Comparing the direct normal form and multiple scales methods through frequency detuning.

Approximate analytical methods, such as the multiple scales (MS) and direct normal form (DNF) techniques, have been used extensively for investigating nonlinear mechanical structures, due to their ability to offer insight into the system dynamics. A comparison of their accuracy has not previously been undertaken, so is addressed in this paper. This is achieved by computing the backbone curves of two systems: the single-degree-of-freedom Duffing oscillator and a non-symmetric, two-degree-of-freedom oscillator. The DNF method includes an inherent detuning, which can be physically interpreted as a series expansion about the natural frequencies of the underlying linear system and has previously been shown to increase its accuracy. In contrast, there is no such inbuilt detuning for MS, although one may be, and usually is, included. This paper investigates the use of the DNF detuning as the chosen detuning in the MS method as a way of equating the two techniques, demonstrating that the two can be made to give identical results up to ε 2 order. For the examples considered here, the resulting predictions are more accurate than those provided by the standard MS technique. Wolfram Mathematica scripts implementing these methods have been provided to be used in conjunction with this paper to illustrate their practicality.

Fibroblast growth factor-2 drives and maintains progressive corneal neovascularization following HSV-1 infection.

Herpes simplex virus type 1 (HSV-1) infection of the cornea induces vascular endothelial growth factor A (VEGF-A)-dependent lymphangiogenesis that continues to develop well beyond the resolution of infection. Inflammatory leukocytes infiltrate the cornea and have been implicated to be essential for corneal neovascularization, an important clinically relevant manifestation of stromal keratitis. Here we report that cornea infiltrating leukocytes including neutrophils and T cells do not have a significant role in corneal neovascularization past virus clearance. Antibody-mediated depletion of these cells did not impact lymphatic or blood vessel genesis. Multiple pro-angiogenic factors including IL-6, angiopoietin-2, hepatocyte growth factor, fibroblast growth factor-2 (FGF-2), VEGF-A, and matrix metalloproteinase-9 were expressed within the cornea following virus clearance. A single bolus of dexamethasone at day 10 post infection (pi) resulted in suppression of blood vessel genesis and regression of lymphatic vessels at day 21 pi compared to control-treated mice. Whereas IL-6 neutralization had a modest impact on hemangiogenesis (days 14-21 pi) and lymphangiogenesis (day 21 pi) in a time-dependent fashion, neutralization of FGF-2 had a more pronounced effect on the suppression of neovascularization (blood and lymphatic vessels) in a time-dependent, leukocyte-independent manner. Furthermore, FGF-2 neutralization suppressed the expression of all pro-angiogenic factors measured and preserved visual acuity.

Randomized, placebo-controlled trial of paroxetine versus imipramine in depressed HIV-positive outpatients.

OBJECTIVE: This study examined whether a selective serotonin reuptake inhibitor (paroxetine) had comparable efficacy but greater tolerability than a tricyclic antidepressant (imipramine) in depressed patients with HIV infection. METHOD: Seventy-five HIV-positive patients (45% of whom had AIDS) were blindly and randomly assigned to receive paroxetine (N = 25), imipramine (N = 25), or placebo (N = 25) in a 12-week trial. The Hamilton Anxiety Rating Scale, the Hamilton Depression Rating Scale, the Clinical Global Impression scale, and the SAFETEE general inquiry (for safety and tolerability) were administered at weeks 2, 4, 6, 8, and 12. RESULTS: Fifty-six (75%) of the 75 patients completed 6 weeks and 34 (45%) completed 12 weeks of the trial. The mean daily doses of both paroxetine (33.9 mg) and imipramine (162.5 mg) were significantly more effective than placebo; they were comparably effective at weeks 6, 8, and 12 according to the intent-to-treat analysis and at week 8 according to the analysis for the subjects who completed the trial (for them, only imipramine was superior to placebo at week 12). There were significantly more dropouts due to side effects from imipramine (48%) than from both paroxetine (20%) and placebo (24%). CONCLUSIONS: Depressed patients with HIV infection responded to imipramine or paroxetine at a higher rate than to placebo irrespective of severity of immunosuppression. Because paroxetine was much better tolerated than imipramine, its overall effectiveness may be greater. However, because of the small study group and the high attrition rate, these findings cannot be generalized and may need replication in a larger study group.

Synthesis of some 5-phenylhexahydroazepino[4,5-b]indoles as potential neuroleptic agents.

5-Phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (3a) and five derivatives have been prepared and screened for neuroleptic activity. None of the compounds antagonized methamphetamine aggregate toxicity in mice. A number of compounds, including 3a and its 3-methyl derivative 3d, showed activity in the antidepressant screens.

