An investigation of reliability and validity of the LS/CMI with French offenders.

INTRODUCTION: The Level of Service/Case Management Inventory (LS/CMI) is one of the best-known recidivism risk instruments. In France, this scale is rarely used because no study had yet been carried out to confirm its psychometric properties on samples of French offenders. The aim of this study was to test the psychometric properties of the LS/CMI on samples of violent French prisoners. METHOD: The Level of Service/Case Management Inventory, the BARR-2002R, Historical Clinic Risk-Scale 20 and the Risk for Sexual Violence Protocol were administered to 128 violent offenders. RESULTS-DISCUSSION: The results showed good internal consistency, reliability and convergent validity of the LS/CMI. Assault, robbery and sexual assault were correlated with the LS/CMI. All of these results are discussed and analysed using the international reference literature. CONCLUSION: Confirmation of the psychometric properties of the LS/CMI among French offenders to allow it to be used to assess the risk of recidivism of offenders.

Effectiveness of Selected Air Cleaning Devices During Dental Procedures.

INTRODUCTION: The recent COVID-19 pandemic has underscored the necessity of protecting health care providers (HCPs) against the transmission of infectious agents during dental procedures. To this end, the effectiveness of several air cleaning devices (ACDs) in reducing HCPs exposure to aerosols generated during dental procedures was estimated, separately or in combination with each other. These ACDs were a chairside unit capturing aerosols at the source of generation, and four ambient ACDs: a portable ambient ACD; a negative pressure module; a custom made, fan-operated and wall-mounted air filter (WMAF); and a smaller and passive version of the latter. The last three ACDs were intended for mobile dental clinics (MDCs) only. MATERIALS AND METHODS: This assessment was performed in two different environments: in a dental clinic operatory and in a MDC. Two dental personnel, acting in the roles of dentist and dental assistant, performed on simulated patient aerosol-generating and non-aerosol-generating procedures. For each 5-minute scenario, the cumulative exposure to airborne particulate matter 10 µm in size or smaller (PM10) was determined by calculating the sum of all 1 second readings obtained with personal and ambient air monitors. The effectiveness of the ACDs in capturing PM10 was estimated based on the capability of the ACDs to keep PM10 level at or below the initial background level. RESULTS: In all conditions assessed in the dental clinic operatory, when both the chairside and portable ambient ACDs were functioning, an estimated effectiveness of 100% in capturing PM10 was achieved. In the MDC, in all conditions where the chairside ACD was used without the negative pressure module, an estimated effectiveness of 100% was also achieved. The simultaneous operation of the negative pressure module in the MDC, which led to a room negative pressure of -0.25 inch wc, reduced the chairside ACD's effectiveness in capturing aerosols. Conversely, the use of the WMAF in the MDC in combination with the chairside ACD further reduced exposure to PM10 below the initial background level. Nonetheless, in all conditions assessed in both settings (dental clinic operatory and MDC), larger visible aerosols were produced, often landing on the surrounding environment. A fair portion of these aerosols landed on the inside of the chairside ACD flange. CONCLUSIONS: This assessment suggests that the use of the tested chairside ACD, by capturing aerosols at the source of generation, had the greatest impact on reducing exposure of dental personnel to PM10 produced during dental procedures. This study also indicates that such exposure is further reduced with the addition of an ambient ACD. However, creating a negative pressure room as high as -0.25 inch wc can lead to air turbulence reducing the effectiveness of ACDs in capturing aerosols at the source. Furthermore, the presence of uncaptured droplets and spatter on the surrounding environment supports the need to complement the use of engineering controls with proper administrative controls and personal protective equipment, as recommended by governmental agencies and the scientific community for preventing the transmission of infection in health care settings.

A retrospective cohort study of cancer incidence among patients treated with radiosynoviorthesis.

Radiosynoviorthesis (RS) is an intra-articular injection of a radioactive colloid for the treatment of synovitis administered most often to patients with rheumatoid arthritis or haemophilia. Although highly cost-effective in comparison with surgical or arthroscopic synovectomy, the risk of cancer associated with this treatment is not well known. We evaluated the incidence of cancer in a group of patients treated with RS. A cohort of 2412 adult patients with a variety of underlying conditions (mainly rheumatoid arthritis) and treated with at least one RS between January 1976 and December 2001, was recruited from two centres in Montréal. Cancer incidence and mortality data for cohort members over that time period were obtained from regulatory agencies using linkage. Background rates for all and specific types of cancer were obtained for the provincial (Québec) and national (Canada) population according to age, gender and calendar period categories. Category-specific rates in the cohort were compared with rates in similar categories from the general population generating standardized incidence ratios (SIR). The effects of specific isotope doses and of number of RS treatments were analysed using a Cox-regression model. No increase in the risk of cancer was observed (SIR 0.96; 95% confidence interval 0.82-1.12). There was no dose-response relationship with the amount of radioisotope administered or number of RS treatments. The study provides some indication for the safety of the procedure but homogenous diagnostic groups of younger patients (such as haemophilic patients) receiving RS will need more evaluation.

