Discovery of the first non-peptide antagonist of the motilin receptor.

A first-in-class non-peptide antagonist of the motilin receptor was identified through electronic screening of our corporate database against a 3D pharmacophore. The pharmacophore was developed from the motilin 22 residue endogenous peptide using NMR structural data, principles of peptide folding, and peptide structure activity relationships. The NMR data supported helical content within the peptide, and both the hydrophobic staple and N-capping box motifs were identified in the motilin sequence. The conformational features of these motifs were imposed on the peptide structure, providing a constrained conformer as a starting point for database searching. A trisubstituted cyclopentene lead was identified directly from the electronic search. Compounds in this series inhibit the binding of 125I-motilin to human antral smooth muscle membrane and antagonize motilin-induced intracellular calcium mobilization in cells expressing the human motilin receptor. A potent compound developed through optimization, RWJ 68023, is active in binding and cell-based functional assays and is also effective in inhibiting motilin-induced contractility in segments of rabbit duodenum. This orally active compound is currently undergoing clinical evaluation for the treatment of gastrointestinal disorders associated with altered motility.

The new pre-preclinical paradigm: compound optimization in early and late phase drug discovery.

The attrition rates of new chemical entities (NCEs) in preclinical and clinical development are staggeringly high. NCEs are abandoned due to insufficient efficacy, safety issues, and economic reasons. Uncovering drug defects that produce these failures as early as possible in drug discovery would be highly effective in lowing the cost and time of developing therapeutically useful drugs. Unfortunately, there is no single factor that can account for these NCE failures in preclinical and clinical development since factors, such as solubility, pKa, absorption, metabolism, formulation, pharmacokinetics, toxicity and efficacy, to name a few, are all interrelated. In addition, there are many problems in scaling-up drug candidates from the laboratory bench scale to the pilot plant scale. To address the problem of attrition rates of NCEs in preclinical and clinical development and drug scale-up issues, pharmaceutical companies need to reorganize their preclinical departments from a traditional linear approach to a parallel approach. In this review, a strategy is put forth to integrate certain aspects of drug metabolism/pharmacokinetics, toxicology functions and process chemistry into drug discovery. Compound optimization in early and late phase drug discovery occurs by relating factors such as physicochemical properties, in vitro absorption, in vitro metabolism, in vivo pharmacokinetics and drug scale-up issues to efficacy optimization. This pre-preclinical paradigm will improve the success rate of drug candidates entering development.

Establishing clinically significant change: increment of precision and the distinction between individual and group level of analysis.

Some essential adaptations to the method for determining clinically significant change originally introduced by Jacobson, Follette and Revenstorf [Jacobson, N. S., Follette, W. C. & Revenstorf, D. (1984a). Psychotherapy outcome research: methods for reporting variability and evaluating clinical significance. Behavior Therapy, 15, 336-352.] are presented. One adaptation deals with the failure in the original method to distinguish between analysis at the individual versus analysis at the group level. A second adaptation entails the provision of a closer approximation of the underlying true scores. This refinement represents an enhancement in precision. Specific aspects of this refinement may be understood in terms of a correction for error-based regression to the mean. Taking into account these adaptations, new procedures are described for determining (clinically significant) change. Some guidelines for the publication of outcome findings are also presented.

Clinically significant and practical! Enhancing precision does make a difference. Reply to McGlinchey and Jacobson, Hsu, and Speer.