Central nervous system activity of 7-substituted 1-azaphenoxathiin analogues and their oxidation products.

A number of 7-substituted 1-azaphenoxathiins and their sulfone oxidation products have been synthesized and screened for central nervous system activity. Some of the compounds have antidepressant activity, with the most active, 7-(trifluoromethyl)-1-azaphenoxathiin 10,10-dioxide (8), having similar potency to imipramine.

Antiulcer agents. 3. Structure-activity-toxicity relationships of substituted imidazo[1,2-a]pyridines and a related imidazo[1,2-a]pyrazine.

Investigation of the interrelationship between structure, antiulcer activity, and toxicology screening data derived from a series of compounds selected from structure-activity studies directed toward identifying a successor to 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, Sch 28080 (1), has identified 3-(cyanomethyl)-2,7-dimethyl-8-(phenylmethoxy)imidazo[1,2 -a]pyridine (5), 3-amino-2-methyl-8-(2-phenylethyl)imidazo[1,2-a]pyridine (6), and 3-amino-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyrazine (7). These analogues exhibit a combination of antisecretory and cytoprotective activity in animal models, while eliminating the adverse effects of the prototype 1. One of these, 3-amino-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyrazine, Sch 32651 (7), has a profile meeting all criteria.

Isobenzofurans as conformationally constrained miconazole analogues with improved antifungal potency.

A series of halogen-substituted isobenzofuran analogues was synthesized, which represented conformationally constrained analogues of miconazole (1). In vitro and in vivo topical antifungal activity against both dermatophytes and Candida species varied widely, but 13c proved to be significantly superior to both 1 and clotrimazole against a vaginal Candida infection in hamsters, while 13b was significantly more active than 1 against a a topical Trichophyton infection in guinea pigs. None of the compounds were orally active. When the most direct analogue of 1 proved to be among the least active, a molecular modeling study was done using 1, the two active analogues 13b and 13c, and the inactive analogue 13a. All four compounds possessed skeletally similar conformations either at or energetically readily accessible from the global minimum energy conformations. This common conformation of the inactive analogue 13a, however, occupies unique molecular volume space associated with two chlorine atoms, which must also present unique electrostatic properties at the receptor. The conformation-activity relationships discussed may contribute toward deduction of additional structural requirements for pharmacophore optimization and more efficacious antifungal drugs.

Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity.

The design and synthesis of novel, orally active, potent, and selective inhibitors of influenza neuraminidase differing structurally from existing neuraminidase inhibitors are described. X-ray crystal structures of complexes of neuraminidase with known five- and six-membered ring inhibitors revealed that potent inhibition of the enzyme is determined by the relative positions of the interacting inhibitor substituents (carboxylate, glycerol, acetamido, hydroxyl) rather than by the absolute position of the central ring. This led us to design potential neuraminidase inhibitors in which the cyclopentane ring served as a scaffold for substituents (carboxylate, guanidino, acetamido, alkyl) that would interact with the four binding pockets of the neuraminidase active site at least as effectively as those of the established six-membered ring inhibitors such as DANA (2), zanamivir (3), and oseltamivir (4). A mixture of the isomers was prepared initially. Protein crystallography of inhibitor-enzyme complexes was used to screen mixtures of isomers in order to identify the most active stereoisomer. A synthetic route to the identified candidate 50 was developed, which featured (3 + 2) cycloaddition of 2-ethylbutyronitrile oxide to methyl (1S,4R)-4[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (43). Structures of the synthetic compounds were verified by NMR spectroscopy using nuclear Overhauser effect methodology. Two new neuraminidase inhibitors discovered in this work, 50 and 54, have IC(50) values vs neuraminidase from influenza A and B of <1 and <10 nM, respectively. These IC(50) values are comparable or superior to those for zanamivir and oseltamivir, agents recently approved by the FDA for treatment of influenza. The synthetic route used to prepare 50 and 54 was refined so that synthesis of pure active isomer 54, which has five chiral centers, required only seven steps from readily available intermediates. Further manipulation was required to prepare deoxy derivative 50. Because the activities of the two compounds are comparable and 54 [RWJ-270201 (BCX-1812)] is the easier to synthesize, it was selected for further clinical evaluation.

Antiulcer agents. 1. Gastric antisecretory and cytoprotective properties of substituted imidazo[1,2-a]pyridines.

A novel class of antiulcer agents, the substituted imidazo[1,2-a]pyridines, is described. The present compounds are not histamine (H2) receptor antagonists nor are they prostaglandin analogues, yet they exhibit both gastric antisecretory and cytoprotective properties. The mechanism of gastric antisecretory activity may involve inhibition of the H+/K+-ATPase enzyme. Structure-activity studies led to the identification of 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, SCH 28080 (27), which was selected for further development and clinical evaluation.