Intravenous immunoglobulin attenuates airway hyperresponsiveness in a murine model of allergic asthma.

BACKGROUND: Intravenous immunoglobulin (IVIG) has potent anti-inflammatory and immune-modulating properties. IVIG has been utilized as a steroid-sparing agent in severe asthma, but the results of clinical trials have been conflicting. OBJECTIVE: To determine whether IVIG is able to attenuate bronchial reactivity, pulmonary inflammation and T cell function using a murine model of allergic airways disease. METHODS: BALB/c or C57BL/6 mice were sensitized to ovalbumin (OVA) or a phosphate-buffered saline control using local nasal sensitization, and then received five intranasal challenges on days 28-32 before sacrifice. Mice were treated intraperitoneally with either IVIG (1-2 g/kg) or equivalent human serum albumin 24 h before the first OVA challenge. Bronchial reactivity to methacholine was examined using the FlexiVent small animal ventilator. We evaluated pulmonary histology, mRNA from lung digests for T-helper type 2 (Th2)-related genes and bronchoalveolar lavage for cell counts and cytokines. Splenocytes were utilized to study OVA-induced cell proliferation, cytokine production and dendritic cell maturation. RESULTS: IVIG markedly attenuated the perivascular and peribronchial pulmonary inflammation, and decreased bronchial hyperresponsiveness to methacholine. IVIG treatment of splenocytes from sensitized animals diminished cellular proliferation to OVA, whereas IVIG treatment in vivo markedly attenuated OVA-driven splenocyte proliferation. This is accompanied by diminished IL-13 and TNF-α levels in splenocyte culture, decreased expression of Jagged-1, increased Delta-4 and decreased GATA-3 mRNA levels, signs that IVIG has suppressed the expected Th2 response that accompanies repeated allergen exposure. Increased regulatory T cells were found in draining pulmonary lymph nodes in IVIG-treated mice but not in controls. CONCLUSIONS AND CLINICAL RELEVANCE: IVIG was effective in ameliorating allergic airway disease in our model. IVIG may be a promising adjunct therapy requiring further study for patients with severe asthma.

B lymphocytes in inflammatory airway diseases.

B lymphocytes are key players in all facets of adaptive immune responses and are responsible for the production of IgE antibodies, initiators of allergic hypersensitivity reactions. Recent evidence indicates that B cells may be a crucial player in allergic and inflammatory airway pathology, directly populating upper and lower airway tissues. This review examines human and animal studies that directly demonstrated the presence of B lymphocytes in airway tissues and elaborates on their function as antibody-secreting cells, antigen-presenting cells and producers of inflammatory and regulatory cytokines. B lymphocytes appear to contribute to multiple facets of immune homeostasis in inflammatory diseases of the upper and lower airways.

Children with atopic histories exhibit impaired lipopolysaccharide-induced Toll-like receptor-4 signalling in peripheral monocytes.

BACKGROUND: The hygiene hypothesis states that early exposure to bacterial products such as lipopolysaccharide (LPS) may be protective against the development of allergic diseases. Whether atopic disease affects the ability of immune cells to respond to LPS is unclear. Our laboratory has demonstrated previously that children express high levels of Toll-like receptor (TLR)-4 on CD4(+) cells in nasal mucosa. OBJECTIVE: To determine if children with a history of allergic disease have impaired responses to LPS on circulating CD4(+) leucocytes. METHODS: Peripheral blood mononuclear cells from children (aged 2-18) and adults with or without a history of atopic conditions were cultured with/without IL-4 or LPS for up to 24 h. Expression of surface TLR-4, CD14, CD4, CD3, as well as of intracellular phosphorylated (p42/p44) ERK and p38 mitogen-activated protein kinase (MAPK) were assessed by flow cytometry. RESULTS: A history of atopy in children was associated with impaired LPS-induced TLR-4-dependent phosphorylation of (p42/44) ERK and p38 MAPK by CD4(+) monocytes. Decreased LPS signalling was reproduced by pre-incubation of control cells with recombinant IL-4. LPS stimulation also decreased TLR-4 expression on monocytes from children without atopic histories but not from atopic subjects. CD4(+) T lymphocytes showed limited LPS responsiveness, regardless of atopic status. In contrast with non-atopic children, TLR-4 expression on monocytes of children with atopic histories decreased as a function of age. CONCLUSIONS: This study provides evidence for defective LPS recognition on circulating CD4(+) leucocytes of subjects with atopic histories compared with those from non-atopic children. CD4(+) TLR4(+) monocytes from children with atopic histories failed to phosphorylate MAPKs. Our results suggest that a history of atopic disease is associated with impaired TLR-4-mediated innate immune function compared with non-atopic children.

