Muscone/RI7217 co-modified upward messenger DTX liposomes enhanced permeability of blood-brain barrier and targeting glioma.

Rationale: The dual-targeted drug delivery system was designed for enhancing permeation of the blood-brain barrier (BBB) and providing an anti-glioma effect. As transferrin receptor (TfR) is over-expressed by the brain capillary endothelial (hCMEC/D3) and glioma cells, a mouse monoclonal antibody, RI7217, with high affinity and selectivity for TfR, was used to study the brain targeted drug delivery system. Muscone, an ingredient of traditional Chinese medicine (TCM) musk, was used as the "guide" drug to probe the permeability of the BBB for drug delivery into the cerebrospinal fluid. This study investigated the combined effects of TCM aromatic resuscitation and modern receptor-targeted technology by the use of muscone/RI7217 co-modified docetaxel (DTX) liposomes for enhanced drug delivery to the brain for anti-glioma effect. Methods: Cellular drug uptake from the formulations was determined using fluorescence microscopy and flow cytometry. The drug penetrating ability into tumor spheroids were visualized using confocal laser scanning microscopy (CLSM). In vivo glioma-targeting ability of formulations was evaluated using whole-body fluorescent imaging system. The survival curve study was performed to evaluate the anti-glioma effect of the formulations. Results: The results showed that muscone and RI7217 co-modified DTX liposomes enhanced uptake into both hCMEC/D3 and U87-MG cells, increased penetration to the deep region of U87-MG tumor spheroids, improved brain targeting in vivo and prolonged survival time of nude mice bearing tumor. Conclusion: Muscone and RI7217 co-modified DTX liposomes were found to show improved brain targeting and enhanced the efficacy of anti-glioma drug treatment in vivo.

Muscone Ameliorates LPS-Induced Depressive-Like Behaviors and Inhibits Neuroinflammation in Prefrontal Cortex of Mice.

Depression is partially caused by inflammation in the central nervous system. Early study demonstrated that musk, glandular secretion from male musk deer, exerted an antidepressant-like effect. The aim of this study was to investigate if muscone, a bioactive ingredient in musk, could ameliorate neuroinflammation and depressive-like behaviors as well as explore the potential action mechanism. Mice were intraperitoneally (i.p.) injected with muscone for 2 weeks prior to administration of lipopolysaccharides (LPS, 1mg/kg, i.p.). Pre-treatment with muscone reversed the LPS-induced decrease in body weight within 24h and ameliorated depressive-like behaviors shown by sucrose preference, tail suspension test, and forced swimming test. LPS-induced activation of microglial cells and elevation in expression of inflammatory cytokines including IL-1ß, RANTES, and MCP-1 in the prefrontal cortex of mice were effectively abrogated by muscone, which significantly down-regulated expression of TLR4, MyD88, Caspase-1, NLRP3, renin, and Ang II. In addition, treatment of BV2 microglia cells with muscone markedly attenuated the LPS-induced rise in protein expression of TLR4, Ang II, and IL-1ß. This study revealed that muscone could ameliorate LPS-induced depressive-like behaviors by repressing neuroinflammation in the prefrontal cortex of mice caused by its suppression on microglia activation and production of inflammatory cytokines via acting on TLR4 pathway and RAS cascade.

Self-Assembled Thermoresponsive Nanogels Prepared by Reverse Micelle → Positive Micelle Method for Ophthalmic Delivery of Muscone, a Poorly Water-Soluble Drug.

This study aimed to design a nanocarrier ophthalmic delivery system of muscone, a poorly water-soluble drug. The muscone thermoresponsive nanogels were self-assembled by reverse micelle → positive micelle method. Muscone was demonstrated to have uniform narrow particle size distribution in nanogel by the dynamic light scattering test. The developed nanocomposite hydrogel had a high muscone loading, and the rheology results showed that the phase transition temperature was 34.05°C. Thixotropy test indicated that the nanogel was able to resist the blinking of eyes because of the thixotropy recovery time, which is <5 s. Compared with muscone eye drops, muscone nanogels showed longer retention time on the corneal surface using fluorescent labeling technology and produced a 3.4-fold increase in apparent permeability coefficients (Papp). Draize testing showed that the developed nanogel caused no eye irritation. In vivo pharmacokinetic study indicated that the nanogel could significantly increase the bioavailability of muscone after administration compared with eye drops. These results indicate that self-assembled thermoresponsive nanogel prepared by reverse micelle → positive micelle method has potential for the ophthalmic delivery of poorly water-soluble drugs.

Analgesic and Anti-Inflammatory Properties of Arylnitroalkenes.

