Sino-Nasal Status in Patients with Chronic Obstructive Pulmonary Disease.

Background. Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease with serious impact on quality of life (QoL). There are limited studies available supporting coexistence of sino-nasal involvement in COPD. Methods. A prospective study was conducted to evaluate sino-nasal status in patients with COPD (n=100) presenting to the Department of Respiratory Medicine, Mahatma Gandhi Medical College and Hospital, Jaipur from July 2011 to October 2012. COPD was diagnosed based on the Global initiative on Obstructive Lung Disease (GOLD) guidelines. Sino-nasal status was assessed by detailed history, radiograph of the para-nasal sinuses (PNS), nasal endoscopy and mucociliary clearance time. Results. Sino-nasal symptoms were present in 74 patients with COPD; nasal discharge (75.7%) being the most common. Tobacco smokers with COPD had a higher occurrence of sino-nasal symptoms (76.8%). Radiograph of para-nasal sinuses showed that maxillary sinus was most commonly involved. Nasal endoscopy revealed discharge in 63.5% cases. Nasal mucociliary clearance time was delayed (>11 to >40 min) in 98% cases. Nasal mucociliary clearance time was significantly delayed (>20 min) in COPD patients who were tobacco smokers as compared to non-smokers (53.7% versus 16.7%) and also related with increasing severity of COPD. Conclusions. Our observations suggest that sino-nasal involvement and delayed mucociliary clearance are common in patients with COPD, especially in tobacco smokers. Assessment of upper airway involvement in all the patients with COPD can help better therapeutic intervention and improvement in QoL.

Decoupling of erosion and precipitation in the Himalayas.

The hypothesis that abrupt spatial gradients in erosion can cause high strain rates in active orogens has been supported by numerical models that couple erosional processes with lithospheric deformation via gravitational feedbacks. Most such models invoke a 'stream-power' rule, in which either increased discharge or steeper channel slopes cause higher erosion rates. Spatial variations in precipitation and slopes are therefore predicted to correlate with gradients in both erosion rates and crustal strain. Here we combine observations from a meteorological network across the Greater Himalaya, Nepal, along with estimates of erosion rates at geologic timescales (greater than 100,000 yr) from low-temperature thermochronometry. Across a zone of about 20 km length spanning the Himalayan crest and encompassing a more than fivefold difference in monsoon precipitation, significant spatial variations in geologic erosion rates are not detectable. Decreased rainfall is not balanced by steeper channels. Instead, additional factors that influence river incision rates, such as channel width and sediment concentrations, must compensate for decreasing precipitation. Overall, spatially constant erosion is a response to uniform, upward tectonic transport of Greater Himalayan rock above a crustal ramp.

Structure-activity relationship studies of 4-substituted-2-guanidinothiazoles: reversible inhibitors of gastric (H+/K+)-ATPase.

The role of physicochemical factors, electronic and hydrophobic, and a hydrogen donor index in the inhibition of gastric (H+/K+)-ATPase by 4-phenyl-2-guanidinothiazoles and the 4-indolyl-2-guanidinothiazoles has been quantitatively analysed. For the first congeneric series, the resonance effect of the ortho- and para-substituents and hydrogen donor property of the meta-substituent in the phenyl ring play crucial role, whereas for 4-indolyl analogues, the hydrophobicity and electron withdrawing effect of X-substituents in the indolyl ring are shown to be important decisive factors. Also the substitution of the guanidine moiety, e.g. by benzyl, raises the activity of proton pump inhibitors. The substitution at 5-position of thiazole ring does not enhance the potency.

A quantitative structure-activity relationship study of ligands exhibiting agonist and antagonist actions with cholecystokinin-receptors.

Observed biological activities of substituted phenyl urea/thiourea tetrapeptides as agonists with the cholecystokinin-alimentary canal (CCK-A) receptor, and (R)-4-benzamido-5-oxopentanoic acid derivatives with both peripheral (CCK-A) and the central (CCK-B) (brain) receptors have been shown to be correlated with various physicochemical, e.g. pi, sigma, and structural, e.g. Vw and dummy, I, parameters. These results were, then interpreted to predict promising criteria for having ligands with better affinity with the CCK receptors.

Quantitative structure-activity relationship studies of inhibitors of gastric (H+/K+)-ATPase.

The (H+/K+)-ATPase enzyme inhibitory activity of omeprazole analogues (Figure 1) and 1-aryl-4-methyl-2,3-dihydropyrrolo[3,2-c]quinolines (Figure 2) was found to be significantly correlated with electronic (sigma) or pKa parameter that governs the basicity of the molecules. The former compounds are representative of irreversible blockers, and the latter of reversible blockers. Inclusion of hydrophobic (pi) and/or steric (Es) parameters sometimes led to improvement in the correlations, suggesting that these parameters may play a role in the formation of a cyclic intermediate. The derived significant correlation equations strongly support a mechanism of action, first proposed by Lindberg et al., involving such a cyclic intermediate.

Quantitative structure-activity relationship study on some ligands acting as inhibitors of benzodiazepine-receptor binding.

