Chiral toxicity of muscone to embryonic zebrafish heart.

Musk compounds are often used as to treat heart-related diseases and are widely used in Asia. Muscone is one of the most important physiologically active compounds of natural musk. Muscone is a chiral compound and can be further classified into S-muscone and R-muscone and both are present in synthetic musk. While these two chiral isomers have significant differences in odor properties, their difference in toxicity is still unknown. This study used zebrafish as an animal model to compare cardiac toxicities of S-muscone and R-muscone. Results showed that both compounds were acutely toxic to zebrafish embryos causing mortality, decreased hatching rate, pericardial edema, and decreased heart beat rate. These toxicities were modulated through increased Myh6 and Myh7 mRNA expression, and decreased thyroid genes (Trh, Thrß, and Dio3) expression. R-muscone caused higher toxicity than S-muscone at the same concentration. For safety, the chiral isomer composition of synthetic muscone should be carefully regulated in the future.

Is there enough evidence to classify cycloalkyl amine substituents as structural alerts?

Basic amine substituents provide several pharmacokinetic benefits relative to acidic and neutral functional groups, and have been extensively utilized as substituents of choice in drug design. On occasions, basic amines have been associated with off-target pharmacology via interactions with aminergic G-protein coupled receptors, ion-channels, kinases, etc. Structural features associated with the promiscuous nature of basic amines have been well-studied, and can be mitigated in a preclinical drug discovery environment. In addition to the undesirable secondary pharmacology, α-carbon oxidation of certain secondary or tertiary cycloalkyl amines can generate electrophilic iminium and aldehyde metabolites, potentially capable of covalent adduction to proteins or DNA. Consequently, cycloalkyl amines have been viewed as structural alerts (SAs), analogous to functional groups such as anilines, furans, thiophenes, etc., which are oxidized to reactive metabolites that generate immunogenic haptens by covalently binding to host proteins. Detailed survey of the literature, however, suggests that cases where preclinical or clinical toxicity has been explicitly linked to the metabolic activation of a cycloalkyl amine group are extremely rare. Moreover, there is a distinct possibility for the formation of electrophilic iminium/amino-aldehyde metabolites with numerous cycloalkyl amine-containing marketed drugs, since stable ring cleavage products have been characterized as metabolites in human mass balance studies. In the present work, a critical analysis of the evidence for and against the role of iminium ions/aldehydes as mediators of toxicity is discussed with a special emphasis on often time overlooked detoxication pathways of these reactive species to innocuous metabolites.

Impact of simulated biological aging on physicochemical and biocompatibility properties of cyclic olefin copolymers.

We study the effect of simulated biological aging on the properties of cyclic olefin copolymers and particularly their biocompatibility. Already reported as biocompatible polymers according to ISO/EN 10993 guidelines, COC are good candidates for medical devices. The influence of two major additives (antioxidants and lubricants) was investigated and comparison with non-aging COC was done. Four in vitro simulated biological conditions were tested: 2 extreme pH (1 and 9) to simulate digestive tract environment; THP-1-derived macrophages contact and pro-oxidant medium with hypochlorite solution simulating the oxidative attack during the foreign body reaction. After one month of incubation with the different media at 37 °C, surface topography was studied by atomic force microscopy (AFM) and IR spectroscopy. Extracts of incubated media were also analysed in chromatography to investigate potential degradation products. Cytotoxicity (MTT and LDH) of the materials was evaluated using cell culture methods with L929 fibroblasts. Oxidative stress (ROS and SOD analysis) and two inflammatory biomarkers (Il-6 and TNF-α secretion) were explored on THP-1-derived macrophages in direct contact with aged COC. Surface topography of COC was modified by aging conditions with an influence of antioxidant presence and under some conditions. HPLC analysis realized on freeze-dried solutions issued from the different incubations showed the presence of traces of low molecular weight compounds issued from polyphenolic antioxidant and from COC degradation. GC-MS analysis carried out directly on the different incubated COC, showed no detectable leachable molecules. No cytotoxicity has been observed with the different aged COC. However, results show that the pH environment had an influence on the cytotoxicity tests with a protecting effect of antioxidant presence; and pro-oxidant incubating conditions decreased cellular viability on COC. pH 1 and pH 9 conditions also induced an increase of ROS production which was partially reduced for COC containing an antioxidant or a lubricant. Il-6 production was globally more important for aged COC compared with basal condition and particularly for oxidative simulated environment. Those results indicate that physiological factors like pH or oxidant conditions have an impact on surface topography and on COC interaction with the biological environment but without compromising their biocompatibility. Antioxidant or lubricant presence could modulate these variations pointing out the necessity of a thoroughly investigation for biocompatibility assessment of COC as a component of implantable devices. COCs show a good biocompatibility even after accelerated aging under extreme biological conditions.