Antiulcer agents. 2. Gastric antisecretory, cytoprotective, and metabolic properties of substituted imidazo[1,2-a]pyridines and analogues.

The search for a successor to 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, Sch 28080 (27), a compound that exhibits gastric antisecretory and cytoprotective properties and has undergone clinical evaluation as an antiulcer agent, has culminated in the identification of four related compounds that exhibit pharmacologic profiles similar to that of 27. In three of these potential successors an amino group functions as a surrogate for the 3-cyanomethyl substituent of the prototype. The present work concerns, in addition to an evaluation of the structure-activity relationships of a series of analogues of 27, preliminary studies of the pharmacodynamics and metabolism of 27, performed with the aid of cyano carbon labeled versions of the drug (13C labeled; 28; 14C labeled, 29). These studies have shown that 27 is well-absorbed and extensively metabolized and that the major metabolite of 27 is the thiocyanate anion. A similar study performed on 3-amino-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, labeled at the 3-position with carbon-13 (41) or carbon-14 (42), revealed that this compound, which has an antisecretory/cytoprotective profile comparable to that of 27, is also metabolized to thiocyanate anion, although this must occur via a different mechanism. The chemistry section includes a discussion of the potential sites of protonation of the pharmacologically similar 3-amino analogue 40 and the structurally related imidazo[1,2-a]pyrazine 67. Predictions based on charge density and protonation product stabilities are presented. That N1 is the site of protonation in these analogues has been definitively demonstrated by X-ray crystal structure analysis, which also unequivocally established the assigned imidazo[1,2-a]pyrazine ring structure.

Antiulcer agents. 4. Conformational considerations and the antiulcer activity of substituted imidazo[1,2-a]pyridines and related analogues.

Definition of the interrelationship between the conformational characteristics of a series of substituted imidazo[1,2-a]pyridines and their antiulcer activity was investigated by examining the conformational properties of 3-cyano-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine (1), using a variety of experimental and theoretical methods. The results of these studies was the identification of two distinctly different candidates, designated the "folded" and the "extended" conformation, respectively, to represent the two possible minimum-energy conformations of 1. In order to select the biologically relevant conformer, a group of 3-substituted 2-methylimidazo[1,2-a]pyridines, having either a cis or a trans 2-phenylethenyl substituent at the 8-position were designed as conceptually simple and synthetically accessible semirigid analogues of the respective candidate conformers. Gastric antisecretory activity was found to reside only in the trans isomers (compounds 11, 15, and 17), which mimic the "extended" conformation. This observation led to the construction of 8,9-dihydro-2-methyl-9-phenyl-7H-imidazo[1,2-a]pyrano[2,3-c]pyridi ne-3- acetonitrile (40), a rigid tricyclic analogue that is effectively locked in the "extended" conformation and that exhibited an antiulcer profile comparable to that of prototype 1. These results unequivocally demonstrate that, in accord with expectation for a drug operating at a specific receptor, the conformational characteristics of the molecule have a substantial effect in determining its antiulcer activity. More precisely, it has been demonstrated that it is the "extended" conformation of 1 that represents the "bioactive" form of the drug. These results constitute the basis for a molecular probe that should aid in the investigation of the as yet uncharacterized gastric proton pump enzyme (H+/K+-ATPase), by means of which 1 and its analogues presumably exert their pharmacologic actions.

Calcium regulation in tissue-cultured human and bovine lens epithelial cells.

PURPOSE: To study calcium regulatory mechanisms in lens cells with particular reference to the relative contributions from the calcium adenosine triphosphatase of plasma and endoplasmic reticulum membranes, respectively. METHODS: The calcium-sensitive fluorescent dye, Fura 2, was incorporated into tissue-cultured human and bovine epithelial cells and internal calcium was calibrated using the ionomycin (1 microM) method. The dynamics of calcium release from the endoplasmic reticulum were also studied in digitonin-permeabilized bovine cells. RESULTS: Tissue-cultured bovine and human lens cells have very similar resting calcium levels (235 +/- 22 nM and 216 +/- 12 nM, respectively). Thapsigargin caused an increase in cytoplasmic calcium both in the presence and absence of external calcium, but the calmodulin antagonist W7 only initiated an increase in the presence of external Ca2+. The effects of thapsigargin and W7 were additive. Exposing lens cells to Na(+)-free perfusing solutions caused a transient increase in internal Ca2+. Bovine lens cells permeabilized by digitonin-released Ca2+ when exposed to inositol (1,4,5) triphosphate and the effect was maximal at 1 microM. CONCLUSIONS: Lens cytoplasmic calcium is controlled by calcium adenosine triphosphatases at the plasma and endoplasmic reticulum membranes. The former is inhibited by W7 and insensitive to thapsigargin whereas the latter is inhibited by thapsigargin, but insensitive to W7. The lens endoplasmic reticulum store is also controlled by an inositol (1,4,5) trisphosphate calcium-release mechanism. Na+/Ca2+ exchange plays a relatively minor role in calcium regulation, at least at resting calcium levels.