UNLABELLED: Based on a secondary analysis of the Jacobson and Truax [Jacobson, N.S. & Truax, P. (1991). CLINICAL SIGNIFICANCE: a statistical approach to defining meaningful change in psychotherapy research. Journal of Consulting and Clinical Psychology, 59, 12-19.] data using both their own traditional approach and the refined method advanced by Hageman and Arrindell [Hageman, W.J.J.M., & Arrindell, W.A. (1999). Establishing clinically significant change: increment of precision and the distinction between individual and group level of analysis. Behaviour Research and Therapy, 37, 1169-1193], McGlinchey and Jacobson [McGlinchey, J. B., & Jacobson, N. S. (1999). Clinically significant but impractical? A response to Hageman and Arrindell. Behaviour Research and Therapy, 37, 1211-1217.] reported practically identical findings on reliable and clinically significant change across the two approaches. This led McGlinchey and Jacobson to conclude that there is little practical gain in utilizing the refined method over the traditional approach. Close inspection of the data used by McGlinchey and Jacobson however revealed a serious mistake with respect to the value of the standard error of measurement that was employed in their calculations. When the proper index value was utilised, further re-analysis by the present authors disclosed clear differences (i.e. different classifications of S's) across the two approaches. Importantly, these differences followed exactly the same pattern as depicted in Table 2 in Hageman and Arrindell (1999). The theoretical advantages of the refined method, i.e. enhanced precision, appropriate distinction between analysis at the individual and group levels, and maximal comparability of findings across studies, exceed those of the traditional method. Application of the refined method may be carried out within approximately half an hour, which not only supports its practical manageability, but also challenges the suggestion of McGlinchey and Jacobson (1999) that the relevant method would be too complex (impractical) for the average scientist. The reader is offered the opportunity of obtaining an SPSS setup in the form of an ASCII text file by means of which the relevant calculations can be carried out. The ways in which the valuable commentaries by Hsu [Hsu, L. M. (1999). A comparison of three methods of identifying reliable and clinically significant client changes: commentary on Hageman and Arrindell. Behaviour Research and Therapy, 37, 1195-1202.] and Speer [Speer, D. C. (1999). What is the role of two-wave designs in clinical research? Comment on Hageman and Arrindell. Behaviour Research and Therapy, 37, 1203-1210.) contribute to a better understanding of the technical/statistical backgrounds of the traditional and refined methods were also discussed.

Back to the future. The challenges of governing community health partnerships.

As the new century approaches, trustees of hospitals and health systems are facing a bewildering array of choices and challenges. The prospect of comprehensive health care reform has faded, the promise of managed care is disintegrating, and escalating costs and declining revenues continue to batter our health care organizations.

Layers of leadership. The challenges of collaborative governance.

If your goal is the health of a population, you can't do it alone. But working with partners requires special skills, not the least which is the ability to share control and put trust in others--in other words, collaborative governance. Here's some guidance for getting to this next level.

Synthesis and 5-lipoxygenase inhibitory activities of some novel 2-substituted 5-benzofuran hydroxamic acids.

A series of 2-substituted benzofuran hydroxyamic acids were synthesized as rigid analogs of simple (benzyloxy)phenyl hydroxamates, evaluated for their in vitro and in vivo 5-lipoxygenase activity and found to be potent inhibitors of the enzyme. Substituents which enhanced lipophilicity near the 2-position of the benzofuran nucleus increased inhibitor potency but reduced oral activity. Incorporation of small polar substituents such as methoxymethylene, hydroxymethylene, and amino (urea) on the acyl group led to more consistent oral activity. The most potent inhibitors of this series in vitro were N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)-ethyl]furancarboxamide (12) and methyl 5-[N-hydroxy-N-[1-(2-(3,4,5-trimethoxyphenyl)-5-benzofuranyl]ethyl]-5- oxopentanoate (17), both with IC50 values of 40 nM, and in vivo the most potent compound was N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)ethyl]urea, 20, with an ED50 = 10.3 mg/kg.

Novel bishydroxamic acids as 5-lipoxygenase inhibitors.

Two series of novel bishydroxamic acids 2 and 3 (types A and B) were synthesized and tested for inhibition of 5-lipoxygenase from rat basophile leukemia (RBL) cells. Both series were potent inhibitors of the isolated enzyme but only the type B reverse hydroxamic acids possessed significant oral activity. The most potent compound, orally, was 3a, [IC50 = 270 nM; ED50 = 1.86 mg/kg], which compares favorably with the clinically useful 5-lipoxygenase inhibitor, zileuton. Unlike known hydroxamic acid inhibitors, the oral activity in this series appears to be associated with the second hydroxamic acid group. The corresponding monohydroxamic acids retained inhibitor potency, in vitro, with reduced oral activity in a mouse zymosan peritonitis model. Compound 4e [IC50 = 7 nM], a monohydroxamic acid derivative related to 3a, is among the most potent inhibitors of the isolated enzyme yet to be reported.

A further refinement of the reliable change (RC) index by improving the pre-post difference score: introducing RCID.

