The use of theophylline in chronic obstructive pulmonary disease.
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Animals↗
Biomedical subjects
R Pauwels
Publications and source records attributed to R Pauwels.
The inhalation device influences lung deposition and bronchodilating effect of terbutaline.
The development of new inhalation devices for asthma drugs raises the issue of the relationship between pulmonary deposition and therapeutic effect of inhaled drugs in patients with obstructive lung diseases. We thus conducted a randomized, double-blind and double-dummy, four-period crossover study in 13 patients with moderate asthma (mean age 36 yr; FEV1 59% of predicted), who inhaled 0.25 and 0.5 mg terbutaline sulphate on separate occasions either via a pressurized metered dose inhaler (pMDI) or Turbuhaler (TBH). Pulmonary deposition was 8.1 +/- 2.7% and 8.3 +/- 2.3%, respectively, of the nominal dose for pMDI and 19.0 +/- 7.3%, and 22.0 +/- 8.1% for TBH. The FEV1 increase after 0.25 mg terbutaline sulphate via TBH was significantly greater than after 0.25 mg via pMDI. No significant differences in FEV1 increase were observed between 0.25 mg via TBH, 0.5 mg via pMDI, or 0.5 mg via TBH. Other lung function variables showed similar dose- and device-related changes. We concluded that: (1) the dose of terbutaline sulphate deposited in the lungs is dependent on which inhalation system is used; (2) TBH delivers about twice the amount of drug to the lungs as the pMDI; and (3) the observed difference in deposition is reflected in the bronchodilating effect.
Administration, Inhalation↗
Severity of asthma is related to endotoxin in house dust.
In sensitized subjects, exposure to the mite allergen appears to be only one of several factors leading to asthma. We hypothesized that in association with allergen exposure, endotoxin, a proinflammatory agent present in house dust (HD), influences the severity of asthma. Using a cross-sectional study design, we investigated a group of 69 consecutive dust mite (HDM)-sensitized subjects defined as having rhinitis (n = 20) or asthma (n = 49); the latter were evaluated functionally and clinically by three different scores and by their need for daily medication. Concentrations of Dermatophagoides pteronyssinus p I allergen (Der p I) (by two-site monoclonal antibody enzyme-linked immunosorbent assay [ELISA]), guanine (by high-pressure liquid chromatography [HPLC]), and endotoxin (by modified Limulus. amebocyte lysate assay) were measured in HD collected in duplicate from the mattresses and floors in each subject's home. The concentrations of Der p I and of guanine in HD collected from mattresses were significantly higher in asthmatic subjects than in those with rhinitis (p < 0.05 and < 0.04, respectively). In subjects (n = 37) exposed to a high level of HDM allergen (i.e., Der p I > or = 10 micrograms/g HD and/or guanine > or = 0.10 mg/100 mg HD), the severity of asthma was unrelated to mite allergen concentration in HD. On the contrary, the severity of asthma was related to concomitant exposure to endotoxin in HD, since the concentration of HD endotoxin was significantly and inversely correlated with FEV1 (p < 0.05), FEV1/FVC (p < 0.02), daily need for oral (p < 0.01) and inhaled (p < 0.01) corticosteroids, daily need for beta 2 agonists (p < 0.001) and xanthines (p < 0.01), and clinical scores such as the modified Aas score (p < 0.01). In HDM-sensitized subjects exposed to a high level of allergen, the concentration of endotoxin measured in HD is an important determinant of asthma severity.
Adult↗
The current place of nedocromil sodium in the treatment of asthma.
Current guidelines for the treatment of asthma are based on the fact that asthma is an inflammatory disease and that all forms of persistent asthma, whether mild, moderate, or severe, require treatment with a controller medication to reverse or prevent the underlying inflammation. A patient can be considered to have mild persistent asthma if symptoms occur one or more times a week (but less than daily), if exacerbations are affecting activity or sleep, if nighttime symptoms occur more than twice a month, or if peak expiratory flow or FEV1 is equal to or greater than 80% of the predicted value or has a variability of 20% to 30%. Just one of these clinical features is needed to define the condition. A patient with this condition should be treated with a controller medication that is taken daily; the physician may choose between a low dose of inhaled corticosteroid, nedocromil sodium or cromolyn sodium, or slow-release theophylline. The choice will vary depending on the physician and the type of patient being treated. Data on clinical efficacy and safety support the current position of nedocromil sodium as a primary treatment for mild persistent asthma.
