Pharmacological effects and mechanisms of muscone.

Musk, the dried secretion from the preputial follicles of the male musk deer (genus Moschus), possesses various pharmacological activities and has been used extensively in traditional Chinese medicine for thousands of years. Muscone is the main active ingredient of musk and exerts pharmacological effects similar to those of musk. Although muscone was notably used to treat various disorders and diseases, such as neurological disorders, chronic inflammation and ischemia-reperfusion injury, most of the mechanisms of the pharmacological action of muscone remain unclear because of slow progress in research before the 21st century. In recent years, the pharmacological activities and mechanisms of muscone have been clarified. The present article summarizes the pharmacological and biological studies on cerebrovascular disease, cardiovascular disease, neurological effects, cancer and others and the associated mechanisms of the action of muscone to date.

Muscone Ameliorates Synaptic Dysfunction and Cognitive Deficits in APP/PS1 Mice.

BACKGROUND: Dysfunction of synaptic plasticity leads to memory impairment in Alzheimer's disease (AD). Muscone (Mus) has shown neuroprotective effects in cerebral ischemic models. However, little is known of Mus effects on AD. OBJECTIVE: To investigate the effects of Mus on memory functions and synaptic plasticity in 6-month-old APP/PS1 double-transgenic mice and explore the potential mechanisms. METHODS: Mus was intraperitoneally injected into APP/PS1 or wild-type mice, and cognitive function was assessed by Novel object recognition and Morris water maze tests. The levels of amyloid-ß (Aß) were evaluated by immunofluorescence staining and ELISA. Synaptic morphology and plasticity were evaluated by Golgi staining and long-term potentiation. Cell viability was examined by Cell Counting Kit-8 assay. The protein levels of histone deacetylase 2 (HDAC2) were accessed by western blotting and Immunofluorescence staining. The protein levels of microtubule associated protein 2 and synaptophysin were analyzed by immunofluorescence staining. The ubiquitination of HDAC2 was examined by co-immunoprecipitation. The interaction of Mus with HDAC2 was predicted by molecular docking analysis. RESULTS: Mus treatment attenuated memory dysfunction, reduced Aß level, and enhanced synaptic plasticity in APP/PS1 mice. In addition, Mus treatment decreased the level of HDAC2 in the hippocampus of APP/PS1 mice and Aß1-42-induced primary neurons, which might be associated with increased HDAC2 ubiquitination induced by HDAC2 and Mus interaction. CONCLUSION: Mus protected against synaptic plasticity and memory impairment in APP/PS1 mice, and enhanced HDAC2 degradation via ubiquitination, indicating that Mus was a potential drug for AD treatment.

Novel preconditioning strategies for enhancing the migratory ability of mesenchymal stem cells in acute kidney injury.

Acute kidney injury (AKI) remains a worldwide public health issue due to its increasing incidence, significant mortality, and lack of specific target-orientated therapy. Developments in mesenchymal stem cell (MSC) research make MSCs a promising candidate for AKI management but relevant clinical trials show confusing results (NCT00733876, NCT01602328). One primary cause of the limited therapeutic effect may result from poor engraftment of transplanted cells. To solve this problem, investigators have developed a series of preconditioning strategies to improve MSC engraftment in animal AKI models. In this review, we summarize these previous studies, providing an integrated and updated view of different preconditioning strategies aimed at promoting the therapeutic effect of MSCs in AKI patients.

Discovery of Potent Benzocycloalkane Derived Diapophytoene Desaturase Inhibitors with an Enhanced Safety Profile for the Treatment of MRSA, VISA, and LRSA Infections.

Blocking the biosynthesis process of staphyloxanthin has emerged as a promising antivirulence strategy. Our previous research revealed that diapophytoene desaturase was an attractive and druggable target against infections caused by pigmented Staphylococcus aureus. Benzocycloalkane-derived compounds were effective inhibitors of diapophytoene desaturase but limited by high hERG (human Ether-a-go-go Related Gene) inhibition activity. Here, we identified a new type of benzo-hepta-containing cycloalkane derivative as diapophytoene desaturase inhibitors. Among the fifty-eight analogues, 48 (hERG inhibition activity, half maximal inhibitory concentration, IC50, of 16.1 µM) and 51 (hERG inhibition activity, IC50 > 40 µM) were distinguished for effectively inhibiting the pigment production of Staphylococcus aureus Newman and three methicillin-resistant Staphylococcus aureus strains, and the four strains were highly sensitize to hydrogen peroxide killing without a bactericidal growth effect. In an in vivo assay, 48 and 51 displayed a comparable effect with linezolid and vancomycin in livers and hearts in mice against Staphylococcus aureus Newman and a more considerable effect against Mu50 and NRS271 with normal administration.