Safety evaluation of the temporary consolidant based on a zebrafish embryo model.

Temporary consolidants, such as cyclododecane, menthol, coumarin, and ethyl maltol, are proved to be effective for urgent conservation in archaeological field. However, the safety of these temporary consolidants is still unknown although they are always heavily used in archaeological field. Thus reports on the toxicity of these temporary consolidants are limited. Here, a zebrafish model was used for safety evaluation of these four temporary consolidants. In the present study, four temporary consolidants, including cyclododecane, menthol, coumarin, and ethyl maltol, at different concentrations were incubated with zebrafish embryos, and their biological toxic effects were firstly evaluated. It was shown that embryo exposure to temporary consolidants resulted in an increased mortality and malformation rate, and a decreased hatching rate. The order of embryo toxicity of the four types of temporary consolidants tested was menthol > coumarin > ethyl maltol > cyclododecane. Although the embryo toxicity of cyclododecane was minimal, some studies have indicated that this temporary consolidant could be bioaccumulated. The results also suggested that the zebrafish embryos can serve as a reliable model for the evaluation of embryo toxicity of temporary consolidants, as this model could offer the possibility to perform the rapid, medium throughput, cost-effective analyses.

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.

Biocompatibility assessment of cyclic olefin copolymers: Impact of two additives on cytotoxicity, oxidative stress, inflammatory reactions, and hemocompatibility.

This work reports the biocompatibility evaluation of cyclic olefin copolymers (COC) as candidates for implantable medical devices. The focus was to establish the influence of two major additives (antioxidant and lubricant) on the overall biocompatibility. The cytotoxicity was evaluated according to ISO 10993-5 guidelines using L929 fibroblasts, HUVEC, and THP-1-derived macrophages. Oxidative stress (ROS, GSH/GSSG, and SOD analysis) and pro-inflammatory cytokines (Il-6 and TNF-α secretion) were quantified using THP-1 cells in direct contact with films. Hemocompatibility was assessed through haemolysis testing, dynamic blood coagulation, platelet adhesion, and activation (membranous P-selectin expression). Results show that the different types of COC have successfully passed the in vitro biocompatibility tests. The presence of antioxidant induces however a slight decrease in ROS production in correlation with a high SOD activity and a modification in blood coagulation profile probably linked to antioxidant recrystallization phenomenon on the surface of COC. The lubricant presence reduced haemolysis, fibrinogen adhesion, and platelet activation. Surface nanotopography of COC highlights different types of needles and globules according to the present additive. Those primary results indicate that COC are promising biomaterial. However, additives influenced some biological parameters pointing out the necessity of a global approach of risk analysis for biocompatibility evaluation. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3333-3349, 2017.

Preparation and characterisation of poly p-phenylene-2,6-benzobisoxazole fibre-reinforced resin matrix composite for endodontic post material: a preliminary study.

OBJECTIVES: Currently used fibre-reinforced composite (FRC) intracanal posts possess low flexural strength which usually causes post fracture when restoring teeth with extensive loss. To improve the flexural strength of FRC, we aimed to apply a high-performance fibre, poly p-phenylene-2, 6-benzobisoxazole (PBO), to FRCs to develop a new intracanal post material. METHODS: To improve the interfacial adhesion strength, the PBO fibre was treated with coupling agent (Z-6040), argon plasma, or a combination of above two methods. The effects of the surface modifications on PBO fibre were characterised by determining the single fibre tensile strength and interfacial shear strength (IFSS). The mechanical properties of PBO FRCs were characterised by flexural strength and flexural modulus. The cytotoxicity of PBO FRC was evaluated by the MTT assay. RESULTS: Fibres treated with a combination of Z-6040 and argon plasma possessed a significantly higher IFSS than untreated fibres. Fibre treated with the combination of Z-6040-argon-plasma FRC had the best flexural strength (531.51 ± 26.43MPa) among all treated fibre FRCs and had sufficient flexural strength and appropriate flexural moduli to be used as intracanal post material. Furthermore, an in vitro cytotoxicity assay confirmed that PBO FRCs possessed an acceptable level of cytotoxicity. CONCLUSIONS: In summary, our study verified the feasibility of using PBO FRC composites as new intracanal post material. Although the mechanical property of PBO FRC still has room for improvement, our study provides a new avenue for intracanal post material development in the future. CLINICAL SIGNIFICANCE: To our knowledge, this is the first study to verify the feasibility of using PBO FRC composites as new intracanal post material. Our study provided a new option for intracanal post material development.

