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S K Sarkar

Publications and source records attributed to S K Sarkar.

At least 19 recordsLinked to original sources
PubMed2006

Distribution and possible source of trace elements in the sediment cores of a tropical macrotidal estuary and their ecotoxicological significance.

The paper presents the first document regarding concentration, distribution and possible sources of selected trace elements (Cu, Fe, Mn, Zn, Cr, Co, Ni, Pb, Al, B and Ba) in core sediments (<63 micro particle size) from the lower stretch of Hugli (Ganges) estuary, northeast coast of Bay of Bengal by ICP-AES and EDXRF to evaluate geochemical processes influencing their distribution and possible environmental consequences. The levels of elements showed a wide range of variations in different core depths, in upper and lower intertidal zones as well as among three sampling stations. The most interesting feature of the study is the downward increase of concentrations of majority of the elements reaching overall maximum values at a depth of 20-28 cm in upper littoral zone of the site located in the extreme downstream stretch of the estuary. Values of organic carbon showed very strong positive correlations with most of the elements as revealed by correlation matrix (r) values. The interelemental relationship revealed the identical behavior of element during its transport in the estuarine environment. The overall variation in concentration can be attributed to differential discharge of untreated effluents originating from industrial, agricultural, and aquacultural sources as well as from domestic sewage along with the fishing and boating activities. The resulting compositional dataset was tested by principal component analyses and cluster analyses. Pollution load index (PLI) and index of Geoaccumulation (Igeo) revealed overall low values but the enrichment factors (EFs) for Pb were typically high for all the stations. The mean concentrations of Zn and to some extent Cu exceeded the Effects Range-Low (ER-L) values in the majority of the cases indicating that there may be some ecotoxicological risk to organisms living in sediments. The concentration of the trace elements reported in this work is useful as baselines for comparison in future sediment quality studies.

Carbon↗
PubMed2005

Interspecific variation in heavy metal body concentrations in biota of Sunderban mangrove wetland, northeast India.

The coastal environment of West Bengal, recognized as the most diversified and productive ecosystem among all the maritime states of India, faces organic pollution from domestic sewage and urban and industrial effluents leading serious impacts on biota. The present paper aims at providing information on concentration level of heavy metals among the tissues of benthic polychaetes, bivalve molluscs and finfishes collected from Sundarban mangrove wetland, northeast coast of India. An overall common trend in bioaccumulation was revealed with the following decreasing order: Zn>Mn>Cu>Cr>Se>Hg with few exceptions. Both species dependent variability and temporal variations were pronounced. A high degree of organ specificity was evident in the bivalves where gill and mantle exhibited higher metal accumulation due to ion exchange property of the mucous layer covering these organs. Variability between closely related species is a reflection of different uptake rates, physiology and impact of environmental factors. The results of this analysis suggest that mollusks can play a significant role in trace metal trophic transfer studies, especially as their representatives are intertidally and subtidally ubiquitous.

Animals↗
PubMed2004

Evaluation of the concentration of HCH, DDT, HCB, PCB and PAH in the sediments along the lower stretch of Hugli estuary, West Bengal, northeast India.

Detailed analyses of persistent organic pollutants (POPs) such as hexachlorocyclohexane (HCH) isomers (HCHs), dichlorodiphenyltrichloro ethane (DDT) and its metabolites (DDTs), hexachlorobenzene (HCB) and congeners of polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs) in surface sediments from the coastal estuarine environment of West Bengal, northeast India allowed the evaluation of the contamination status, distribution and possible pollution sources. HCH, DDT, HCB, PCB and PAH were identified compounds in all the samples, whereas the concentrations of chlorinated pesticides (trans-eptachlorepoxide, dieldrin, endrin, metaoxychlor and mirex) were below the detection limits and were not of great concern. The pesticides did demonstrate markedly different distributions reflecting different agricultural and domestic usage in the region. The range of concentrations of HCH, HCB, DDT and PCBs in the sediments were 0.11-0.40, <0.05-0.98, 0.18-1.93 and 0.18-2.33 ng/g dry wt, respectively. Overall elevated levels of HCB, DDT and PCB were recorded at Babughat, a very closely located site of the metropolitan megacity Calcutta. Fluoranthene (flu) and pyrene (py), the dominant 4-ring PAHs, also showed an abrupt elevated concentrations at Babughat with values of 214 and 144 ng/g dry wt, respectively. Among the isomers and metabolites of HCH, DDT and PCB, alpha-HCH, pp'-DDT and PCB (101), PCB (118), PCB(153) and PCB (138) were found to be dominant. High ratios of metabolites of DDT to SigmaDDTs reveal recent use of DDT in this coastal environment. Fluoranthene, pyrene, 1,2-benzo(a)anthracene and chrysene formed the dominant congeners out of 19 identified PAHs. The sources of contamination are closely related to human activities such as domestic and industrial discharge, automobile exhausts, street runoff, slum sewage, agricultural chemicals and soil erosion due to deforestation as well as atmospheric transport. This study is compared to other coastal and estuarine environments in India and abroad. The baseline data can be used for regular ecological monitoring, considering the industrial and agricultural growth around this important estuarine ecosystem.