A randomized, double-blinded, placebo-controlled trial of pseudocatalase cream and narrowband ultraviolet B in the treatment of vitiligo.

BACKGROUND: Pseudocatalase cream in conjunction with narrowband ultraviolet B (NB-UVB) has previously been reported to result in repigmentation of vitiliginous skin. OBJECTIVES: The purpose of this 24-week, double-blind, placebo-controlled, randomized, single-centre trial was to assess the efficacy of pseudocatalase cream and NB-UVB vs. placebo and NB-UVB for the treatment of vitiligo. METHODS: Patients with active vitiligo on their face and/or hands applied either pseudocatalase cream or placebo to their whole body, twice daily for 24 weeks. NB-UVB therapy was administered three times a week for the duration of the trial. Efficacy was assessed primarily by digital image analysis of photographs. RESULTS: Thirty-two patients were randomized to either the pseudocatalase arm (n = 14) or placebo (n = 18). Between-group analysis did not show a statistically significant improvement in percentage area affected in the pseudocatalase cream group when compared with placebo. However, a statistically significant improvement was found within each group by week 12, which was maintained throughout the study. CONCLUSIONS: NB-UVB treatment is a moderately effective treatment for vitiligo. Pseudocatalase cream does not appear to add any incremental benefit to NB-UVB alone.

Novel Temperature-Dependent Development Rate Models for Postdiapause Egg Eclosion of Three Important Arthropod Pests Found in Commercial Christmas Tree Plantations of Southern Québec, Canada.

The balsam twig aphid Mindarus abietinus Koch (Hemiptera: Aphididae), the spruce spider mite Oligonychus ununguis (Jacobi) (Acari: Tetranychidae), and the pine needle scale Chionaspis pinifoliae (Fitch) (Hemiptera: Diaspididae) are three important pests for the Christmas tree industry of Québec, Canada. Temperature-dependent development rates for postdiapause overwintering eggs of these species have never been studied for populations of southern Québec, where the vast majority of Christmas trees are grown. The accumulation of physiological time in growing degree days (GDD) is a standard tool to predict egg eclosion dates for pests, when first generation immatures are most vulnerable to insecticidal control. Development rates for postdiapause eggs were tested at four or five constant temperatures in the 11-23°C range under controlled conditions, based on time before hatching for eggs collected in a balsam fir plantation in late winter. The standard linear model and three published nonlinear models were fitted to the data and compared for their ability to estimate key biological temperature parameters and to predict development rates of postdiapause eggs. Validation of model predictions of egg eclosion time on balsam fir in the field was reasonably accurate using the classical linear model where field-accumulated GDD were calculated with a particular interpretation of the average method based on daily maximum and minimum temperatures. The linear model could predict mean egg eclosion within around 5 d of eclosion dates observed in the field.

[Mother-daughter relationship inventory]. / L'inventaire des relations mère-fille.

The present paper centers on the validation of the French-version of the mother-daughter relationship inventory (MDREL), a self-reported questionnaire developed by Inazu and Fox (1980) and translated by Achim. This nine-item self-reported questionnaire assesses young women's perceptions pertaining to the social-emotional support conveyed by their mother, as well as the overall quality of their mother-daughter relationship. The MDREL is the product of factor analyses conducted on 23 statements concerning young women's perception regarding the following dimensions: presence of an open-communication between the mother and the daughter; presence of uncertainties and ambiguities in the description made by the daughter concerning her relationship with her mother; ambivalence expressed by the daughter in regards to mother-daughter rapprochement and intimacy. This instrument is of great interest as it specifically assesses the perceived quality of the mother-daughter relationship during adolescence, a period in which the mother remains an authority-figure and the daughter's sexuality is activated. A total of 126 young women completed the French-version of this self-reported questionnaire. Results indicate good psychometric properties in both validity and reliability. Factor analyses of the French-version of the MDREL yielded two distinct factors, namely an allo-centered and a self-centered assessment. This French-version of the MDREL named l'Inventaire des relations mère-fille (IRMF) can thus be used in studies that focus on mother-daughter relationships. The problematic overtone present in many items suggests that this instrument can be administered to clinical populations.