Previously reported quantitative structure-activity study on 1-aryl-3-methylpyrazolo[4,5-c]quinolin-4-ones is extended to include recently reported 1-aryl[1]benzopyrano-pyrazol-4-ones. It has been shown that the ability of these compounds to displace [3H]-flunitrazepam from bovine brain membrane is significantly correlated with steric and hydrophobic constants of aryl substituents. For 1,3-diaryl-pyrazolo[4,5-c]quinolin-4-ones, however, only hydrophobic interaction of meta-substituents is found to be relevant.

Quantitative structure-activity relationship study of 2-[(2-benzimidazolylsulphinyl)methyl]-aniline inhibitors of H+/K+ ATPase.

The H+/K+ ATPase enzyme inhibitory activity of 2-[(2-benzimidazolylsulphinyl)methyl]anilines was found to be significantly correlated with hydrophobic, pi or van der Waals volume, Vw, electronic, sigma and molar refraction, MR parameters. The derived correlations support the concept that the basic centre of the anilines is involved in the rate of reaction of the compounds. Hydrophobic interaction of meta-substituents and the bulk of substituents on the benzimidazolyl moiety also contribute significantly in the realisation of enzyme inhibition.

Inhibitors of blood platelet cAMP phosphodiesterase: a QSAR analysis.

A quantitative structure-activity relationship (QSAR) analysis of two related series of the derivatives of 7-substituted imidazo [4,5-b]-quinolin-2-one active as inhibitors of human blood platelet cAMP phosphodiesterase (PDE) is presented with a view to reflecting upon the parametric requirements of the side chain as well as of the N-1 and N-3 substitutions on the heterocycle. For the first series (Figure 1) consisting of 114 congeners and having a more flexible functionalized side chain at the 7-position and only binary variations (Me or H) at N-1 and N-3, it has been shown that bulk (Vw), of the functionalized side chain tends to potentiate the inhibitory activity of a derivative while positions N-1 and N-3 should better remain unsubstituted, as reflected through the dummy variables. A similar analysis of the compounds of the second series (Figure 2), where a less flexible side chain is linked through a basic nitrogen, has provided a parabolic dependence of inhibition activity on Vw. From this relationship, a limiting size of the side chain, seems to be necessary for triggering a minimal response.

A quantitative analysis of binding affinities of ligands active at adenosine receptors.

Binding affinities, pKi's, of 1,3-dipropyl-8-phenylxanthines and 8-substituted xanthines as selective antagonists at A(1)- and A(2)- adenosine receptors, were quantitatively analysed in terms of hydrophobic parameter, pi, and van der Waals volume, Vw. For ligands of the first series, the hydrophobicity of para-substituents and the bulk of meta-substituents are shown to be the deciding factors. Similarly, for the other series, the binary substitutions at X-, Y- and R-positions, highlighted by respective dummy variables, and the bulk rendered by groups at R(1)-position, are found to be significantly correlated with A(1)- and A(2)-receptor affinities. Additionally, the Free-Wilson study of this series resulting into individual substituent contribution, provides similar inferences to these, but in a more exact manner. This study also hints at the possibility of a different accommodation site at the receptor for the R(1)-substituents of the congeners on account of conformational dissimilarity of A(1)- and A(2)-receptors.

Quantitative structure-activity relationship study of some benzodiazepine-receptor ligands having inverse agonist/antagonist and agonist actions.

Quantitative structure-activity relationship (QSAR) analyses of three different series of benzodiazepine ligands, pyridodiindoles, and beta-carbolines, having inverse agonist/antagonist and agonist actions have been performed with a view to understanding their likely mode of action at the benzodiazepine-receptor (BzR). From this study, the in vitro radioligand displacement activities of substituted 7,12-dihydropyrido[3,2-b: 5,4-b']diindoles (Figure 1) were found to be significantly correlated with resonance effect of R-substituents, van der Waals volumes at positions-1 and -3, hydrophobic constant at position-2 and field effect at position-4 of X-substituents. For 3-substituted beta-carbolines, a similar analysis has established that R-substituents at position-3 of beta-carbolines (Figure 2) are involved in strong hydrophobic interaction with some hydrophobic pocket on the receptor. For the analogues of 6-(benzyloxy)-4-(methoxymethyl)-beta-carbolines-3-carboxylic acid ethyl ester (Figure 3), however, the combined hydrophobicities of 6- and 4-substituents were shown to be important in determining ligand binding behaviour. The significant correlations so obtained are in agreement with the proposed models (Figures 4 and 5) of pharmacophores of inverse agonist/antagonist and of agonist sites at the BzR.

Study of serum phosphohexose isomerase (PHI) levels in the management of head and neck malignancies.

The enzyme phosphohexose isomerase PHI was estimated in 43 patients of head and neck malignancy. The serum level of this enzyme was found to be raised in all the cancer patients. It was found that there were significantly higher levels of serum PHI in cases with metastatic lesions. The rise in PHI values was proportionate with the clinical stage of tumor. 29 Patients, out of 43 who had taken complete treatment weresubjected to post therapeutic PHI level estimations and the response to treatment was evaluated. Study showed that estimation of serum PHI levels have significant role in diagnosis of cancer, early detection of residual growth, recurrent growth and secondaries.