L-656,224 (7-chloro-2-[(4-methoxyphenyl)methyl]-3- methyl-5-propyl-4-benzofuranol): a novel, selective, orally active 5-lipoxygenase inhibitor

L-656,224 (7-chloro-2-[(4-methoxyphenyl)methyl]-3-methyl-5-propyl-4-benzofuranol) was a potent inhibitor of leukotriene biosynthesis in intact rat and human leukocytes and CXBG mastocytoma cells (IC50 values, 18-240 nM) and of crude human leukocyte and highly purified porcine leukocyte 5-lipoxygenase (IC50 value, 4 X 10(-7) M). The selectivity of L-656,224 for 5-lipoxygenase was shown through the relative lack of activity of the compound on 12-lipoxygenase, 15-lipoxygenase, cyclooxygenase, catalase, and myeloperoxidase. The compound showed (i) oral activity against hyperalgesia induced in the rat paw by injection of yeast or platelet-activating factor, (ii) dyspnea in sensitized inbred rats induced by an aerosol of antigen, and (iii) bronchoconstriction induced by an aerosol of Ascaris in squirrel monkeys, suggesting a role for 5-lipoxygenase inhibitors in the treatment of asthma and peripheral pain.     

Compositional dissimilarity as a robust measure of ecological distance

The robustness of quantitative measures of compositional dissimilarity between sites was evaluated using extensive computer simulations of species' abundance patterns over one and two dimensional configurations of sample sites in ecological space. Robustness was equated with the strength over a range of models, of the linear and monotonic (rank-order) relationship between the compositional dissimilarities and the corresponding Euclidean distances between sites measured in the ecological space. The range of models reflected different assumptions about species' response curve shape, sampling pattern of sites, noise level of the data, species' interactions, trends in total site abundance, and beta diversity of gradients.The Kulczynski, Bray-Curtis and Relativized Manhattan measures were found to have not only a robust monotonic relationship with ecological distance, but also a robust linear (proportional) relationship until ecological distances became large. Less robust measures included Chord distance, Kendall's coefficient, Chisquared distance, Manhattan distance, and Euclidean distance.A new ordination method, hybrid multidimensional scaling (HMDS), is introduced that combines metric and nonmetric criteria, and so takes advantage of the particular properties of robust dissimilarity measures such as the Kulczynski measure.We thank M. P. Austin for encouraging this study, and I. C. Prentice, E. Van der Maarel, and an anonymous reviewer for helpful comments. E. M. Adomeit provided technical assistance.     

Sepharose-linked concanavalin A in the purification and characterization of glycoprotein hormones of the bovine pituitary

Affinity chromatography on concanavalin A-Sepharose is a time saving step in both large and small scale isolations of the bovine pituitary glycoprotein hormones. After ion-exchange chromatography, the final yield of purified lutropin is 40-50% of material in starting concentrates and of purified thyrotropin is approximately 20%. The final products have the same electrophoretic and immunological properties and amino acid compositions as previous preparations. Less than 3% of the immunoreactive lutropin, follitropin and thyrotropin are present as non-glycosylated forms in either crude pituitary extracts or concentrates. Thyrotropin and follitropin elute from the immobilized lectin as a single fraction, whereas lutropin separates into two glycosylated fractions. Gel filtration of both crude extracts and the glycoprotein fractions shows that less than 5% of the immunoreactivity of the hormones is present as material of apparently high molecular weight. Substantial alpha subunit immunoreactivity, however, is in three fractions (as found by others in human pituitary extracts) corresponding to "high molecular weight material" (7%), intact hormones (46%) and free subunit (47%).     

Hyperoxia causes oxygen free radical-mediated membrane injury and alters myocardial function and hemodynamics in the newborn

Newborn children can be exposed to high oxygen levels (hyperoxia) for hours to days during their medical and/or surgical management, and they also can have poor myocardial function and hemodynamics. Whether hyperoxia alone can compromise myocardial function and hemodynamics in the newborn and whether this is associated with oxygen free radical release that overwhelms naturally occurring antioxidant enzymes leading to myocardial membrane injury was the focus of this study. Yorkshire piglets were anesthetized with pentobarbital sodium (65 mg/kg), intubated, and ventilated to normoxia. Once normal blood gases were confirmed, animals were randomly allocated to either 5 h of normoxia [arterial Po(2) (Pa(O(2))) = 83 +/- 5 mmHg, n = 4] or hyperoxia (Pa(O(2)) = 422 +/- 33 mmHg, n = 6), and myocardial functional and hemodynamic assessments were made hourly. Left ventricular (LV) biopsies were taken for measurements of antioxidant enzyme activities [superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT)] and malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) as an indicator of oxygen free radical-mediated membrane injury. Hyperoxic piglets suffered significant reductions in contractility (P < 0.05), systolic blood pressure (P < 0.03), and mean arterial blood pressure (P < 0.05). Significant increases were seen in heart rate (P < 0.05), whereas a significant 11% (P < 0.05) and 61% (P < 0.001) reduction was seen in LV SOD and GPx activities, respectively, after 5 h of hyperoxia. Finally, MDA and 4-HNE levels were significantly elevated by 45% and 38% (P < 0.001 and P = 0.02), respectively, in piglets exposed to hyperoxia. Thus, in the newborn, hyperoxia triggers oxygen free radical-mediated membrane injury together with an inability of the newborn heart to upregulate its antioxidant enzyme defenses while impairing myocardial function and hemodynamics.     