Agriculture↗
PubMed2004

High radioactive concentration of 99mTc from a zirconium [99Mo]molybdate gel generator using an acidic alumina column for purification and concentration.

BACKGROUND: Newer applications of radiopharmaceuticals in nuclear medicine require pertechnetate of moderate to high radioactive concentration. Hence there is a need to develop simple procedures for the concentration of pertechnetate, and such a procedure is given in this paper. METHODS: Ten to 20 ml of sodium [Tc]pertechnetate eluted in de-ionized water from a zirconium [Mo]molybdate (ZrMo) gel column generator was passed through 2 g of an acidic alumina bed (35 x 8 mm) in order to remove the co-eluted traces of Mo and to retain the pertechnetate. The retained pertechnetate was then re-eluted, quantitatively, in 3 ml of normal saline, from the alumina column. RESULTS: About a 4-fold increase in radioactive concentration of Tc was obtained (cf. approximately 10-12 ml normal saline is required for the elution of Tc from the gel column). Generators containing up to 22.2 GBq (600 mCi) Mo in 6-7 g ZrMo gel column (35 x 13 mm) were prepared and a radioactive concentration of Tc up to 4 GBq x ml (110 mCi x ml) was obtained on the first day of use. The overall recovery of Tc was >90%, Mo breakthrough was 10 to 10% and the duration of concentration was 3-5 min. The chemical impurity in terms of Al, Mo and Zr was <10 ppm each. The same procedure for the concentration of pertechnetate was applied to generators with 12-15 g ZrMo gel beds to obtain a higher capacity Tc gel generator, with similar findings.

Aluminum Oxide↗
PubMed2003

The river Ganga of northern India: an appraisal of its geomorphic and ecological changes.

The Ganga is the most important perennial river originating from Gangotri in the snow-bound Himalayas about 3,900 m above mean sea level. Gorging a distance of about 220 km in the Himalayas, it enters the plain at Hardwar and after meandering and braiding over a distance of about 2,525 km through the Indo-Gangetic plains, ultimately joins the Bay of Bengal. The course of this river has been changed due to: (i) subsurface geotectonic movement leading to change in slope of the deltaic plain and subsidence of the Bengal basin; (ii) changing pattern of water discharge with time; (iii) variations in sediment load. The environment of Ganga basin is also deteriorating with time due to severe natural episodes of periodic floods and storms as well as anthropogenic factors such as population growth, deforestation, agricultural activities, urbanisation, fertiliser and fossil fuel consumption and construction activities such as dams and bridges. All these have inconceivable adverse impacts on the health and natural regeneration capacity of the river basin. The presence of micropollutants in water and sediments of this river turns the system into being unsustainable to the biota. The present study synthesises the available information on the changes of its geological, geomorphological and ecological aspects and suggests some remedial measures to be adopted now and in future.

Agriculture↗
PubMed2002

A novel 99mTc delivery system using (n,gamma)99Mo adsorbed on a large alumina column in tandem with Dowex-1 and AgCl columns.