[The neurostimulator for brachial plexus blockade by the axillary approach: a metaanalysis on its efficacy to increase the success rate]. / Méta-analyse: intérêt du neurostimulateur dans l'amélioration du taux de succès du bloc axillaire.

OBJECTIVE: To evaluate the effectiveness of the neurostimulator to improve the success rate of a brachial plexus blockade by the axillary approach. STUDY DESIGN: Metaanalysis. METHODS: Ten prospective randomized studies comparing a neurostimulating technique (NST) of brachial plexus blockade performed by the axillary approach to another technique were kept for analysis. A successful block was defined as blockade of the four following nerves: radial, median, ulnar and musculocutaneous. Data were entered on an intention to treat basis and were analyzed with a random model. A p<0.05 was considered significant. RESULTS: Data were heterogenous (p < 0.001) and the Cochran-Mantel-Haenzel test showed that the neurostimulator does not improve the success rate of brachial plexus blocks performed by the axillary approach when all available studies are considered as a whole (p = 1). For the subgroup of studies where four nerves were stimulated however, the NST decreases the incidence of failed block by 25% (95% CI = 7-42%) (p < 0.0001). There were 12 patients with systemic signs of local anesthetics toxicity when a NST was used compared to 28 when it was not (p = 0.04), relative risk of 0.7 (95% CI= 0.6-0.8). CONCLUSION: This study shows that the neurostimulator improves the success rate of brachial plexus blocks performed by the axillary approach only when three nerves or more are stimulated and its use decreases the incidence of systemic local anaesthetics toxicity.

Physical and genetic mapping of cloned ribosomal DNA from Toxoplasma gondii: primary and secondary structure of the 5S gene.

The ribosomal DNA (rDNA encoding rRNA) of the obligately intracellular protozoan parasite, Toxoplasma gondii, was identified, cloned, physically mapped, its copy number determined, and the 5S gene sequenced. Using total RNA as a probe, a collection of recombinant lambda phages containing copies of rDNA were isolated from a lambda 2001 tachyzoite genomic library. Northern gel hybridization confirmed specific homology of the 7.5-kb rDNA unit, subcloned into pTZ18R, to T. gondii rRNA. The mapped rDNA found in pTOX1 contained small ribosomal subunit (SS; 18S)- and large ribosomal subunit (LS; 26S)-encoding genes localized using intragenic heterologous probes from the conserved sequences of the SS (18S) and LS (28S) Xenopus laevis genes. the physical mapping data, together with partial digestion experiments and Southern gel hybridization, confirmed a 7.5-kb rDNA unit arranged in a simple head-to-tail fashion that is tandemly repeated. We estimated the rDNA repeat copy number in T. gondii to be 110 copies per haploid tachyzoite genome. Parts of the SS gene and the complete 5S gene were sequenced. The 5S gene was found to be within the rDNA locus, a rare occurrence found only in some fungi and protozoa. Secondary-structure analysis revealed an organization remarkably similar to the 5S RNA of eukaryotes.

Cloning and expression of rhesus monkey cathepsin K.

Cathepsin K is a cysteine protease involved in degradation of human type I collagen and plays a primary role in bone resorption. We have cloned rhesus monkey cathepsin K by reverse transcriptase-polymerase chain reaction (RT-PCR) from rhesus ovary poly A+ RNA. The sequence for the rhesus enzyme is 98% identical to that of the human with 100% identity within the mature active form of cathepsin K. Rhesus monkey cathepsin K was transiently expressed in Chinese hamster ovary (CHO) cells and found to be secreted as the proenzyme in the culture media and 50% activated to the mature form intracellularly. The substrate specificity preference of aminomethylcoumarin and rhodamine peptide substrates was Leu > Phe > Pro in the P2 position when tested with constant arginine at P1. The enzyme activity expressed in CHO cell extracts was sensitive to inhibition by E-64 and cystatin with IC50s of 3.5 nmol/L and 13 ng/mL, respectively. The apparent second order rate constants of inactivation by E-64 were 66,000 M(-1) s(-1) and 130,000 M(-1) s(-1) for the recombinantly expressed rhesus monkey and human cathepsin K, respectively. The high similarity between the sequences and the kinetic properties of rhesus monkey and human cathepsin K establishes this monkey species as a suitable animal model for development of novel cathepsin K inhibitors as antiresorptive agents.