Polycyclic cage structures as lipophilic scaffolds for neuroactive drugs.

Polycyclic cage scaffolds have been successfully used in the development of numerous lead compounds demonstrating activity in the central nervous system (CNS). Several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, and stroke, as well as drug abuse, can be modulated with polycyclic cage derivatives. These cage moieties, including adamantane and pentacycloundecane derivatives, improve the pharmacokinetic and pharmacodynamic properties of conjugated parent drugs and serve as an important scaffold in the design of therapeutically active agents for the treatment of neurological disorders. In this Minireview, we focus on the recent developments in the field of polycyclic cage compounds, as well as the relationship between the lipophilic character of these cage-derived drugs and the ability of such compounds to target and reach the CNS and improve the pharmacodynamic properties of compounds conjugated to it.

Protective effects of muscone on ischemia-reperfusion injury in cardiac myocytes.

ETHNOPHARMACOLOGICAL RELEVANCE: Musk has been traditionally used in Chinese medicine as the main ingredient of many formulations for the treatment of chest pain and angina pectoris. AIM OF THE STUDY: To investigate the protective effects of muscone (the active ingredient of musk) on ischemia-reperfusion (I/R) injury induced by hypoxia and low glucose in primary cultured rat cardiac myocytes. MATERIALS AND METHODS: Primary cultures of neonatal rat cardiac myocytes were subjected to ischemia-reperfusion in media, with or without muscone. Cell viability, release of lactic acid dehydrogenase (LDH), superoxide dismutase (SOD) activity, malondialdehyde (MDA) levels, creatine kinase (CK) and caspase-3 activities, as well as intracellular free Ca(2+) concentrations, were measured. Cellular apoptosis and mitochondrial membrane potential (MMP) were assessed by flow cytometry, and the expression of Bcl-2 and Bax proteins was assessed by Western blotting. RESULTS: Following the exposure of cardiac myocytes to ischemia-reperfusion, there was a marked decrease in pulsating frequency, cell viability, SOD activity, MMP, and the expression of Bcl-2 protein, accompanied by increased LDH release, MDA production, CK and caspase-3 activities, intracellular free Ca(2+) concentrations, rate of apoptosis, and expression of Bax protein. Pretreatment with muscone (0.215, 0.43, 0.86 µg/mL) prior to I/R injury significantly attenuated the above changes. CONCLUSION: Muscone has a protective effect against I/R injury in cardiac myocytes, indicating that muscone may potentially provide therapeutic benefit in I/R injury by inhibiting cellular oxidative stress and apoptosis.

Discovery of novel 1-phenyl-cycloalkane carbamides as potent and selective influenza fusion inhibitors.

A novel class of HA inhibitors (4a) was identified based on ligand similarity search of known HA inhibitors. Parallel synthesis and further structural modifications resulted in 1-phenyl-cyclopentanecarboxylic acid (4-cyano-phenyl)-methyl-amide 4t as a potent and selective inhibitor to phylogenetic H1 influenza viruses with an EC(50) of 98 nM against H1N1 A/Weiss/43 strain and over 1000-fold selectivity against host MDCK cells.

Comparison of the therapeutic effects of different compositions of muskone in the treatment of experimental myocardial infarct in rats and analgesia in mice.

The aim of this study was to compare the therapeutic effects of muskone, a traditional preparation containing slender Dutchmanspipe root (MCS) used to treat angina pectoris and related conditions, muskone containing inula root (MCI) in place of MCS, and muskone (M) without either slender Dutchmanspipe root (S) or inula root (I) on acute myocardial infarct (AMI) in rats and the pain response in mice. The AMI model was established by ligating the left anterior descending coronary artery (LAD). The AMI rats were treated with MCS, MCI, M, S and I, respectively, before the surgical operation. Plasma endothelin (ET), 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)), thromboxane (TXB(2)) and myocardial apoptosis were detected, the ratio of 6-keto-PGF(1alpha) level to TXB(2) level (6-keto-PGF(2alpha)/TXB(2)) was calculated, and the infarct size was determined. In the pain relieving study, the prophylactic treatments with MCS, MCI, M, S, I and aspirin were administered to the mice once a day for 5 days, the response latency and the number of abdominal contractions after the stimulus of intraperitoneal injection of acetic acid were recorded. The results show that MCS, MCI and M significantly ameliorated plasma ET, TXB(2), 6-keto-PGF(1alpha) and 6-keto-PGF(2alpha)/TXB(2) levels, reduced infarct size and opposed myocardial apoptosis. Simultaneously, they also significantly reduced the abdominal contractions and also prolonged the response latency induced by acetic acid in the mice. S and I only showed a degree of relieving pain, but their efficacy was weaker than that of MCS, MCI and M, and they had little cardioprotective effect. In conclusion, MCS, MCI and M had a significant cardioprotective and analgesic effect, and they had similar efficacy. S and I only had a secondary analgesic effect. Removing S from the MCS or replacing S with I did not influence the cardioprotective effect and analgesic effect.