99Mo of specific activity 7.4-14.8GBq (200-400mCi)/g was adsorbed on a 'jumbo' alumina column (40g, 90mm(H) x 20mm (dia.); 50g, 65mm(H) x 35mm(dia.). [99mTc]TcO4-, eluted with 50-70ml normal saline and applied to a tiny column of a strong anion exchanger, Dowex-1 x 8, 10-15 mg, 8-12 mm(H) x 1 mm(dia.). Pertechnetate was eluted from the Dowex-1 column with 5-6 ml of 0.2M Nal followed by washing with 1.5-1.8 ml water. Iodide was removed from this eluate by passage through a 1 g AgCl column (12 mm (H) x 8 mm (dia.)). The final product, pertechnetate, was recovered in 6.5-7.8 ml, while the NaCl content was close to that of normal saline. Each elution operation was complete in approximately 45 min. The mean practical yield was approximately 86% (n = 5). Closed cycle operation with sterile connecting tubes and multi-way stop-cocks was practised. The quality of the [99mTc]NaTcO4 thus obtained complies with the specifications applicable for radiopharmaceutical use. The major merit over other post-elution concentration methods is that the new procedure can function nearly independently of the volume of the primary eluate (in normal saline) from the alumina column generator (ACG). 99mTc generators containing as much as 80-100 g alumina for holding 14.8-18.5GBq (400-500 mCi) 99Mo (at the reference time) are feasible using approximately 15 mg Dowex-1 bed mass. A relatively user-friendly--cum--producer-friendly 99mTc generator system has been demonstrated making use of the inexpensive and easy to prepare (n,gamma)99Mo. The method is also applicable for the more costly 188W-188Re generator.

Journal Article↗
PubMed2001

Eprosartan reduces cardiac hypertrophy, protects heart and kidney, and prevents early mortality in severely hypertensive stroke-prone rats.

OBJECTIVE: Eprosartan is a selective angiotensin II type I receptor antagonist approved for the treatment of hypertension. In the present studies, eprosartan's ability to provide end-organ protection was evaluated in a model of cardiomyopathy and renal failure in stroke-prone rats (SP). METHODS: SP were fed a high fat (24.5% in food) and high salt (1% in water) diet (SFD). Eprosartan (60 mg/kg/day) or vehicle (saline control) (n = 25/group) was administered by intraperitoneally-implanted minipumps to these SP on the SFD for 12 weeks. Normal diet fed SP and WKY rats (n = 25/group) were also included for comparison (i.e. served as normal controls). Mortality, hemodynamics, and both renal and cardiac function and histopathology were monitored in all treatment groups. RESULTS: Eprosartan decreased the severely elevated arterial pressure (-12%; P < 0.05) produced by SFD but did not affect heart rate. Vehicle-treated SP-SFD control rats exhibited significant weight loss (-13%; P < 0.05) and marked mortality (50% by week 6 and 95% by week 9; P < 0.01). Eprosartan-treated SP-SFD rats maintained normal weight, and exhibited zero mortality at week 12 and beyond. Eprosartan prevented the increased urinary protein excretion (P < 0.05) that was observed in vehicle-treated SP-SFD rats. Echocardiographic (i.e. 2-D guided M-mode) evaluation indicated that SP-SFD vehicle control rats exhibited increased septal (+22.2%) and posterior left ventricular wall (+30.0%) thickness, and decreased left ventricular chamber diameter (-15.9%), chamber volume (-32.7%), stroke volume (-48.7%) and ejection fraction (-22.3%), and a remarkable decrease in cardiac output (-59.3%) compared to controls (all P < 0.05). These same parameters in eprosartan-treated SP-SFD rats were normal and differed markedly and consistently from vehicle-treated SP-SFD rats (i.e. treatment prevented pathology; all P < 0.05). Cardiac-gated MRI data confirmed the ability of eprosartan to prevent cardiac pathology/remodeling (P < 0.05). Histopathological analysis of hearts and kidneys indicated that eprosartan treatment significantly reduced end-organ damage (P < 0.01) and provided corroborative evidence that eprosartan reduced remodeling of these organs. Vehicle-treated SP-SFD rats exhibited a 40% increase in the plasma level of pro-atrial natiuretic factor that was reduced to normal by eprosartan (P < 0.05). CONCLUSION: These data demonstrate that eprosartan, at a clinically relevant dose, provides significant end-organ protection in the severely hypertensive stroke-prone rat. It preserves cardiac and renal structural integrity, reduces cardiac hypertrophy and indices of heart failure, maintains normal function of the heart and kidneys, and eliminates premature mortality due to hypertension-induced end-organ failure.