Asthma↗
Quantitative structural activity relationship study of bis-tetraazacyclic compounds. A novel series of HIV-1 and HIV-2 inhibitors.
This work describes a study of quantitative structural activity relationships (QSAR) of bis-tetraazamacrocyclic compounds. These compounds represent a novel class of very potent and selective anti-HIV inhibitors, with a new mode of action. The QSAR study correlates structural features of the compounds with anti-HIV activity, resulting in a model which has a high predictive capacity (predictive r2 = 0.79). This predictive model will be of major importance for the design of new anti-HIV inhibitors of this class. Use is made of partial least-squares (PLS) analysis, with the novelty being that structural features derived by inclusion of all sterically allowed conformations for each molecule are included in the analysis. PLS analysis was made of descriptors, including structural parameters, macrocyclic ring size, metal chelating ability, etc., and those features necessary for the observed antiviral activities of these compounds were deduced from the models. Since all sterically allowed conformations are included in the analysis, the flexibility of the molecules is also taken into account. In addition, a correlation is found (indicated by a predictive r2 value of 0.61) between inhibition of HIV-1 (HIV-2) and syncytium formation inhibition in the presence of bis-cyclam analogues, leading to the suggestion of a common target, namely, gp120, being involved in both inhibition of virus replication and syncytium formation.
Antiviral Agents↗
Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-tetraazamacrocycles that inhibit HIV replication. Effects of macrocyclic ring size and substituents on the aromatic linker.
We have previously described the potent and selective inhibition of several strains of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) by JM2763, an n-propyl-linked dimer of the 1,4,8,11-tetraazamacrocyclic (cyclam) ring system. Upon further investigation, we have also found that incorporating an aromatic rather than aliphatic linker leads to analogs with higher antiviral potency. The prototype, JM3100 (19a, isolated as the octahydrochloride salt), which contains a p-phenylenebis(methylene) moiety linking the cyclam rings, inhibited the replication of HIV-1 (IIIB) and HIV-2 (ROD) at EC50's of 4.2 and 5.9 nM, respectively, while remaining nontoxic to MT-4 cells at concentrations exceeding 421 microM. In order to identify the structural features of bis-tetraazamacrocycles required for potent activity, we have prepared a novel series of phenylenebis(methylene)-linked analogs, in which the macrocyclic ring size was varied from 12 to 16 ring members. Depending upon the substitution of the phenylenebis(methylene) linker (para or meta), sub-micromolar anti-HIV activity was exhibited by analogs bearing macrocycles of 12-14 ring members but with varying cytotoxicity to MT-4 cells. Furthermore, while we found that identical macrocyclic rings are not required for activity, substituting an acyclic polyamine equivalent for one of the cyclam rings in 19a resulted in a substantial reduction in anti-HIV potency, clearly establishing the importance of the constrained macrocyclic structure. A short series of transition metal complexes of 19a were also prepared and evaluated. Complexes of low kinetic stability such as the bis-zinc complex retained activity comparable to that of the parent compound. Finally, the activity of bicyclam analogs appears to be insensitive to the electron-withdrawing or -donating properties of substituents introduced onto the linker, but sterically hindering groups such as phenyl markedly reduced activity. As a result, several analogs with anti-HIV potency comparable to that of 19a have been identified.
Antiviral Agents↗
Antiviral effects of plasma and milk proteins: lactoferrin shows potent activity against both human immunodeficiency virus and human cytomegalovirus replication in vitro.
Native and chemically derivatized proteins purified from serum and milk were assayed in vitro to assess their inhibiting capacity on the cytopathic effect of human immunodeficiency virus (HIV)-1 and human cytomegalovirus (HCMV) on MT4 cells and fibroblasts, respectively. Only native and conformationally intact lactoferrin from bovine or human milk, colostrum, or serum could completely block HCMV infection (IC50 = 35-100 micrograms/mL). Moreover, native lactoferrin also inhibited the HIV-1-induced cytopathic effect (IC50 = 40 micrograms/mL). When negatively charged groups were added to lactoferrin by succinylation, there was a 4-fold stronger antiviral effect on HIV-1, but the antiviral potency for HCMV infection was mostly decreased. Lactoferrin likely exerts its effect at the level of virus adsorption or penetration (or both), because after HCMV penetrated fibroblasts, the ongoing infection could not be further inhibited.
