: An open-label trial was performed in 12 adults with seasonal allergic rhinitis without asthma. Epinephrine pharmacokinetics, pharmacodynamics, and safety were compared between FMXIN002 (1.6 mg and 3.2 mg) administered intranasally with/without a nasal allergen challenge and IM (0.3 mg) EpiPen. RESULTS: FMXIN002 3.2 mg, administered after a nasal allergen challenge, displayed a shorter Tmax than EpiPen (median: 2.5 minutes vs 9.0 minutes, statistically nonsignificant [NS]) and a significantly shorter time when the measured analyte concentration is 100 pg/mL during the absorption phase pg/mL (median: 1.0 minutes vs 3.0 minutes for FMXIN002, P < .02). Moreover, FMXIN002 3.2 mg administered after the challenge test has resulted in a doubling of the maximal measured plasma analyte concentration over the sampling period (1110 vs 551 pg/mL, NS); area under the curve from 0 to 8 hours was 56% higher (672 vs 431 hours pg/mL, compared with EpiPen, NS). Pharmacodynamic response was comparable at all treatments. FMXIN002 was well tolerated, and treatment-emergent adverse events (AEs) were mild, local, and resolved spontaneously. No AEs were reported after the administration of EpiPen in our study. FMXIN002 was stable for 2 years at room temperature conditions. However, variability in the pharmacokinetics (expressed in coefficient of variation) is high. Having a prior nasal allergen challenge results in a substantial increase and speed of absorption. CONCLUSIONS: Intranasal absorption of dry powder epinephrine is faster than EpiPen offering a clinical advantage in the short therapeutic window for the treatment of anaphylaxis. The FMXIN002 product offers a needle-free, pocket-size, safe, user-friendly, and stable alternative to epinephrine autoinjectors.

Backbone cyclic peptidomimetic melanocortin-4 receptor agonist as a novel orally administrated drug lead for treating obesity.

The tetrapeptide sequence His-Phe-Arg-Trp, derived from melanocyte-stimulating hormone (alphaMSH) and its analogs, causes a decrease in food intake and elevates energy utilization upon binding to the melanocortin-4 receptor (MC4R). To utilize this sequence as an effective agent for treating obesity, we improved its metabolic stability and intestinal permeability by synthesizing a library of backbone cyclic peptidomimetic derivatives. One analog, peptide 1 (BL3020-1), was selected according to its selectivity in activating the MC4R, its favorable transcellular penetration through enterocytes and its enhanced intestinal metabolic stability. This peptide was detected in the brain following oral administration to rats. A single oral dose of 0.5 mg/kg in mice led to reduced food consumption (up to 48% vs the control group) that lasted for 5 h. Repetitive once daily oral dosing (0.5 mg/kg/day) for 12 days reduced weight gain. Backbone cyclization was shown to produce a potential drug lead for treating obesity.

Lipid peroxidation by "free" iron ions and myoglobin as affected by dietary antioxidants in simulated gastric fluids.

Grilled red turkey muscle (Doner Kabab) is a real "fast food" containing approximately 200 microM hydroperoxides, homogenized in simulated gastric fluid and oxidized more rapidly at pH 3.0 than at pH 5.0, after 180 min, producing 1200 and 600 microM hydroperoxides, respectively. The effects of "free" iron ions and metmyoglobin, two potential catalyzers of lipid peroxidation in muscle foods, were evaluated for linoleic acid peroxidation at pH 3.0 of simulated gastric fluid. The prooxidant effects of free iron ions on linoleic acid peroxidation in simulated gastric fluid was evaluated in the presence of ascorbic acid. At low concentrations of ascorbic acid, the effects were prooxidative, which was reversed at high concentrations. In the presence of metmyoglobin, ascorbic acid with or without free iron enhanced the antioxidative effect. Lipid peroxidation by an iron-ascorbic acid system was inhibited totally by 250-500 microM catechin at pH 3.0. The catechin antioxidant effect was determined also in the iron-ascorbic acid system containing metmyoglobin. In this system, catechin totally inhibited lipid peroxidation at a concentration 20-fold lower than without metmyoglobin. The ability of catechin to inhibit lipid peroxidation was also determined at a low pH with beta-carotene as a sensitive target molecule for oxidation. The results show that a significant protection was achieved only with almost 100-fold higher antioxidant concentration. Polyphenols from different groups were determined for the antioxidant activity at pH 3.0. The results show a high antioxidant activity of polyphenols with orthodihydroxylated groups at the B ring, unsaturation, and the presence of a 4-oxo group in the heterocyclic ring, as demonstrated by quercetin.

Lipid hydroperoxidase activity of myoglobin and phenolic antioxidants in simulated gastric fluid.