Naphthalenic lignan lactones as selective, nonredox 5-lipoxygenase inhibitors. Synthesis and biological activity of (methoxyalkyl)thiazole and methoxytetrahydropyran hybrids.

Combinations of structural elements found in (methoxyalkyl)thiazole 1a and methoxytetrahydropyran 2a with a naphthalenic lignan lactone produce the potent 5-lipoxygenase (5-LO) inhibitors 3 and 4. While the nature of link Y-Z has a major effect on the in vitro activity of compounds 1 and 2, inhibitors 3 and 4 retain their potencies with either an oxymethylene (Y = O, Z = CH2) or a methyleneoxy (Y = CH2, Z = O) link. Compound 4b inhibits the oxidation of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid by 5-LO (IC50 = 14 nM) and the formation of leukotriene B4 in human polymorphonuclear leukocytes (IC50 = 1.5 nM) as well as in human whole blood (IC50 = 50 nM). Compound 4b is a selective 5-LO inhibitor showing no significant inhibition of human 15-lipoxygenase or porcine 12-lipoxygenase or binding to human 5-lipoxygenase-activating protein up to 10 microM and inhibits leukotriene biosynthesis by a direct, nonredox interaction with 5-LO. Compound 15, the open form of lactone 4b, is well absorbed in the rat and is transformed into the active species 4b. In addition, 15 is orally active in the rat pleurisy model (ED50 = 0.6 mg/kg) and in the functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at 0.3 mg/kg).

Thiopyrano[2,3,4-cd]indoles as 5-lipoxygenase inhibitors: synthesis, biological profile, and resolution of 2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy]-4,5 -dihydro-1H-thiopyrano[2,3,4-cd]indol-2-yl]ethoxy]butanoic acid.

Leukotriene biosynthesis inhibitors have potential as new therapies for asthma and inflammatory diseases. The recently disclosed thiopyrano[2,3,4-cd]indole class of 5-lipoxygenase (5-LO) inhibitors has been investigated with particular emphasis on the side chain bearing the acidic functionality. The SAR studies have shown that the inclusion of a heteroatom (O or S) in conjunction with an alpha-ethyl substituted acid leads to inhibitors of improved potency. The most potent inhibitor prepared contains a 2-ethoxybutanoic acid side chain. This compound, 14d (2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methox y]- 4,5-dihydro-1H-thiopyrano[2,3,4-cd]indol-2-yl]ethoxy]-butanoic acid, L-699,333), inhibits 5-HPETE production by human 5-LO and LTB4 biosynthesis by human PMN leukocytes and human whole blood (IC50s of 22 nM, 7 nM and 3.8 microM, respectively). The racemic acid 14d has been shown to be functionally active in a rat pleurisy model (inhibition of LTB4, ED50 = 0.65 mg/kg, 6 h pretreatment) and in the hyperreactive rat model of antigen-induced dyspnea (50% inhibition at 2 and 4 h pretreatment; 0.5 mg/kg po). In addition, 14d shows excellent functional activity against antigen-induced bronchoconstriction in the conscious squirrel monkey [89% inhibition of the increase in RL and 68% inhibition in the decrease in Cdyn (0.1 mg/kg, n = 3)] and in the conscious sheep models of asthma (iv infusion at 2.5 micrograms/kg/min). Acid 14d is highly selective as an inhibitor of 5-LO activity when compared to the inhibition of human 15-LO, porcine 12-LO and ram seminal vesicle cyclooxygenase (IC50 > 5 microM) or competition in a FLAP binding assay (IC50 > 10 microM). Resolution of 14d affords 14g, the most potent diastereomer, which inhibits the 5-HPETE production of human 5-LO and LTB4 biosynthesis of human PMN leukocytes and human whole blood with IC50s of 8 nM, 4 nM, and 1 microM respectively. The in vitro and in vivo profile of 14d is comparable to that of MK-0591, which has showed biochemical efficacy in inhibiting ex vivo LTB4 biosynthesis and urinary LTE4 excretion in clinical trials.

Substituted thiopyrano[2,3,4-c,d]indoles as potent, selective, and orally active inhibitors of 5-lipoxygenase. Synthesis and biological evaluation of L-691,816.