Animals↗
Asthma mechanisms, determinants of severity and treatment: the role of nedocromil sodium. Report of a workshop held in Whistler, British Columbia, Canada, 18-19 May 1995.
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Anti-Asthmatic Agents↗
Future of anti-inflammatory therapy in asthma.
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Anti-Inflammatory Agents↗
Allergen-induced airway inflammation and bronchial responsiveness in wild-type and interleukin-4-deficient mice.
T helper 2 (Th2)-like cytokines are thought to play a crucial role in the pathogenesis of airway inflammation in atopic asthma, leading to bronchial hyperresponsiveness. To investigate the role of the principal Th2 cytokine interleukin-4 (IL-4) in asthma, we examined the allergen-induced changes in airway morphology and bronchial responsiveness (BR) in an in vivo mouse model. C57BL/6 mice were actively sensitized to ovalbumin (OVA) and exposed daily to aerosolized OVA or saline (SAL) for 7 days. Twenty-four hours after the last allergen exposure, total and differential counts of bronchoalveolar lavage cells revealed a significant increase of eosinophils and lymphocytes in OVA-exposed immunized mice compared with SAL-exposed animals. In IL-4-deficient (IL-4-/-) mice, treated in the same way, there were substantially fewer eosinophils in bronchoalveolar lavage compared with wild-type mice. Allergen exposure of actively sensitized wild-type mice induced a significant increase of BR to carbachol and to serotonin compared with SAL-exposed mice. In contrast, OVA exposure of immunized IL-4-/- mice did not augment BR to serotonin compared with SAL-challenged IL-4-/- mice. In conclusion, these data indicate that repeated allergen exposure in sensitized mice induces airway inflammation and bronchial hyperresponsiveness, and that IL-4 plays a predominant role in the pathogenesis of both phenomena.
Allergens↗
Bioequivalence of inhaled drugs.
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Administration, Inhalation↗
Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance.
The locations of HIV-1 RT nucleoside and non-nucleoside inhibitor-binding sites and inhibitor-resistance mutations are analyzed in the context of the three-dimensional structure of the enzyme and implications for mechanisms of drug inhibition and resistance are discussed. In order to help identify residues that may play a role in inhibitor binding, solvent accessibilities of amino acids that comprise the inhibitor-binding sites in the structure of HIV-1 RT complexed with a dsDNA template-primer are analyzed. While some mutations that cause resistance to nucleoside analogs, such as AZT, ddI, and ddC, are located near enough to the dNTP-binding site to directly interfere with binding of nucleoside analogs, many are located away from the dNTP-binding site and more likely confer resistance by other mechanisms. Many of the latter mutations are located on the surface of the DNA-binding cleft and may lead to altered template-primer positioning or conformation, causing a distortion of the geometry of the polymerase active site and consequent discrimination between normal and altered dNTP substrates. Other nucleoside analog-resistance mutations located on the periphery of the dNTP-binding site may exert their effects via altered interactions with dNTP-binding site residues. The structure of the hydrophobic region in HIV-1 RT that binds non-nucleoside inhibitors, for example, nevirapine and TIBO, has been analyzed in the absence of bound ligand. The pocket that is present when non-nucleoside inhibitors are bound is not observed in the inhibitor-free structure of HIV-1 RT with dsDNA. In particular it is filled by Tyr181 and Tyr188, suggesting that the pocket is formed primarily by rotation of these large aromatic side-chains. Existing biochemical data, taken together with the three-dimensional structure of HIV-1 RT, makes it possible to propose potential mechanisms of inhibition by non-nucleoside inhibitors. One such mechanism is local distortion of HIV-1 RT structural elements thought to participate in catalysis: the beta 9-beta 10 hairpin (which contains polymerase active site residues) and the beta 12-beta 13 hairpin ("primer grip"). An alternative possibility is restricted mobility of the p66 thumb subdomain, which is supported by the observation that structural elements of the non-nucleoside inhibitor-binding pocket may act as a "hinge" for the thumb.(ABSTRACT TRUNCATED AT 400 WORDS)
Amino Acid Sequence↗
Triterpene derivatives that block entry of human immunodeficiency virus type 1 into cells.