Our recent study demonstrated the potential of gastric fluid at pH 3.0 to accelerate lipid peroxidation and cooxidation of dietary constituents in the stomach medium. Metmyoglobin is known to catalyze the breakdown of lipid hydroperoxides to free radicals, a reaction that could enhance the propagation step and general lipid peroxidation. During this reaction, a part of the free radicals is autoreduced by metmyoglobin. At pH 3.0, metmyoglobin at low concentration was almost 7 x 10(4) times as effective as at pH 7.0 in enhancing the rate of lipid peroxidation. Our study demonstrated that metmyoglobin, at a low concentration (approximately 1:30), as compared with that of the hydroperoxides in the lipid system, worked prooxidatively increasing the amounts of linoleate hydroperoxides. However, at a high concentration (approximately 1:3), metmyoglobin acted antioxidatively and decomposed hydroperoxides, whose concentrations then remained at zero for a long time. Catechin, a known polyphenol, supports the inversion of metmyoglobin catalysis, from prooxidation to antioxidation. The antioxidative activity of the couple metmyoglobin-catechin was better at pH 3.0 than at pH 7.0, indicating that this reaction is more dependent on metmyoglobin than on catechin. During this reaction, catechin or quercetin not only donates reducing equivalents to prevent lipid peroxidation but also prevents the destruction and polymerization of metmyoglobin. The results of this research highlighted the important and possible reactions of heme proteins and polyphenols as couple antioxidants, working as hydroperoxidases or as pseudo-peroxidases. We hypothesize that the occurrence of these reactions in the stomach could have an important impact on our health and might help to better explain the health benefits of including foods rich in polyphenol antioxidants in the meal, especially when consuming red meat.

Lipid peroxidation and coupled vitamin oxidation in simulated and human gastric fluid inhibited by dietary polyphenols: health implications.

The Western diet contains large quantities of oxidized lipids, because a large proportion of the food in the diet is consumed in a fried, heated, processed, or stored form. We investigated the reaction that could occur in the acidic pH of the stomach and accelerate the generation of lipid hydroperoxides and cooxidation of dietary vitamins. To estimate the oxygen content in the stomach after food consumption, oxygen released from masticated bread (20 g) into deoxygenated water (100 mL) was measured. Under these conditions, the oxygen concentration rose by 250 microM and reached a full oxygen saturation. The present study demonstrated that heated red meat homogenized in human gastric fluid, at pH 3.0, generated hydroperoxides and malondialdehyde. The cross-reaction between free radicals produced during this reaction cooxidized vitamin E, beta-carotene, and vitamin C. Both lipid peroxidation and cooxidation of vitamin E and beta-carotene were inhibited at pH 3.0 by red wine polyphenols. Ascorbic acid (44 mg) at a concentration that represented the amount that could be ingested during a meal inhibited lipid peroxidation only slightly. Red wine polyphenols failed to prevent ascorbic acid oxidation significantly but, in conjunction with ascorbic acid, did inhibit lipid peroxidation. In the presence of catechin, a well-known polyphenol found in red wine, ascorbic acid at pH 3.0 works in a synergistic manner preventing lipid peroxidation and beta-carotene cooxidation. The present data may explain the major benefits to our health and the crucial role of consuming food products rich in dietary antioxidants such as fruits, vegetables, red wines, or green tea during the meal.

Antioxidant and prooxidant effects of phenolics on pancreatic beta-cells in vitro.

A number of natural phenolic compounds display antioxidant and cell protective effects in cell culture models, yet in some studies show prooxidant and cytotoxic effects. Pancreatic beta-cells have been reported to exhibit particular sensitivity to oxidative stress, a factor that may contribute to the impaired beta-cell function characteristic of diabetes. The aim of this study was to examine the potential of natural phenolics to protect cultured pancreatic beta-cells (betaTC1 and HIT) from H(2)O(2) oxidative stress. Exposure of cells to H(2)O(2) led to significant proliferation inhibition. Contrary to what one should expect, simultaneous exposure to H(2)O(2) and the phenolics, quercetin (10-100 microM), catechin (50-500 microM), or ascorbic acid (100-1000 microM), led to amplification of proliferation inhibition. At higher concentrations, these compounds inhibited proliferation, even in the absence of added H(2)O(2). This prooxidant effect is attributable to the generation of H(2)O(2) through interaction of the added phenolic compounds with as yet undefined componenets of the culture media. On the other hand, inclusion of metmyoglobin (30 microM) in the culture medium significantly reduced the prooxidant impact of the phenolics. Under these conditions, quercetin and catechin significantly protected the cells against oxidative stress when these components were present during the stress period. Furthermore, significant cell protection was observed upon preincubation of cells with chrysin, quercetin, catechin, or caffeic acid (50 microM, each) prior to application of oxidative stress. It is concluded that provided artifactual prooxidant effects are avoided, preincubation of beta-cells with relatively hydrophobic natural phenolics can confer protection against oxidative stress.

Can apple antioxidants inhibit tumor cell proliferation? Generation of H(2)O(2) during interaction of phenolic compounds with cell culture media.

It has recently been suggested that the ability of apple extracts to inhibit proliferation of tumor cells in vitro may be due to phenolic/flavonoid antioxidants. Our study demonstrates that this inhibition is caused indirectly by H(2)O(2) generated through interaction of the phenolics with the cell culture media. The results indicate that many previously reported effects of flavonoids and phenolic compounds on cultured cells may result from similar artifactual generation of oxidative stress. We suggest that in order to prevent such artifacts, the use of catalase and/or metmyoglobin in the presence of reducing agents should be considered as a method to decompose H(2)O(2) and prevent generation of other reactive oxygen species, which could affect cell proliferation. The use of tumor cells and "nontumor cells" in a bioassay to measure antioxidant activity, in this context, is potentially misleading and should be applied with caution.