Inhibition of glutathione reductase by flavonoids. A structure-activity study.

A structure-activity study of fourteen chemically related flavonoids was conducted to evaluate their abilities to inhibit glutathione reductase (GR). By comparing the I50 values of flavonoids from different classes possessing an identical hydroxyl configuration, we determined the following order of potency for inhibition of GR: anthocyanidin > dihydroflavonol = chalcone > flavonol > catechin. Enzyme inhibition by delphinidin chloride and myricetin was partially prevented in a N2 atmosphere which implicates a role for oxygen in the mechanism of inhibition. To determine the role of oxygen species in enzyme inhibition, GR was preincubated with either mannitol, diethylenetriaminepenta-acetic acid (DETAPAC), superoxide dismutase (SOD), catalase (CAT), or SOD and CAT prior to assays for enzyme inhibition by flavonoids. Enzyme inhibition by delphinidin chloride and myricetin was suppressed by the addition of SOD, suggesting that superoxide (O2-.) is involved. However, inhibition by quercetin and morin was not sensitive to antioxidants. To further investigate the role of O2-. in GR inhibition, a superoxide generating system was utilized in the presence and absence of flavonoid. The O2-. generating system failed to inhibit GR in the absence of flavonoid but enhanced the inhibition by myricetin, indicating that the O2-. did not directly inhibit GR but reacted directly with certain flavonoids to form a reactive intermediate which, in turn, inhibited GR. These findings suggest that the mechanism of inhibition of GR by flavonoids is complex and may have oxygen-dependent and oxygen-independent components.

Relationship between inhibition of mitochondrial respiration by naphthoquinones, their antitumor activity, and their redox potential.

The physicochemical properties of a series of 1,4-naphthoquinones were correlated with their activities against Sarcoma-180 by Hodnett et al. [J. med. Chem. 26, 570 (1983)]. Redox potential was the most important molecular parameter determining antitumor activity in this series of compounds, suggesting that interference with electron transport contributes to their cytotoxicity. We evaluated this same series of quinones for their abilities to inhibit the beef heart mitochondrial succinoxidase and NADH-oxidase enzyme systems. They exhibited a broad range of inhibitory potencies. There was a strong relationship between succinoxidase inhibition, antitumor activity (T/C ratio), and redox potential. The redox potentials of the quinones which inhibited succinoxidase lay within the narrow range of endogenous components of the respiratory chain. In contrast, inhibition of NADH-oxidase was related to redox potential but did not significantly predict antitumor activity. These results suggest that inhibition of mitochondrial succinoxidase may be a useful preliminary screen for antitumor activity.

Antidepressant efficacy in HIV-seropositive outpatients with major depressive disorder: an open trial of nefazodone.

BACKGROUND: Treatment studies of major depression in patients who are seropositive for the human immunodeficiency virus (HIV) have shown comparable efficacy for both tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Nefazodone appears to be more tolerable than TCAs and similar to SSRIs. This study examined the efficacy and tolerability of nefazodone in an open 12-week trial of HIV-seropositive outpatients with major depressive disorder. METHOD: Fifteen HIV-seropositive patients with DSM-IV major depressive disorder and a 21-item Hamilton Rating Scale for Depression (HAM-D) score of > or =18 were treated with open-label nefazodone for 12 weeks. Hamilton Rating Scale for Anxiety, HAM-D, Clinical Global Impressions scale, and Systematic Assessment for Treatment Emergent Events general inquiry (for safety and tolerability) scores were obtained at weeks 2, 4, 6, 8, and 12. RESULTS: Of 15 patients receiving nefazodone, 4 discontinued treatment (1 for adverse effects). Of 11 patients who completed the trial, 8 (73%) were classified as full responders with a 50% reduction in HAM-D scores and final CGI score of 1 or 2, and 10 (91%) were classified as partial responders (only 50% reduction in HAM-D scores). Nefazodone-treated subjects experienced few total adverse effects (mean = 1.5), no sexual side effects, and low rates of adverse-effect-related dropout (1 subject, 7%). CONCLUSION: Depressed HIV-seropositive outpatients respond to nefazodone comparably to other outpatient populations and have few adverse effects, suggesting that nefazodone may have a role in the treatment of depression in HIV-seropositive patients. Potential drug interactions with protease inhibitors indicate that it is essential to evaluate for appropriate dosing to avoid adverse effects and increase overall antidepressant efficacy.