Thiopyrano[2,3,4-c,d]indoles are a new class of 5-lipoxygenase (5-LO) inhibitors. SAR studies have demonstrated that the thiopyran ring, the 5-phenylpyridine substituent, and an acidic functional group on a four-carbon C-2 side chain are all required for optimal inhibitor potency. In contrast, the indolic nitrogen may be substituted with a variety of lipophilic groups. As a result of the SAR investigation, 44 (L-691,816; 5-[3-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy ]- 4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]-2,2-dimethylpro pyl]-1H- tetrazole) has been identified as a potent inhibitor of the 5-LO reaction both in vitro and in a range of in vivo models. Compound 44 inhibits 5-HPETE production by both rat and human 5-LO and LTB4 synthesis in human PMN leukocytes (IC50s 16, 75, and 10 nM, respectively). The mechanism of inhibition of 5-LO activity by compound 44 appears to involve the formation of a reversible deadend complex with the enzyme and does not involve reduction of the nonheme iron of 5-LO. Compound 44 is highly selective for 5-LO when compared to the inhibition of human FLAP, porcine 12-LO, and also ram seminal vesicle cyclooxygenase. In addition, 44 is orally active in a rat pleurisy model (inhibition of LTB4, ED50 = 1.9 mg/kg; 8 h pretreatment) as well as in the hyperreactive rat model of antigen-induced dyspnea (ED50 = 0.1 mg/kg; 2-h pretreatment). Excellent functional activity was also observed in both the conscious allergic monkey and sheep models of asthma. In the latter case, the functional activity observed correlated with the inhibition of urinary LTE4 excretion.

2,3-Diarylcyclopentenones as orally active, highly selective cyclooxygenase-2 inhibitors.

Cyclopentenones containing a 4-(methylsulfonyl)phenyl group in the 3-position and a phenyl ring in the 2-position are selective inhibitors of cyclooxygenase-2 (COX-2). The selectivity for COX-2 over COX-1 is dramatically improved by substituting the 2-phenyl group with halogens in the meta position or by replacing the phenyl ring with a 2- or 3-pyridyl ring. Thus the 3,5-difluorophenyl derivative 7 (L-776,967) and the 3-pyridyl derivative 13 (L-784,506) are particularly interesting as potential antiinflammatory agents with reduced side-effect profiles. Both exhibit good oral bioavailability and are potent in standard models of pain, fever, and inflammation yet have a much reduced effect on the GI integrity of rats compared to standard nonsteroidal antiflammatory drugs.

Substituted (pyridylmethoxy)naphthalenes as potent and orally active 5-lipoxygenase inhibitors; synthesis, biological profile, and pharmacokinetics of L-739,010.

Dioxabicyclooctanyl naphthalenenitriles have been reported as a class of potent and nonredox 5-lipoxygenase (5-LO) inhibitors. These bicyclo derivatives were shown to be metabolically more stable than their tetrahydropyranyl counterparts but were not well orally absorbed. Replacement of the phenyl ring in the naphthalenenitrile 1 by a pyridine ring leads to the potent and orally absorbed inhibitor 3g (L-739,010, 2-cyano-4-(3-furyl)-7-[[6-[3-(3-hydroxy-6,8-dioxabicyclo[3.2.1] octanyl)]-2-pyridyl]methoxy]naphthalene). Compound 3g inhibits 5-HPETE production by human 5-LO and LTB4 biosynthesis by human PMN leukocytes and human whole blood (IC50S of 20, 1.6, and 42 nM, respectively). Derivative 3g is orally active in the rat pleurisy model (inhibition of LTB4, ED50 = 0.3 mg/kg) and in the anesthetized dog model (inhibition of ex vivo whole blood LTB4 and urinary LTE4, ED50 = 0.45 and 0.23 microgram/kg/min, respectively, i.v. infusion). In addition, 3g shows excellent functional activity against ovalbumin-induced dyspnea in rats (60% inhibition at 0.5 mg/kg, 4 h pretreatment) and Ascaris-induced bronchoconstriction in conscious sheep (50% and > 85% inhibition in early and late phases, respectively at 2.5 micrograms/kg/min, i.v. infusion) and, more particularly in the conscious antigen sensitive squirrel monkey model (53% inhibition of the increase in RL and 76% in the decrease of Cdyn, at 0.1 mg/kg, po). In rats and dogs, 3g presents excellent pharmacokinetics (estimated half-lives of 5 and 16 h, respectively) and bioavailabilities (26% and 73% when dosed as its hydrochloride salt at doses of 20 and 10 mg/kg, respectively, in methocel suspension). Based on its overall biological profile, compound 3g has been selected for preclinical animal toxicity studies.