In a recent work, we described the design and synthesis of arylnitroalkenes, able to scavenge macrophagederived oxidants, in particular peroxynitrite and peroxynitrite derived radicals. Four compounds emerged as potential leads, 1,1-dimethylamino-4-(2-nitro-1Z-ethenyl)benzene (1), 1,1-dimethylamino-4-(2-nitro-1Z-propenyl)benzene (2), 5- (2-nitro-1Z-ethenyl)benzo[d][1,3]dioxol (3), and 5-(2-nitro-1Z-ethenyl)benzo[d][1,3]dioxol (4). In the present work, the possibility of the preclinical validation of these molecules as anti-inflammatory and analgesic was explored in appropriate in vivo mouse models. Compounds 1, 2 and 4, administered orally as a single dose (30 µmol kg-(1)) to the mice showed anti-inflammatory and analgesic properties similar to classic nonsteroidal anti-inflammatory agents. The pharmacological effects were consistent with the inhibitory effect observed on prostaglandin endoperoxide H synthase (PGHS). In fact, both PGHS-1 and PGHS-2 were inhibited by the compounds, with compound 2 being more specific as PGHS-2 inhibitor with a specificity index superior to 70%. Conversely to classical nonsteroidal anti-inflammatory drugs, compound 2 inhibited peroxidase half reaction of the enzyme (IC50 2.3 µM) while the cyclooxygenase activity of hrPGHS-2 remained unchanged. In vitro experiments were reinforced by docking and molecular dynamics simulations showing arylnitroalkene moiety located in the region of the peroxidase active site, competing with the peroxide intermediate. The absence of toxicity and mutagenicity of the compounds was also demonstrated.

[Mechanism research of aromatics borneol and muscone].

OBJECTIVE: To study the effects of borneol and muscone on membrane fluidity, membrane potential, Na+, K(+)-ATPase activity and calcium ions of blood brain barrier (BBB) model cells (MDCK and MDCK-MDR1) for exploring the mechanism of aromatics. METHODS: MDCK and MDCK-MDR1 cells were incubated and the experiment was performed as following. Cells were incubated with aromatic herbs for 3 h. The membrane fluidity were detected by FRAP. The changes of membrane potentials and the concentration of calcium ions were detected by flow cytometer. RESULTS: Borneol (55.6, 111.2 microg/mL) and muscone (8.34, 16.68 microg/mL) significantly enhanced the cell membrane fluidity. Borneol (27.8, 55.6, 111.2 microg/mL) and muscone (4.17, 8.34, 16.68 microg/mL) made the MDCK and MDCK-MDR1 membrane potentials less negative or depolarized. Borneol increased the concentration of intracellular free calcium in MDCK while decreased the concentration of intracellular free calcium in MDCK-MDR1 cells. Muscone increased the concentration of calcium in MDCK and MDCK-MDR1 cells. Na+, K(+)-ATPase activity was significantly increased in borneol and muscone group. CONCLUSION: The regulating effect of membrane fluidity, membrane potential, Na+, K(+)-ATPase activity and calcium ions in MDCK and MDCK-MDR1 cells might be one of the mechanisms of borneol and muscone's BBB opening function.

Administration of BMSCs with muscone in rats with gentamicin-induced AKI improves their therapeutic efficacy.

The therapeutic action of bone marrow-derived mesenchymal stem cells (BMSCs) in acute kidney injury (AKI) has been reported by several groups. However, recent studies indicated that BMSCs homed to kidney tissues at very low levels after transplantation. The lack of specific homing of exogenously infused cells limited the effective implementation of BMSC-based therapies. In this study, we provided evidence that the administration of BMSCs combined with muscone in rats with gentamicin-induced AKI intravenously, was a feasible strategy to drive BMSCs to damaged tissues and improve the BMSC-based therapeutic effect. The effect of muscone on BMSC bioactivity was analyzed in vitro and in vivo. The results indicated that muscone could promote BMSC migration and proliferation. Some secretory capacity of BMSC still could be improved in some degree. The BMSC-based therapeutic action was ameliorated by promoting the recovery of biochemical variables in urine or blood, as well as the inhibition of cell apoptosis and inflammation. In addition, the up-regulation of CXCR4 and CXCR7 expression in BMSCs could be the possible mechanism of muscone amelioration. Thus, our study indicated that enhancement of BMSCs bioactivities with muscone could increase the BMSC therapeutic potential and further developed a new therapeutic strategy for the treatment of AKI.

Grandlure dosage and attraction of boll weevils (Coleoptera: Curculionidae).