Enhancing effect of borneol and muscone on geniposide transport across the human nasal epithelial cell monolayer.

Geniposide is widely used in the treatment of cerebral ischemic stroke and cerebrovascular diseases for its anti-thrombotic and anti-inflammatory effects. Recent studies demonstrated that geniposide could be absorbed promptly and thoroughly by intranasal administration in mice and basically transported into the brain. Here, we explored its transport mechanism and the effect of borneol and muscone on its transport by human nasal epithelial cell (HNEC) monolayer. The cytotoxicity of geniposide, borneol, muscone and their combinations on HNECs was evaluated by the MTT assay. Transcellular transport of geniposide and the influence of borneol and muscone were studied using the HNEC monolayer. Immunostaining and transepithelial electrical resistance were measured to assess the integrity of the monolayer. The membrane fluidity of HNEC was evaluated by fluorescence recovery after photobleaching. Geniposide showed relatively poor absorption in the HNEC monolayer and it was not a P-gp substrate. Geniposide transport in both directions significantly increased when co-administrated with increasing concentrations of borneol and muscone. The enhancing effect of borneol and muscone on geniposide transport across the HNEC may be attributed to the significant enhancement on cell membrane fluidity, disassembly effect on tight junction integrity and the process was reversible. These results indicated that intranasal administration has good potential to treat cerebrovascular diseases.

High-strength poly(para-phenylene) as an orthopedic biomaterial.

Poly(para-phenylene) (PPP) exhibits exceptional mechanical strength, stiffness, toughness, and chemical inertness, although it is not currently used in any biomedical applications. The purpose of this study is to serve as a preliminary investigation into the potential of PPP as a biomaterial in orthopedic load-bearing applications. Nuclear magnetic resonance (NMR) analysis confirmed a polymer structure composed of an aromatic backbone and side groups. Tensile PPP specimens along with samples from several other polymers often used for orthopedic applications were elongated to failure after being soaked in phosphate buffered saline (PBS) for 1 h, 1 day, 1 week, 2 weeks, 1 month, and more than 1 year. Results showed that PBS absorption of the PPP plateaued at 1 week at values of ∼0.7 wt % and remained within one standard deviation when soaked for over 1 year. PBS absorption did not affect elastic modulus (5.0 GPa), yield strength (141 MPa), fracture strength (120 MPa) and strain-to-failure (17%) more than one standard deviation. Zero-to-tension fatigue testing established an endurance limit of approximately 35 MPa, which was relatively insensitive to frequency (1-10 Hz). Eagle's minimum essential medium (MEM) elution assay with fibroblasts confirmed that the PPP was noncytotoxic. Relative to other polymers used for load-bearing biomedical applications, PPP displays promising mechanical properties that remain stable in aqueous solution. Lastly, prototype PPP and polyetheretherketone (PEEK) bone plates were manufactured and tested, with the PPP plate showing a 38% higher maximum tensile load before failure.

Simulation of chemical metabolism for fate and hazard assessment. IV. Computer-based derivation of metabolic simulators from documented metabolism maps.

Computer simulation of xenobiotic metabolism and degradation is usually performed proceeding from a set of expert-developed rules modelling the actual enzyme-driven chemical reactions. With the accumulation of extensive metabolic pathway data, the analysis required to derive such chemical reaction patterns has become more objective, but also more convoluted and demanding. Herein we report on our computer-based approach for the analysis of metabolic maps, leading to the construction of reaction rules statistically suitable for simulation purposes. It is based on the set of so-called bare transformations which encompass all unique reaction patterns as obtained by a heuristically enhanced maximum common subgraph algorithm. The bare transformations guarantee that no existing metabolite is missed in simulation at the expense of an enormous amount of false positive predictions. They are rendered more selective by correlating the generated true and false positives to the locations of typical chemical functional groups in the potential reactants. The approach and its results are illustrated for a metabolic map collection of 15 cycloalkanes.