A profile of medically serious suicide attempts.

BACKGROUND: This study identified factors associated with medically serious suicide attempts (requiring medical hospitalization). METHOD: Demographic information, current psychiatric mental state, suicide attempt and psychiatric history characteristics, and DSM-IV diagnoses were compared between 65 patients hospitalized for a medically serious suicide attempt (MSSA) and 32 patients seen in the emergency room for suicide attempt but not medically hospitalized (NMSSA). RESULTS: Those with MSSAs had a higher rate of substance-induced mood disorder (but not substance abuse or dependence), while those with NMSSA had more attempts, more years since first attempt, and a higher rate of sexual and physical abuse, traumatic life events, borderline personality disorder, and bipolar disorder. CONCLUSION: Substance-induced mood disorder is an important diagnosis in the evaluation of suicidal patients. The vulnerability of mood effects caused by substance abuse may lead to a more serious suicide attempt despite less extensive psychiatric problems. The most important early psychiatric intervention may be the immediate recognition and aggressive treatment of an individual's affective and substance use disorders.

Maternal acceptance of voluntary human immunodeficiency virus antibody testing during the newborn period with the Guthrie card.

In order to provide the opportunity for women delivering newborns to have human immunodeficiency virus (HIV) testing we piloted a hospital-based voluntary HIV testing program during the newborn period using the Guthrie card. During the study period 789 women were offered newborn HIV antibody testing. Test acceptance during the newborn period (61.0%) was comparable to that reported for the prenatal period (60.6%). Overall 77.4% of women were tested in the newborn period or reported being tested in the prenatal period. Prenatal test acceptance best predicted newborn HIV test acceptance (odds ratio, 3.37; 95% confidence interval, 2.40 to 4.74). When compared to HIV testing during the newborn period prenatal HIV testing is preferable because it enables the recognition of HIV infection early during pregnancy and allows the mother the option to elect zidovudine therapy and potentially prevent infection in her newborn. However, when prenatal HIV testing is not routinely made available or cannot be assured, women should be offered the opportunity to be tested during the newborn period.

Cataracts in childhood leukaemia.

The incidence and severity of cataract were studied in 37 children who had completed treatment for acute lymphoblastic leukaemia. Twelve (32%) had posterior subcapsular lens opacities. Treatment had included corticosteroids and cranial irradiation, but no dose relationship was evident. The boys were more severely affected than the girls. Although none of the lens opacities was optically significant, clinicians should be aware of the potential risk to vision.

Brief application of simplified habit reversal to treat stuttering in children.

We evaluated a brief therapy protocol involving the simplified regulated breathing method as a treatment for stuttering in children. The simplified treatment included awareness training, competing response training, and social support. Treatment was implemented in a multiple baseline across subjects design for 5 boys between the ages of 5 and 11. Each child received a 1 h treatment session, and 1/2 h booster sessions as needed. Four of the 5 children reduced their stuttering to less than 3% stuttered words (the criterion for successful treatment) after one 1 h treatment session. These results were maintained for 3 of the subjects from 6 to 9 months posttreatment. Social validity measures revealed significant differences between ratings on baseline and posttreatment speech samples. Treatment acceptability and credibility measures indicated that the subjects' guardians found the simplified regulated breathing method a reasonable treatment for stuttering in children.

On the disposal of contaminated milk in coastal waters.

Estimates have been made of the reduction in dissolved oxygen levels in coastal waters that would result from the disposal of contaminated milk following a radiological accident. Two contrasting sites were chosen: the Bristol Channel near Hinkley Point and the coast of Cumbria near Sellafield. The results suggest that the dilution would be sufficiently strong near Hinkley Point, due to vigorous tidal mixing, that the impact on the DO levels of the coastal waters would be negligible. However, at both Sellafield and Heysham the disposal of milk could result in a reduction of the DO by 1-2 mg l(-1). In contrast to shallow estuarine waters, the recovery of oxygen levels due to the effects of re-aeration through surface gas exchange is unlikely to be significant due to the depth of the coastal waters. However, the recovery of the dissolved oxygen levels to ambient conditions following the completion of the discharge would occur on a time scale of about 17 days due to mixing of the DO deficit plume into the surrounding waters.