Acrylates↗
PubMed2001

Post-elution concentration of 99mTcO4- by a single anion exchanger column. I: Feasibility of extending the useful life of column chromatographic 99mTc generator.

99mTc eluate in 0.7/0.35 M acetic acid and in 1:1 v/v 0.7 M acetic acid: 0.025 M ammonium acetate (30-40 ml) was conveniently concentrated by passing through a small column of a readily available weak anion exchanger, DEAE cellulose, (200 mg, 6 x 8 mm) and subsequent elution with 3 ml normal saline, with greater than 90% recovery. The quality of pertechnetate thus obtained and its compatibility for preparing 99mTc compounds were satisfactory. This method was successfully applied to the alumina column chromatographic generator produced in-house and to a commercial 99Mo-99mTc generator after extensive clinical use. Potential for much higher concentration factors with compacted anion exchanger cartridges as well as applicability for 188W-188Re generator are discussed.

Journal Article↗
PubMed2001

Differences in pathogenicity of herpes simplex virus serotypes 1 and 2 may be observed by histopathology and high-resolution magnetic resonance imaging in a murine encephalitis model.

The mouse model for herpes simplex-induced encephalitis (HSE) is an established preclinical tool for evaluating the efficacy of new therapeutic interventions. We evaluated the utility of high-resolution in vivo MRI in observing the progression of experimental HSE during the first week postinfection. Female BALB/c mice were inoculated intracerebrally with HSV-1 or HSV-2 by microinjection. Each animal was evaluated daily by high-resolution (4.7 Tesla) T(2) weighted MRI and clinical disease scoring (neurological and behavioral). Lesions induced by a high dose of HSV-1 (1000 PFU) were detectable by MRI without administration of contrast agent whereas for low dose HSV-1 (100 PFU), administration of contrast agent was necessary to visualize the lesions in the brain. The correlation between the MRI and histologic results was excellent. No HSV-2 induced lesions were observed by MRI. Although both HSV serotypes caused similar clinical disease, significant type differences were found by histologic and MRI examinations. HSV-1 caused necrotizing meningoencephalitis, whereas HSV-2 induced mostly meningitis. The data indicate that in vivo high-resolution MRI may be useful to longitudinally evaluate HSV-1-related pathology in a mouse model of HSE and potentially could be used for monitoring the efficacy of anti-infective therapeutic approaches.

Animals↗
PubMed2001

Post-elution concentration of 99TcmO4- by a single anion exchanger column: II. Preparation and evaluation of jumbo alumina column chromatographic generator for 99Tcm.

We report on the preparation and evaluation of a large size (jumbo) alumina column (approximately 40 g, 90 x 20 mm) chromatographic generator and post-elution concentration of 99Tcm using a single column of a weak anion exchanger. The generator was eluted with approximately 40 ml of a modified single salt buffer solution of 1:1 v/v 0.025 M or 0.05 M NH4OAc:0.7 M AcOH. This eluate was then passed through a small column of DEAE cellulose, a common weak anion exchanger, to trap 99TcmO4-, which was recovered by elution in 6 ml of normal saline. This amounts to a 5- to 7-fold increase in radioactive concentration (RAC) of 99Tcm, when compared to the RAC on direct elution with normal saline from the same jumbo alumina column generator. The overall yield of 99Tcm was in the range of 70-90%. 99Mo breakthrough was 10(-3)-10(-4)%, radiochemical purity was > 98%, and chemical purity, in terms of Al and Mo content, < 10 ppm each. The compatibility of pertechnetate obtained by this method for preparing 99Tcm labelled formulations such as Tc-MDP and 99Tcm-ethyl cysteinate dimer was found to be satisfactory. These promising results open up the feasibility of using (n, gamma) 99Mo adsorbed on a large (40-60 g) alumina column as a relatively more user-friendly source of 99Tcm in comparison to methyl ethyl ketone extraction, and as a producer-friendly process in comparison to the zirconium molybdate gel method.