The effects of grandlure dosage on of boll weevil, Anthonomus grandis grandis Boheman (Coleoptera: Curculionidae), attraction were assessed. Traps collected more boll weevils under field and laboratory conditions as the amount of grandlure in laminated plastic strips was increased from 0 to 10, 30, and 60 mg. Spreading the point source of the lure by cutting the strip into quarters and positioning each quarter on separate corners of the large capacity trap to create an expanded source for the pheromone plume, however, resulted in fewer trap captures than traps with quartered lures all positioned on a single corner. The large capacity trap with the quartered lure on one corner also caught more weevils than the traps with an intact lure fastened to one corner. Although aging lure strips for three weeks reduced emissions of the four pheromone components and their attractiveness to boll weevils, cutting the aged lure into quarters resulted in greater emissions and attraction than lures that were aged intact or as quarters. Some pheromone components volatilized faster than others, resulting in time-related changes in blend ratios, but the underlying factor in boll weevil attraction to grandlure strips was dosage, the amount of volatilized pheromone available for interacting with an adult boll weevil.

[Study of diffusion of muscone in different inclusion complexes and liposome through mouse (correction of rat) skin in vitro].

OBJECTIVE: To compare the penetrating rate of muscone in different inclusion complexes and liposome. METHOD: The transdermal effect of muscone in different inclusion complexes and liposome was studied comparatively on mouse [corrected] skin with 40% EtOH as the absorption solution and with an improved Franz diffuse cell. RESULT: Among the different inclusion complexes and liposome, the penetrating rate of muscone in the HP-beta-cyclodextrin inclusion and the liposome were higher than muscone, and that of muscone in the beta-cyclodextrin inclusion is the lowest. CONCLUSION: The HP-beta-cyclodextrin inclusion and the liposome can hence the muscone transdermal speed.

Psychological effects of musky compounds: comparison of androstadienone with androstenol and muscone.

Previously, we have shown that delta4,16-androstadien-3-one modulates psychological state, reducing negative mood and increasing positive mood (Jacob and McClintock, 2000; Jacob et al., 2001a). In order to determine whether similar musky compounds also produce these effects, we compared the effects of androstadienone to those of androstenol and muscone, measuring the psychological states of 37 participants. Androstenol and muscone were chosen because they too have a musky odor at high concentrations, while androstenol is a steroid like androstadienone and muscone is not. In a controlled laboratory setting, we conducted a double-blind, within-subject, repeated-measures experiment counterbalanced for order of presentation. Under each participant's nose, a nanomolar amount of each compound was presented, masked by clove oil to minimize perceptible olfactory differences. Participants completed a baseline psychological battery and twice again at 25-min intervals after exposure. Androstadienone's effects on psychological state were unique in comparison with those of androstenol and with muscone. Exposure through passive inhalation, rather than dermal contact, was sufficient for these effects. Although this is additional evidence that androstadienone may be a pheromone, it is yet to be determined whether humans exude concentrations into the air adequate for social communication or process this chemical information within natural social contexts.

An examination of the interactions between the antinociceptive effects of morphine and various mu-opioids: the role of intrinsic efficacy and stimulus intensity.

UNLABELLED: We examined the effects of several opioids that vary in intrinsic efficacy at the mu-opioid receptor alone and in combination with morphine in a rat warm water tail withdrawal procedure using 50 degrees C and 52 degrees C water (i.e., low- and high-stimulus intensities). Morphine, levorphanol, dezocine, and buprenorphine produced dose-dependent increases in antinociception using both stimulus intensities. Butorphanol produced maximal levels of antinociception at the low, but not at the high, stimulus intensity, whereas nalbuphine failed to produce antinociception at either stimulus intensity. For cases in which butorphanol and nalbuphine failed to produce antinociception alone, these opioids dose-dependently antagonized the effects of morphine. When levorphanol, dezocine, and buprenorphine were combined with morphine, there was a dose-dependent enhancement of morphine's effects. Similar effects were obtained at the low-stimulus intensity when butorphanol was administered with morphine. In most cases, the effects of these combinations could be predicted by summating the effects of the drugs when administered alone. These results indicate that the level of antinociception produced by an opioid is dependent on the intrinsic efficacy of the drug and the stimulus intensity. Furthermore, the level of antinociception produced by the opioid, not necessarily the opioids' intrinsic efficacy, determines the type of interaction among opioids. IMPLICATIONS: Compared with high-efficacy opioids, lower efficacy opioids produce lower levels of pain relief, especially in situations of moderate to severe pain. When opioids are given in combination, the effects can only be predicted on the basis of the antinociception obtained when the drugs are administered alone.

Single- and multiple-dose pharmacokinetics of dezocine in patients with acute or chronic pain.