Toward the development of chemoprevention agents. Part 1: Design, synthesis, and anti-inflammatory activities of a new class of 2,5-disubstituted-dioxacycloalkanes.

A new class of 2,5-disubstituted-dioxacycloalkanes were designed and synthesized via stereoselective synthetic method as cancer chemoprevention agents. The anti-inflammatory activities of these compounds were tested using the xylene-induced mouse ear edema model. Some of these compounds exhibited comparable or better anti-inflammatory activities than that of aspirin suggesting that they can be further developed as potential anti-inflammatory drug lead compounds. In addition, treatment of these anti-inflammatory agents did not prolong tail bleeding time in mice. The structure/activity relationships were also analyzed among these compounds.

Stereoselective synthesis and anti-inflammatory activities of 6- and 7-membered dioxacycloalkanes.

A class of 5-trifluoroacetylamino-1,3-dioxacycloalkanes, 5-benzoylamino-1,3-dioxacycloalkanes, and 5-amino-1,3-dioxacycloalkane compounds were stereoselectively synthesized as potential anti-inflammatory drug candidates. The anti-inflammatory activities of these compounds were tested using the xylene-induced mouse ear edema model, from which multiple compounds possessing anti-inflammatory properties which surpass aspirin were identified; these compounds were then compared to establish structure-activity relationships.

Capsaicin-induced hyperalgesia and mu-opioid-induced antihyperalgesia in male and female Fischer 344 rats.

The influence of sex in determining responses to opioid analgesics has been well established in rodents and monkeys in assays of short-lasting, phasic pain. The purpose of this investigation was to use a capsaicin model of tonic pain to evaluate sex differences in hyperalgesia and mu-opioid-induced antihyperalgesia in Fischer 344 (F344) rats. Capsaicin injected into the tail produced a dose-dependent thermal hyperalgesia in males and females, with the dose required to produce a comparable level of hyperalgesia being 3.0-fold higher in males than in females. These sex differences were modulated by gonadal hormones, inasmuch as gonadectomy increased the potency of capsaicin in males and decreased its potency in females. Morphine, buprenorphine, and dezocine administered by various routes [systemic (s.c.), local (in the tail), and central (i.c.v.)] generally produced marked antihyperalgesic effects in males and females. Although in most instances these opioids were equally potent and effective in males and females, selected doses of local and i.c.v. administered buprenorphine produced greater effects in females. When administered locally, the antihyperalgesic effects of morphine were mediated by peripheral opioid receptors in both males and females, since this effect was not reversed by i.c.v. naloxone methiodide. These data contrast with the finding that mu-opioids are more potent in male rodents in assays of phasic pain, thus suggesting that distinct mechanisms underlie male and female sensitivity to opioid antinociception in phasic and tonic pain models. These findings emphasize the need to test male and female rodents in tonic pain assays that may have greater relevance for human pain conditions.

Use of analgesics during propofol sedation: a comparison of ketorolac, dezocine, and fentanyl.

STUDY OBJECTIVE: To evaluate the comparative efficacy and side effect profile of ketorolac 60 mg, dezocine 6 mg, and fentanyl 100 micrograms when used as analgesic supplements to a propofol infusion during monitored anesthesia care (MAC). DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Ambulatory surgery facility at a university medical center. PATIENTS: 80 outpatients undergoing breast biopsy or inguinal herniorraphy procedures under MAC. INTERVENTIONS: All patients received midazolam 2 mg intravenously (IV) followed by 1 ml of the study medication containing either dezocine 3 mg IV, ketorolac 30 mg IV, fentanyl 50 micrograms IV, or normal saline. A propofol infusion was initiated at 75 micrograms/kg/min and then varied to maintain a stable level of sedation (i.e., Observer Assessment of Alertness/Sedation scale score of 3). An additional 1 ml of the same study medication was administered IV 2 to 3 minutes prior to infiltration of the local anesthetic solution. During the operation, supplemental (rescue) medication consisted of fentanyl 25 micrograms IV, bolus injections in all four treatment groups. MEASUREMENTS AND MAIN RESULTS: Propofol infusion and supplemental fentanyl dosage requirements, oxygen saturation values, respiratory rates, recovery times, and postoperative side effects were recorded. Visual analog scales were used to assess sedation, anxiety, pain, and nausea preoperatively (baseline), upon entry into the postanesthesia care unit, and at 30-minute intervals until discharge. The fentanyl and dezocine groups required lower average infusion rates of propofol to maintain a stable level of sedation than the control (saline) group. The saline and ketorolac groups required rescue analgesic medication more frequently and/or larger supplemental dosages of fentanyl than the two opioid analgesic treatment groups. Compared with the three analgesic treatment groups, postoperative pain scores were only marginally higher in the control group. Ketorolac-treated patients had consistently (but not significantly) shorter recovery times to oral intake, ambulation, and discharge than those in the dezocine or fentanyl groups. No postoperative nausea, vomiting, or pruritus was reported in the ketorolac group. CONCLUSION: Compared with ketorolac 60 mg, fentanyl 100 micrograms and dezocine 6 mg produced a greater decrease in the propofol sedation requirement during MAC. However, the use of ketorolac in combination with propofol for MAC was associated with an improved recovery profile.