A series of triterpene compounds characterized by a stringent structure-activity relationship were identified as potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) replication. Currently studied botulinic derivatives have 50% inhibitory concentrations (IC50) against HIV-1 strain IIIB/LAI in the 10 nM range in several cellular infection assays but are inactive against HIV-2. These compounds did not significantly inhibit the in vitro activities of several purified HIV-1 enzymes. Rather, they appeared to block virus infection at a postbinding, envelope-dependent step involved in the fusion of the virus to the cell membrane.
Antiviral Agents↗
Bronchopneumonia caused by Propionibacterium acnes.
Propionibacterium acnes was identified as the pathogen in a case of subacute lung infection by examination of an open lung biopsy specimen. The patient was a 65-year-old male with exacerbation of chronic lung disease. The organism was isolated in pure culture and was present in large numbers on Gram stain. Histological examination demonstrated active interstitial fibrosis; macrophages laden with Propionibacterium acnes antigen were revealed using a peroxidase-antiperoxidase stain. This is the first report of subacute infection of pulmonary tissue due to this organism.
Aged↗
Characterization of HIV-1 strains isolated from patients treated with TIBO R82913.
The drug sensitivities of human immunodeficiency virus type 1 (HIV-1) isolates from a group of four untreated and seven TIBO R82913-treated patients were determined in a reverse transcriptase (RT) assay. Five of the treated patients harbored HIV-1 isolates with R82913 sensitivity comparable to that of the isolates of untreated patients, ranging from almost 2-fold higher sensitivity to 13-fold lower sensitivity than that of recombinant p66 RT. From one of the seven treated patients, an HIV-1 strain with a 20-fold reduced sensitivity to R82913 could be isolated; and from another patient, a strain with 100-fold reduced sensitivity (resistance) was isolated. The drug-resistant strain in this patient emerged after 3 weeks of treatment and was due to the Y188L mutation in its RT. On passaging the virus in cord blood lymphocytes, but not in CEM cells, the resistant virus was lost in favor of a different HIV-1 strain harboring the wild-type Y188 with a sensitivity to R82913 comparable to that of wild-type p66 RT. In several HIV-1 isolates (from treated and untreated patients), some HIV-2- and CIVgab-specific amino acids were found. One of these substitutions, that is, I/V179D (from an untreated patient), conferred a sevenfold reduced RT sensitivity to R82913.
Acquired Immunodeficiency Syndrome↗
New tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione derivatives are potent inhibitors of human immunodeficiency virus type 1 replication and are synergistic with 2',3'-dideoxynucleoside analogs.
Tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) derivatives were shown to specifically block human immunodeficiency virus type 1 (HIV-1) replication through a unique interaction with the HIV-1 reverse transcriptase (RT). Through further modification of the lead compounds and structure-activity relationship analysis several new TIBO derivatives that show high potency, selectivity, and specificity against HIV-1 have been obtained. A new TIBO derivative, R86183, inhibits the replication of HIV-1, but not HIV-2, in a variety of CD4+ T-cell lines and peripheral blood lymphocytes, at a concentration of 0.3 to 30 nM, which is at least 4 orders of magnitude lower than the 50% cytotoxic concentration. Whereas an HIV-1 strain containing the Leu-100-->Ile mutation in the RT gene is about 400-fold less susceptible, R86183 still inhibits the replication of an HIV-1 strain containing the Tyr-181-->Cys RT mutation by 50% at a concentration of 130 nM. R86183 inhibits the poly(C).oligo(dG)12-18-directed HIV-1 RT reaction by 50% at a concentration of 57 nM. The antiviral activity of 22 TIBO derivatives in cell culture correlated well with their activity against HIV-1 RT. No such correlation was found for their cytotoxicity. The combination of R86183 with either zidovudine or didanosine resulted in a synergistic inhibition of HIV-1 (strain IIIB) replication. Combination of R86183 with the protease inhibitor Ro31-8959 was found to be additive. Also described is a dilution protocol circumventing overestimation and underestimation of antiviral activity due to adherence to plastic surfaces.