The development of methods for demonstrating clinical (in addition to statistical) significance has been referred to as one of the major advances in outcome research. In a recent article, Speer (1992; Journal of Consulting and Clinical Psychology, 60, 402-408) suggested that the Reliable Change (RC) Index neglects possible confounding of improvement rate estimates by regression to the mean, to which latter's existence he concludes when a negative correlation between initial score and amount of change is observed. Speer (1992) proposed an alternative method that incorporates an adjustment which minimizes this confound when statistical regression has been empirically shown to be present. In the present paper, it is argued that both the rationale for arriving at this alternative method and the method itself are erroneous. Introducing RCID, the present authors provide a modification and refinement of the RC Index by improving the pre-post difference score, taking into account regression to the mean due to measurement unreliability. Further advantages of the RCID Index are briefly discussed.

Benzothiazole hydroxy ureas as inhibitors of 5-lipoxygenase: use of the hydroxyurea moiety as a replacement for hydroxamic acid.

A novel series of N-[(2-benzothiazolylthio)alkyl]-N'-hydroxyurea derivatives (9-25) was synthesized and evaluated for biological activity as inhibitors of 5-lipoxygenase both in vivo (mouse zymosan peritonitis assay) and in vitro (Ca2+ ionophore-stimulated human peripheral blood leukocyte model). The compounds of this series were based on the corresponding hydroxamic acid derivatives (1, 3, 4, and 5) which were moderately active in vitro but inactive in vivo. A number of compounds in the hydroxyurea series exhibited oral activity for 5-lipoxygenase inhibition. Results of studies relating structure to in vivo and in vitro 5-lipoxygenase activity are reported.

Reproductive performance in genetic lines selected for high or average milk yield.

Genetic lines were created by selection of service sires differing by approximately 450 kg of milk for estimated transmitting ability. High line sires were selected from the best available proven sires. Selection continued over 24 yr with up to eight generations of selection. Records from 708 nulliparous, 575 first parity, and 437 second parity animals were analyzed. High milk yield was associated with longer days open and calving intervals in both first and second parities. A 1000-kg increase in 305-d milk production was associated with average increases in both days open and calving interval of around 7 d in first parity and 13 d in second parity and with average increases in days to first detected estrus of 4.5 d in first parity. Difference between genetic lines for milk yield was 804 kg in first parity and 772 kg in second parity. Days open and calving interval were less for the average line in both parities and differed by 10 d in second parity. Other reproductive differences were small or insignificant. Selection for yield has affected reproductive fitness modestly.

Antinociceptive action of McN-5195 in rodents: a structurally novel (indolizine) analgesic with a nonopioid mechanism of action.

McN-5195 [(+/-)-trans-3-(2-bromophenyl)-octahydroindolizine] inhibited at nontoxic doses the nociceptive response in tail-pinch, tail-flick and 48 degrees C hot-plate tests of mice, with ED50 values of 38.2, 33.9 and 30.9 mg/kg i.p., respectively, and of rats, with ED50 values (i.p.) of 33.2 mg/kg (tail-flick) and 33.3 mg/kg (hot-plate). The compound was p.o. active in the acetylcholine-induced irritant test (ED50 = 20.1 mg/kg) in mice and the air-induced irritant test (ED50 = 33.2 mg/kg) in rats. McN-5195 blocked thalamic activity (multiunit recordings from the ventral posterolateral nucleus) evoked by noxious stimulation of the contralateral hindlimb of anesthetized rats, but did not alter thalamic activity during non-noxious stimulation. The antinociceptive action of McN-5195 was not blocked by naloxone and was not diminished in morphine-tolerant animals. McN-5195 did not affect arachidonate metabolism and was not active against carrageenan-induced paw edema or in an adjuvant arthritis test in rats. McN-5195 did not bind to opiate, serotonin S1 or S2, dopamine D2, alpha-1, alpha-2, beta adrenergic or gamma-aminobutyric acid-A receptors and did not inhibit the synaptic uptake of norepinephrine, serotonin, dopamine or gamma-aminobutyric acid. McN-5195-induced antinociception was not affected by reserpine or phentolamine pretreatment and was not reduced in clonidine-tolerant animals. Ketanserin and yohimbine inhibited McN-5195-induced antinociception by an indirect mechanism. Tolerance did not develop to chronic administration of McN-5195 (120 mg/kg 3 times per day for 10 days). We conclude that McN-5195 is a structurally novel (indolizine) antinociceptive agent that produces its analgesic action via a nonopioid mechanism, not involving products of arachidonate metabolism.

A practical rationale for trustee education.

In addition to the need for effective trustee orientation, continuous development is important for all board members to help them focus on strategic goals and develop leadership skills.