Fragrance material review on 3-methyl-1-cyclopentadecanone.

A toxicologic and dermatologic review of 3-methyl-1-cyclopentadecanone when used as a fragrance ingredient is presented. 3-Methyl-1-cyclopentadecanone is a member of the fragrance structural group macrocyclic ketones and derivatives. The fragrance ingredient described herein is one of 11 structurally diverse C15, C16 and C17 compounds that include three saturated and eight unsaturated ketones. For the latter, the double bond is not adjacent (in conjugation with) to the ketone group. This review contains a detailed summary of all available toxicology and dermatology papers that are related to 3-methyl-1-cyclopentadecanone and is not intended as a stand-alone document. Available data were evaluated, then summarized, and includes: physical properties, acute toxicity, skin irritation, skin sensitization, phototoxicity, toxicokinetics, repeated dose, and genotoxicity data. A safety assessment of the entire macrocyclic ketones and derivatives will be published simultaneously with this document. Please refer to Belsito et al. (2011) for an overall assessment of the safe use of this material and all macrocyclic ketones and derivatives in fragrances. Belsito, D., Bickers, D., Bruze, M., Calow, P., Dagli, M., Fryer, A.D., Greim, H., Hanifin, J.H., Miyachi, Y., Saurat, J.H., Sipes, I.G., 2011. A Toxicologic and Dermatologic Assessment of Macrocylic Ketones and Derivatives When Used as Fragrance Ingredients.

Increased asthma and respiratory symptoms in children exposed to petrochemical pollution.

BACKGROUND: Epidemiologic studies show statistical associations between levels of air pollutants and respiratory outcomes. OBJECTIVE: We sought to determine the effects of exposure to petrochemical pollution on the respiratory health of children. METHODS: Children aged 6 to 12 years living close to the petrochemical plants in La Plata, Argentina (n = 282), were compared with those living in a region with exposure to heavy traffic (n = 270) or in 2 relatively nonpolluted areas (n = 639). Parents answered a validated questionnaire providing health and demographic data. A random sample (n = 181) had lung function measured. Particulate matter and outdoor and indoor volatile organic compound levels were measured during 4-week study periods and reported as overall means for each study area. RESULTS: Children living near the petrochemical plant had more asthma (24.8% vs 10.1% to 11.5%), more asthma exacerbations (6.7 vs 2.9-3.6 per year), more respiratory symptoms (current wheeze, dyspnea, nocturnal cough, and rhinitis), and lower lung function (>13% decrease in FEV(1) percent predicted) than those living in other regions. Length of residence in the area was a significant risk factor, but age, sex, body mass index, proximity to busy roads and other nonpetrochemical industries, length of breast-feeding, and socioeconomic and demographic characteristics of children or their families were not. CONCLUSION: Exposure to particulate matter and volatile organic compounds arising from petrochemical plants but not from high traffic density was associated ith worse respiratory health in children.

Pollutant emissions from gasoline combustion. 1. Dependence on fuel structural functionalities.

To study the formation of air pollutants and soot precursors (e.g., acetylene, 1,3-butadiene, benzene, and higher aromatics) from aliphatic and aromatic fractions of gasoline fuels, the Utah Surrogate Mechanisms is extended to include submechanisms of gasoline surrogate compounds using a set of mechanism generation techniques. The mechanism yields very good predictions of species concentrations in premixed flames of n-heptane, isooctane, benzene, cyclohexane, olefins, oxygenates, and gasoline using a 23-component surrogate formulation. The 1,3-butadiene emission comes mainly from minor fuel fractions of olefins and cyclohexane. The benzene formation potential of gasoline components shows the following trends as functions of (i) chemical class: n-paraffins < isoparaffins < olefins < naphthalenes < alkylbenzenes < cycloparaffins < toluene; (ii) carbon number: n-butane < n-pentane < n-hexane; and (iii) branching: n-hexane < isohexane < 2,2,4-trimethylpentane < 2,2,3,3-tetramethylbutane. In contrast, fuel structure is not the main factor in determining acetylene formation. Therefore, matching the benzene formation potential of the surrogate fuel to that produced by the real fuel should have priority when selecting candidate surrogate components for combustion simulations.