The pharmacokinetic properties of dezocine were examined in 15 patients with acute or chronic pain. In 3 groups of 5 patients each, serum levels were determined at various intervals after single intravenous doses of 5, 10, and 20 mg. After these single doses, dezocine was very rapidly distributed (mean t1/2 alpha less than 2 minutes), and then rather rapidly eliminated (mean t1/2 beta about 4 hours); the apparent volume of distribution was large (mean Vz beta about 6 L/kg) as was the total clearance (mean CL about 1.5 L/h/kg). In 2 groups of 5 patients each, serum levels were determined after the first and third of 3 intravenous doses of 5 or 20 mg given at 3-hour intervals. The pharmacokinetic parameters after these multiple doses were consistent with those after the single doses. Although some observations were suggestive, there was no unequivocal evidence that the pharmacokinetics were dose-related. In 7 serum samples containing dezocine at concentrations ranging from 12.8 to 522 ng/mL, the mean (+/- SE) proportion of dezocine bound to protein was 91.6 +/- 0.8%.

Serial intravenous doses of dezocine, morphine, and nalbuphine in the management of postoperative pain for outpatients.

Adult patients who had arthroscopic surgery under general anesthesia and requested postoperative pain relief were randomized to receive treatment in a double-blind protocol with 5 mg of intravenous dezocine (20 patients), morphine (22 patients), nalbuphine (18 patients), or saline (24 patients). At 10-min intervals, starting with the first dose of analgesic, patients could choose up to three additional doses of the primary treatment, or choose an alternative analgesic if the primary drug was unsatisfactory. One to four doses of morphine were given as the alternate treatment if the initial treatment was dezocine or nalbuphine, and one to four doses of dezocine were given if the initial treatment was saline or morphine. The proportion of patients treated successfully by the initial treatments (i.e., not requesting alternate treatment), with P value for difference from placebo treatment, were saline 25%, nalbuphine 33% (P = 0.048), morphine 54% (P = 0.04), and dezocine 75% (P = 0.003). Dezocine and morphine are more efficacious than nalbuphine in the management of early postoperative pain. As an alternate analgesic in this study, dezocine required fewer doses to achieve patient satisfaction and was thus more efficacious than morphine. The incidence of treatment-related, adverse effects was different from that of saline or other treatments only for nalbuphine-related pain or burning on injection and dezocine-related facial itching. With respect to analgesic actions and side effects, dezocine seems more like morphine than nalbuphine.

Repeated intrathecal injections of dezocine produce antinociception without evidence for neurotoxicity in the rat: a study of morphometric evaluation of spinal cord histology.

This study was designed to determine the antinociceptive and spinal cord histologic effects of a new agonist/antagonist opioid drug dezocine. This drug was injected intrathecally in rats at a dose of 50 or 125 micrograms twice daily for 14 days. The tail-flick test showed that the antinociceptive effect declined gradually, with no detectable effects by day 14. Quantitative histologic techniques and light and electron microscopy showed that neither dose, compared with vehicle, created any morphologic changes in the spinal cord that could be attributed to a neurotoxic or otherwise degenerative effect of the drug. In conclusion, dezocine is a drug that gives rise to sustained antinociceptive effects when administered intrathecally and causes no morphologic changes in the rat spinal cord that could be indicative of neurotoxic potential.

Inhalation kinetics of C6 to C10 aliphatic, aromatic and naphthenic hydrocarbons in rat after repeated exposures.

The toxicokinetic properties of C6 to C10 n-alkanes, aromates and naphthenes have been investigated in rats during inhalation of 100 p.p.m. of the single hydrocarbons for 3 days, 12 hr/day. The concentration of hydrocarbon was measured by head space gas chromatography in blood, brain, liver, kidneys and perirenal fat at days 1, 2 and 3, immediately after termination of exposure and 12 hr after exposure on day 3. The main conclusions drawn from the study were: a) Aromatic hydrocarbons show high concentrations in blood and low concentrations in organs. b) Naphthenic hydrocarbons show low concentrations in blood and high concentrations in organs. c) n-Alkanes show very low concentrations in blood, relatively high concentrations in brain and a high potential for accumulation in fat with repeated exposures. d) Biological concentrations of hydrocarbons within one class increase in general with increasing molecular weight, though with specific exceptions. e) Accumulation is obviously influenced by differences in metabolism and enzyme induction potential. f) Lipid solubility is not the only parameter relevant for the evaluation of hydrocarbon accumulation.

Toxicity of chronic spinal analgesia in a canine model: neuropathologic observations with dezocine lactate.