Antiviral Agents↗
Highly potent and selective inhibition of human immunodeficiency virus by the bicyclam derivative JM3100.
Bicyclams, in which the cyclam (1,4,8,11-tetraazacyclotetradecane) moieties are tethered via an aliphatic bridge (i.e., propylene, as in JM2763) are potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) (E. De Clercq, N. Yamamoto, R. Pauwels, M. Baba, D. Schols, H. Nakashima, J. Balzarini, Z. Debyser, B. A. Murrer, D. Schwartz, D. Thornton, G. Bridger, S. Fricker, G. Henson, M. Abrams, and D. Picker, Proc. Natl. Acad. Sci. USA 89:5286-5290, 1992). We have now found that the bicyclam JM3100, in which the cyclam moieties are tethered by an aromatic bridge [i.e., phenylenebis(methylene)], inhibits the replication of various HIV-1 and HIV-2 strains in various cell lines at a 50% effective concentration (EC50) of 1 to 10 ng/ml, which is about 100-fold lower than the concentration required for JM2763 to inhibit HIV replication and at least 100,000-fold lower than the cytotoxic concentration (> 500 micrograms/ml). In primary T4 lymphocytes or primary monocytes, JM3100 proved inhibitory to HIV-1(IIIB) and several clinical HIV-1 isolates at an EC50 of less than 1 ng/ml. On the basis of time-of-addition experiments, JM3100 appeared to interact with a viral uncoating event, and this was further corroborated by an uncoating assay in which RNase sensitivity of [5-3H]uridine-labeled virions was monitored. In addition, but possibly mechanistically related, JM3100 blocks formation of infectious particles. JM3100 was also found to interfere directly with virus-induced syncytium formation, albeit at a higher concentration (1 to 2 microgram/ml) than that required for inhibition of viral replication. Following subcutaneous injection of 10 mg of JM3100 per kg of body weight to rabbits, anti-HIV activity was detected in serum corresponding to serum drug levels exceeding for at least 6 h by >100-fold the EC(50) required to inhibit HIV replication in vitro. When combined with either 3'-azido-2',3' -dideoxythymidine or 2',3' -dideoxyinosine, JM3100 achieved a additive inhibition of HIV replication, and when repeatedly subcultivated in the presence of JM3100, the virus remained sensitive to the compound for at least 30 passages (120 days) in cell culture.
Animals↗
Preparation and anti-HIV activity of O-acylated heparin and dermatan sulfate derivatives with low anticoagulant effect.
In order to increase the ratio of anti-HIV activity to anticoagulant activity, glycosaminoglycan derivatives selectively substituted at OH and/or COOH groups were prepared. Standard heparin, heparin fragments, or dermatan sulfate were converted to their tributylammonium or tetrabutylammonium salts. Their selective O-acylation to various (controlled) degrees was carried out in a homogeneous way in N,N-dimethylformamide using carboxylic acid anhydrides and 4-(dimethylamino)pyridine as catalyst. Esterification of the COOH groups was performed by the addition of alkyl halide to an N,N-dimethylformamide solution of glycosaminoglycan tetrabutylammonium salts. The in vitro anticoagulant activity, the activity against HIV-1 and HIV-2 cytopathicity, the cytotoxicity, and the activity on the induction of giant cell formation were determined. O-acylation (O-butyrylation or O-hexanoylation) of the heparin fragments obtained by periodate depolymerization (compounds 2d and 2e), and their esters (compounds 7i and 7j), yielded products with very low anticoagulant effects in vitro, yet potent activity against both HIV-1 and HIV-2 induced cytopathicity, and low, if any, cytotoxicity. As compared to other anionic polysaccharides, these acylated derivatives are more active as inhibitors of HIV-induced giant-cell formation. Their anti-HIV activity is related to the degree of O-acylation and is mainly due to the inhibition of virus adsorption to the target cells.
Acylation↗