Dioxabicyclooctanyl naphthalenenitriles as nonredox 5-lipoxygenase inhibitors: structure-activity relationship study directed toward the improvement of metabolic stability.

Naphthalenic lignan lactone 3a (L-702,539), a potent and selective 5-lipoxygenase (5-LO) inhibitor, is extensively metabolized at two different sites: the tetrahydropyran and the lactone rings. Early knowledge of the metabolic pathways triggered and directed a structure-activity relationship study aimed toward the improvement of metabolic stability in this series. The best modifications discovered, i.e., replacement of the lactone ring by a nitrile group, replacement of the tetrahydropyran ring by a 6,8-dioxabicyclo[3.2.1]octanyl moiety, and replacement of the pendant phenyl ring by a 3-furyl ring, were incorporated in a single molecule to produce inhibitor 9ac (L-708,780). Compound 9ac inhibits the oxidation of arachidonic acid to 5-hydroperoxy-eicosatetraenoic acid by 5-LO (IC50 = 190 nM) and the formation of leukotriene B4 in human polymorphonuclear leukocytes (IC50 = 3 nM) as well as in human whole blood (IC50 = 150 nM). The good inhibitory profile shown by naphthalenenitrile 9ac is accompanied by an improved resistance to oxidative metabolism. In addition, 9ac is orally active in the functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at 0.1 mg/kg).

Clinical pharmacokinetics of neuromuscular relaxants in pregnancy.

Despite an increased in bodyweight, plasma volume by 45% and blood volume by 35% that might influence the volume of distribution of polar drugs, the apparent volume of distribution at steady state (Vss), volume of distribution (Vd) and the apparent volume of the central compartment (Vc) of atracurium, vecuronium and pancuronium are unchanged during pregnancy. With an elimination that is independent of renal, hepatic and enzymatic functions, the clearance of atracurium is also unchanged. This is corroborated by an unchanged clinical duration of atracurium during pregnancy. The clearance of pancuronium is increased by 27% during caesarean section. This may be explained by the increased glomerular filtration rate reported in pregnant women. The clinical duration of vecuronium in term and postpartum women is twice that reported in nonpregnant women. On the other hand, an increase in the clearance clearance of vecuronium during cesarean sections has been reported. The umbilical/maternal vein concentration ratio (UV/MV) of nondepolarising neuromuscular relaxants varies from 7 to 26% and clinical doses of these drugs may induce partial residual curarisation in neonates. Fetal concentrations of non-depolarising neuromuscular relaxants are proportional to the maternal dose injected as demonstrated for pancuronium and vecuronium. Increasing UV/MV with longer drug injection to delivery intervals have been demonstrated for drugs with a high molecular weight, such as atracurium, but not for those with a low molecular weight, such as vecuronium, while conflicting results have been reported for pancuronium. Despite decreased plasma pseudocholinesterases, the clinical duration of succinylcholine 1 mg/kg is unchanged in pregnant women, and only is slightly increased in postpartum women. On the other hand, larger doses of succinylcholine have induced prolonged apnoea and phase II block. The use of a pretreatment dose of a nondepolarising neuromuscular relaxant to decrease fasciculations and subsequent postoperative muscle pain is not only unnecessary in pregnant women but may be hazardous, since it may produce unexpected significant curarisation with respiratory distress. At clinical doses, transplacental passage of succinylcholine is insufficient to produce curarisation of neonates except in those born to mothers with abnormal plasma pseudocholinesterases. Magnesium sulfate, used in the treatment of pre-eclampsia, will enhance the blocking effects of nondepolarising neuromuscular relaxants but will have no effects on the characteristics of paralysis of succinylcholine. Histamine type 2 antagonists used to decrease the risk of aspiration during induction of anaesthesia do not influence the blocking properties of neuromuscular relaxants, while metoclopramide prolongs the block of succinylcholine.

Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX-2 inhibitor.

1. DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furan one) was identified as a novel orally active and highly selective cyclo-oxygenase-2 (COX-2) inhibitor. 2. In CHO cells stably transfected with human COX isozymes, DFU inhibited the arachidonic acid-dependent production of prostaglandin E2 (PGE2) with at least a 1,000 fold selectivity for COX-2 (IC50 = 41 +/- 14 nM) over COX-1 (IC50 > 50 microM). Indomethacin was a potent inhibitor of both COX-1 (IC50 = 18 +/- 3 nM) and COX-2 (IC50 = 26 +/- 6 nM) under the same assay conditions. The large increase in selectivity of DFU over indomethacin was also observed in COX-1 mediated production of thromboxane B2 (TXB2) by Ca2+ ionophore-challenged human platelets (IC50 > 50 microM and 4.1 +/- 1.7 nM, respectively). 3. DFU caused a time-dependent inhibition of purified recombinant human COX-2 with a Ki, value of 140 +/- 68 microM for the initial reversible binding to enzyme and a kappa 2 value of 0.11 +/- 0.06 s-1 for the first order rate constant for formation of a tightly bound enzyme-inhibitor complex. Comparable values of 62 +/- 26 microM and 0.06 +/- 0.01 s-1, respectively, were obtained for indomethacin. The enzyme-inhibitor complex was found to have a 1:1 stoichiometry and to dissociate only very slowly (t1/2 = 1-3 h) with recovery of intact inhibitor and active enzyme. The time-dependent inhibition by DFU was decreased by co-incubation with arachidonic acid under non-turnover conditions, consistent with reversible competitive inhibition at the COX active site. 4. Inhibition of purified recombinant human COX-1 by DFU was very weak and observed only at low concentrations of substrate (IC50 = 63 +/- 5 microM at 0.1 microM arachidonic acid). In contrast to COX-2, inhibition was time-independent and rapidly reversible. These data are consistent with a reversible competitive inhibition of COX-1. 5. DFU inhibited lipopolysaccharide (LPS)-induced PGE2 production (COX-2) in a human whole blood assay with a potency (IC50 = 0.28 +/- 0.04 microM) similar to indomethacin (IC50 = 0.68 +/- 0.17 microM). In contrast, DFU was at least 500 times less potent (IC50 > 97 microM) than indomethacin at inhibiting coagulation-induced TXB2 production (COX-1) (IC50 = 0.19 +/- 0.02 microM). 6. In a sensitive assay with U937 cell microsomes at a low arachidonic acid concentration (0.1 microM), DFU inhibited COX-1 with an IC50 value of 13 +/- 2 microM as compared to 20 +/- 1 nM for indomethacin. CGP 28238, etodolac and SC-58125 were about 10 times more potent inhibitors of COX-1 than DFU. The order of potency of various inhibitors was diclofenac > indomethacin approximately naproxen > nimesulide approximately meloxicam approximately piroxicam > NS-398 approximately SC-57666 > SC-58125 > CGP 28238 approximately etodolac > L-745,337 > DFU. 7. DFU inhibited dose-dependently both the carrageenan-induced rat paw oedema (ED50 of 1.1 mg kg-1 vs 2.0 mg kg-1 for indomethacin) and hyperalgesia (ED50 of 0.95 mg kg-1 vs 1.5 mg kg-1 for indomethacin). The compound was also effective at reversing LPS-induced pyrexia in rats (ED50 = 0.76 mg kg-1 vs 1.1 mg kg-1 for indomethacin). 8. In a sensitive model in which 51Cr faecal excretion was used to assess the integrity of the gastrointestinal tract in rats, no significant effect was detected after oral administration of DFU (100 mg kg-1, b.i.d.) for 5 days, whereas chromium leakage was observed with lower doses of diclofenac (3 mg kg-1), meloxicam (3 mg kg-1) or etodolac (10-30 mg kg-1). A 5 day administration of DFU in squirrel monkeys (100 mg kg-1) did not affect chromium leakage in contrast to diclofenac (1 mg kg-1) or naproxen (5 mg kg-1). 9. The results indicate that COX-1 inhibitory effects can be detected for all selective COX-2 inhibitors tested by use of a sensitive assay at low substrate concentration. The novel inhibitor DFU shows the lowest inhibitory potency against COX-1, a consistent high selectivity of inhibition of COX-2 over COX-1 (>300 fold) with enzyme, whole cell and whole blood assays, with no detectable loss of integrity of the gastrointestinal tract at doses >200 fold higher than efficacious doses in models of inflammation, pyresis and hyperalgesia. These results provide further evidence that prostanoids derived from COX-1 activity are not important in acute inflammatory responses and that a high therapeutic index of anti-inflammatory effect to gastropathy can be achieved with a selective COX-2 inhibitor.