The chronic spinal toxicity of dezocine lactate was investigated in mongrel dogs. Dogs received chronic intrathecal infusion from implanted infusion pumps for 28-136 days. Infusion of saline via intrathecal catheters produced leptomeningeal fibrosis, sometimes with spinal cord compression. Dezocine lactate infusion, in addition to similar leptomeningeal changes, was also associated with severe parenchymal lesions in all cases. The exact cause of this toxicity cannot be specifically assigned; potential contributing factors include catheter-induced reaction, pH of the drug, lactate concentration, osmolality and the pharmacologic agent itself. Leptomeningeal reaction in control dogs limits the value of chronic intrathecal dog models for assessment of spinal drug toxicity.

Comparison of intramuscular dezocine with butorphanol and placebo in chronic cancer pain: a method to evaluate analgesia after both single and repeated doses.

Sixty hospitalized subjects with chronic moderate to severe pain as a result of advanced cancer were enrolled in a randomized, parallel, double-blind trial comparing single doses and multiple doses of intramuscular dezocine (10 mg) with butorphanol (2 mg) and placebo. During the initial 6-hour efficacy evaluation, analgesia was measured using verbal and visual scriptors and vital signs, and acute toxicity information was recorded. Subjects with initial pain relief entered the 7-day multidose portion of the trial, and efficacy and toxicity data were recorded daily. After the initial dose the peak analgesia of the active agents was similar, but the duration of analgesia was longer with dezocine. After multiple doses, dezocine was superior to butorphanol in terms of length of treatment. Dezocine had less toxicity than had butorphanol after both single and repeated doses, further suggesting that dezocine may be beneficial in managing chronic cancer pain. The described study design is unique in that it compares the analgesic efficacy and toxicity of several analgesics with placebo after both single and multiple doses in the same subject. This method may prove to be an alternative pain model to evaluate chronic cancer pain.

Postoperative pain relief: a double-blind comparison of dezocine, butorphanol, and placebo.

The safety and efficacy of single intramuscular doses of dezocine (10 or 15 mg) were compared with butorphanol (2 mg) and placebo in 157 patients with moderate to severe postoperative pain. A verbal pain intensity scale, an analog pain intensity scale, and a verbal pain relief scale were used to record the patients' subjective assessments. The results of this study indicate that a single 10 or 15 mg intramuscular injection of dezocine is safe and more effective than placebo for four to six hours, respectively, in the treatment of moderate to severe postoperative pain (P less than .05). During the first hour of treatment the pain relief afforded by 2 mg of butorphanol was significantly greater than that afforded by 10 mg of dezocine (P less than .05), but both doses of dezocine provided long-lasting relief. The scores on all three efficacy scales were highest with the 15 mg dose of dezocine after the first hour, while the 10 mg dose of dezocine and butorphanol were compared during this period. Nausea and vomiting were the most commonly reported side effects; injection site reactions were reported more frequently in the butorphanol group.

Pharmacokinetics of dezocine, a new analgesic: effect of dose and route of administration.

The pharmacokinetics of intravenous (IV) dezocine, and bioavailability of intramuscular (IM) and subcutaneous (SQ) dezocine, were evaluated in healthy male volunteers. Elimination half-life following 5, 10, and 20 mg IV doses averaged 2.6-2.8 h, and was independent of dose. Clearance decreased slightly, although significantly, with dose. After Deltoid IM injection, dezocine was rapidly absorbed (peak level: 0.6 h after dose), with bioavailability 97%. Thus dezocine has extensive distribution, high clearance and short half-life over a range of IV doses. It is rapidly and completely absorbed following IM or SQ administration.

The metabolic disposition of dezocine in rhesus monkeys and female rats given 14C-dezocine intragastrically.

The metabolic disposition of 14C-dezocine has been investigated in male rhesus monkeys and female rats given intragastric 1- and 5- mg/kg doses, respectively. In both species the dose appeared to be rapidly and extensively absorbed. Concentrations of radioactivity were detected in monkey plasma 15 min after drug administration (the earliest sampling time) and reached a peak between 0.5 and 2 hr, whereas in the rat, high concentrations of radioactivity were detected in plasma and most tissues at 15 min. Biliary secretion was extensive in the monkey, but in the monkey as well as in the rat, the ultimate excretion of the radioactive dose was primarily through renal elimination. Tissue uptake of unconjugated drug was extensive in both species, and concentrations of drug in brain were substantially higher than those in plasma. Metabolism was mainly by glucuronidation in both species and also by sulfate formation in the female rat. Two minor imine metabolites produced by N-oxidation were indicated after a comparison with synthetic standards.