Beyond TPH: health-based evaluation of petroleum hydrocarbon exposures.

The term "total petroleum hydrocarbons" (TPH) is a widely used, but loosely defined, parameter quantified by a number of different methodologies for expressing the aggregate amount of petroleum hydrocarbon compounds (PHCs) in a sample. Because of the shortcomings associated with comparing data from different methods, and the difficulty of assessing potential toxicities of complex mixtures of hydrocarbons, a new approach at more fully and explicitly defining the PHC composition of samples and predicting human noncancer health risks from those exposures has been developed. This new approach is the subject of this paper. This method can be used to perform site-specific risk assessments or to develop health-based cleanup standards for petroleum hydrocarbons. The technique divides the broad chemical classes of PHC (i.e., saturated versus unsaturated) into subgroups of compounds based on numbers of carbon atoms in the compounds within each subgroup. The mass of compounds in each subgroup is then translated into discrete estimates of health risk for specified exposure scenarios. The subgroups were identified from qualitative and quantitative changes in the nature of noncancer toxicities recorded in the literature. For saturated compounds, toxicity changes as carbon chain length increases (measured by numbers of carbon atoms). A "reference compound" was chosen for each range of compounds, usually because its toxicity was relatively well characterized. A published oral reference dose (RfD) was identified for these compounds, or in the absence of a published value, an oral dose-response value was developed from available toxicity information. For saturated PHCs (alkanes, cycloalkanes, and isoalkanes) the subgroups' reference compounds and assigned toxicity value used are C5 to C8 (n-hexane, 0.06 mg/kg/day); C9 to C18 (n-nonane, 0.6 mg/kg/day); and C19 to C32 (eicosane, 6.0 mg/kg/day). For unsaturated compounds (aromatics), one reference RfD was identified for all compounds: C9 through C32 (pyrene, 0.03 mg/kg/day). Dependent upon the analytical technique used for separation of compounds, the unsaturated alkenes may be grouped and subsequently quantified with either the saturate or unsaturate groups. The implications of possible association with either group and contributions to risk estimates are probably not significant. Alkenes make up a small fraction of most fuel products, and they bear structural similarity to the alkanes and are not particularly toxicologically active. If grouped analytically with the aromatics the alkene contribution to toxicity estimates would likely be minor and not be an underestimate of its true toxicity. The mass of PHC in each segment of a chromatogram is quantified and converted to a medium-specific concentration which is then entered into standard medium intake equations to arrive at a daily dose of PHC. This dose is then used with the toxicity value identified for the particular segment of the chromatogram to derive a hazard quotient. The quotients can then be summed across fractions to yield a total hazard index. The noncancer health risks from the aromatics benzene, toluene, and xylenes are evaluated separately using standard risk assessment techniques.

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.

Ventilatory and analgesic effects of dezocine in humans.

The respiratory depressant and analgesic effects of intravenous dezocine were evaluated in six healthy volunteers. Single 0.15 mg/kg doses were compared with identical amounts of morphine, and the two drugs were given in combination. Five successive 0.15 mg/kg doses of dezocine also were given to identify dose-effect relationships. Respiratory center sensitivity was monitored by carbon dioxide (CO2) rebreathing and mouth occlusion pressure (P0.1) measurement, while analgesia to experimental pain was tested with submaximal tourniquet ischemia. Single 0.15 mg/kg doses of dezocine produced significantly more tolerance to experimental pain and greater respiratory depression than a comparable dose of morphine in the first hour, but effects of both drugs were similar thereafter. Multiple doses of dezocine progressively increased pain tolerance from 46 +/- 14% above control with the first dose to 70 +/- 18% above control with the second dose (cumulative total 0.30 mg/kg). Additional dezocine doses did not result in significantly more analgesia. Depression of CO2 sensitivity followed a similar pattern. Morphine 0.15 mg/kg, when given to subjects who had received a prior dose of dezocine, produced no additional effect beyond that observed with dezocine. With the reverse sequence, dezocine increased the respiratory depression of morphine but also produced a dramatic increment in analgesia, which suggested an additive action. Dezocine is therefore an effective analgesic with morphine-like effects. In human subjects it appears to be a slightly more potent analgesic than morphine in identical clinical doses (0.15 mg/kg). Dezocine is similar to other agonist-antagonist analgesics in that it exhibits a ceiling effect for respiratory depression that parallels its analgesic activity.