Arylacetamide kappa opioid receptor agonists with reduced cytochrome P450 2D6 inhibitory activity

Some kappa opioid receptor agonists of the arylacetamide class, for example, ICI 199441 (1), were found to strongly inhibit the activity of cytochrome P450 2D6 (CYP2D6) (1: CYP2D6 IC50=26 nM). Certain analogs bearing a substituted sulfonylamino group, for example, 13, were discovered to have significantly reduced CYP2D6 inhibitory activity (13: CYP2D6 IC50>10 microM) while displaying high affinity toward the cloned human kappa opioid receptor, good kappa/delta and kappa/mu selectivity, and potent in vitro and in vivo agonist activity.     

The tarso-pretarsal chordotonal organ as an element in cockroach walking

Many types of sense organs have been demonstrated to show repetitive discharges during walking that could provide informational cues about leg movements and other parameters of locomotion. We have recorded activities of receptors of the distal (tarsal) segments of the cockroach hindleg in restrained and freely moving animals while they were videotaped. These recordings show peaks of activities at the onset and termination of the stance phase. We have morphologically and physiologically identified a joint angle receptor, the tarso-pretarsal chordotonal organ, that contributes to the discharges seen late in stance, prior to the onset of leg flexion in swing. This sense organ encodes the angle and rate of change of the most distal leg joint and specifically discharges when the claws are disengaged from the substrate. Applied displacements of the claws in restrained preparations elicit reflex activation of the tibial flexor muscle and a crossed extensor reflex in the opposite hindleg. These reflexes could function to insure that leg flexion in swing does not occur until the claws are disengaged and to enhance support by the opposite hindleg. Thus, the regular discharges of the chordotonal organ could assure efficient and coordinated muscle contractions and movements during normal, unperturbed walking. Accepted: 2 January 1997     

Integrating conservation and development: effective trade-offs between biodiversity and cost in the selection of protected areas

Strategies are needed for reconciling competing demands at the regional level when areas are to be selected for protection and there are associated costs, possibly equivalent to forgone development opportunties. As an alternative to the fixed scaling (or weighting) of costs and benefits required by cost-benefit analysis, multi-criteria analyses allow the exploration of alternative weightings and a summary trade-off curve to determine preferred solutions. For alternative sets of areas, total cost could be plotted against total represented biodiversity, but a more consistent approach should look at trade-off space at the level of individual areas. For a given weighting, an area is assigned protection if and only if its contribution to total biodiversity, CB, exceeds its equivalent cost, EC (in biodiversity units). Because CB for a given area depends on which other areas are also protected, it can be more or less than EC. Here we develop an iterative strategy for selecting areas, such that, for a given weighting, an area is in the final protected set if and only if its final CB value is greater than its EC value. Sensitivity analysis is used to identify those areas that: (1) are assigned protection even when low weight is given to biodiversity, or (2) are not assigned protection even when high weight is given to biodiversity. This approach is applicable in principle to any surrogate measure for biodiversity; here examples are presented in which environmental data are summarized as an environmental space.     

Combination therapy with flutamide and castration (orchiectomy or LHRH agonist): the minimal endocrine therapy in both untreated and previously treated patients

Patients (154) with clinical stage D2 prostate cancer with no previous endocrine therapy or chemotherapy received the combination therapy with the pure antiandrogen Flutamide and the LHRH agonist [D-Trp6]LHRH ethylamide for an average of 22 months (3-49 months). The objective response to the treatment was assessed according to the criteria of the US NPCP. There was a 6.3-fold increase (29.2 vs 4.6%) in the percentage of patients who achieved a complete response as compared to the results achieved in five recent studies limited to removal (orchiectomy) or blockade (DES or Leuprolide) of testicular androgens. Only 4.5% of patients did not respond to the combination therapy as compared to an average of 18% by standard therapy. The duration of response is also significantly increased in the patients who received the combination therapy. The death rate was decreased by approximately 2-fold between 2 and 3 yr of treatment. The marked (6.3-fold) improvement in the rate of complete objective responses coupled with the 4-fold decrease in the number of non-responders, the increased duration of the positive responses and the 2-fold decrease in the death rate at 2-3 yr of treatment are obtained with the combination therapy using Flutamide and castration with no or minimal secondary effects.