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.

N6-substituted adenosine receptor agonists: potential antihypertensive agents.

Adenosine is known to exert a wide range of pharmacological effects including hypotension. This effect of adenosine suggested that modified analogues of adenosine might provide useful antihypertensive agents. Thus, we prepared a series of novel N6-benzocycloalkyladenosines and studied their receptor binding and antihypertensive activity. The structure-activity relationship study shows that the adenosine analogues having the hydrophobic phenyl moiety one carbon away from the C6-nitrogen have modest affinity and selectivity for the A1 receptor, whereas those with the phenyl moiety two carbons away from the C6-nitrogen have excellent affinity and selectivity for the A1 receptor. Many of these analogues showed excellent antihypertensive activity with a wide range of effects on heart rate. There is no direct correlation between the receptor binding affinities and antihypertensive activity; however, it is more closely associated with A1 than A2 affinity. The bradycardic effect of these agonists seems to be due to the A1 affinity. From this set, compound 3 was further evaluated in secondary antihypertensive screens. It lowered the blood pressure dose dependently with effects lasting for over 20 h following administration of a 30 mg/kg dose. Compound 3 was also effective in lowering blood pressure in a renal hypertensive rat model. Thus, appropriately modified N6-substituted adenosines represent a novel class of antihypertensive agents.

Dezocine. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy.

Dezocine is an analgesic agent with opioid agonist and antagonist activity. After parenteral administration of therapeutic doses it is approximately equipotent with morphine, and has proved at least as effective an analgesic as morphine, pethidine (meperidine) and butorphanol in moderate to severe postoperative pain. However, preliminary pharmacodynamic data indicate that the ceiling of analgesic activity of dezocine occurs at a higher level of analgesia than that of reference agonist/antagonist agents. Also, the drug exhibited a morphine-like degree of anaesthetic-sparing activity in animals. Although long term data are very limited, single doses of dezocine are well tolerated, with mild and transient sedation and gastrointestinal upset the principal adverse effects. As with some other agonist/antagonist analgesics, a 'ceiling' effect to dezocine-induced respiratory depression occurs with increasing dosage, beyond which further depression has not been observed. In single analgesic doses, however, dezocine is a slightly more potent respiratory depressant than morphine. Clinically important haemodynamic changes have not been observed with usual analgesic doses of dezocine. As an agonist/antagonist opioid, the dependence liability of dezocine would be expected to be lower than that of pure agonist opioids, but extended clinical use is required before more definitive conclusions can be drawn in this regard. Unlike older drugs of its type, dezocine produced opiate-like subjective effects and was identified as morphine-like by drug abusers. Thus, provided the promising conclusions of currently available clinical studies are confirmed with its wider use, dezocine should be a useful additional agent for the treatment of moderate to severe postoperative pain.

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.

Intravenous dezocine for postoperative pain: a double-blind, placebo-controlled comparison with morphine.

Dezocine, a new mixed agonist-antagonist opioid analgesic, and morphine were compared in a double-blind study in 206 patients with postoperative pain. The analgesic efficacy of single intravenous injections of dezocine (2.5, 5.0, and 10.0 mg), morphine (5.0 mg), and placebo was assessed by verbal and visual scales at regular intervals for six hours after administration. All active treatments provided greater pain relief than placebo. Pain relief with dezocine 5 and 10 mg was significantly greater (P less than .05) than with placebo for up to four and five hours, respectively, and with morphine up to one hour. Pain relief scores were significantly higher (P less than .05) with morphine than with placebo at all observations except that of the fifth hour, and higher with dezocine 2.5 mg than with placebo for the first 30 minutes. Doses of 5 and 10 mg of dezocine produced approximately the same peak analgesic effect, with the larger dose having a longer duration of effect. All active treatments produced mild to moderate sedation. Side effects were few and mild or moderate with all of the treatments. The physician's and the patients' evaluations favored dezocine in a dose-dependent order, with morphine 5 mg rated lower than dezocine 5 mg and higher than dezocine 2.5 mg.