Aluminum Oxide↗
PubMed2001

Effect of sewage water on the growth and yield parameters of wheat and blackgram with different fertilizer levels.

Impact of biologically treated domestic sewage water was studied on the growth and yield attributing characters of wheat and blackgram under different fertilizer levels in the field condition. There was no significant difference on the yield and yield attributing characters of wheat. However, yield attributing characters like number of tillers/plant, panicle length (cm), number of grains/panicle and 1,000 grain weight showed increasing trend to the tune of 13.29, 1.59. 5.49 and 3.79 per cent respectively over the tubewell irrigated crop. Yield was also increased to the tune of 3.63 per cent when the crop was irrigated with sewage water. Interactions between irrigation and fertilizer levels were also insignificant. However, sewage water with N60P45K45 responded better on tillering, panicle length, number of grains/panicle and yield of wheat. In case of blackgram, treated sewage water had no significant effect on the grwoth and yield attributing characters, rather sewage water had some negative effect on these parameters. Interactions between irrigation and fertilizer levels were insignificant. But tubewell irrigation with N10P10K10 was more responsive on growth parameters. When the crop was grown with tubewell irrigation and without fertilizer, yield attributing characters were more positively responded.

Agriculture↗
PubMed2001

Intrathecal midazolam for postoperative pain relief in caesarean section delivery.

Postoperative pain relief is a growing concern to an anaesthesiologist since no single analgesic is free from side-effects. Moreover, it becomes a challenge after caesarean section delivery to provide postoperative pain relief without much sedation, respiratory depression or problems like nausea, vomiting, so that early baby acceptance and care by mother is promoted. Antinociceptive effect of midazolam is well established by now and its safety is documented. This observation was made in a blind randomised study of 40 women of ASA I/II to evaluate postoperative pain relief using intrathecal midazolam in caesarean section delivery. Group A patients (n=20) received 1.5 ml of 5% lignocaine only and group B patients (n=20) received mixture of 1.5 ml 5% lignocaine with 2 mg midazolam (preservative free) through intrathecal route at L3.4 interspace; vital parameters were monitored intra-operatively and postoperatively and Apgar score of baby in 1st and 5th minute of deliverywas assessed. It was observed intrathecal midazolam produced highly significant (p<0.001) postoperative pain relief together with anti-emetic effect and tranquillity of patients of caesarean section delivery.

Adjuvants, Anesthesia↗
PubMed2000

Application of in vivo and ex vivo magnetic resonance imaging for evaluation of tranilast on neointima formation following balloon angioplasty of the rat carotid artery.

OBJECTIVE: Recent studies suggest that tranilast inhibits a variety of agents implicated in neointimal growth and restenosis in experimental animal models and humans. We report here a study evaluating the efficacy of tranilast in the rat carotid artery balloon angioplasty model, a model that mimics many aspects of the percutaneous transluminal angioplasty procedure in humans. Efficacy was determined based on in vivo and ex vivo magnetic resonance imaging (MRI) as well as by histomorphometry. The utility of this study, using a reverse paradigm, is to investigate if agents successful in the clinic can demonstrate efficacy in this animal model primary screen as measured by MRI and histomorphometry. METHODS: Tranilast (300 mg/kg/day, p.o.) was administered to Sprague-Dawley rats 3 days prior to balloon injury and continued for 14 days after injury. Three methods of measuring the vascular injury that occurs in this model were employed: (1) in vivo MRI, used to measure in vivo lumen volumes for the carotid artery once at baseline (pre-surgery) and again at 14 days post angioplasty; (2) ex vivo MRI (and histomorphometry), used to evaluate the total arterial wall thickness and the intima-to-media ratio; and (3) analysis of collagen density, used to evaluate the efficacy of tranilast to abrogate collagen synthesis and deposition following vascular injury. RESULTS: Tranilast provided 33% protection (P<0.05) from angioplasty-induced lumen narrowing as measured by MRI in vivo. The results of the ex vivo MR analysis of total wall thickness showed a 14% protection of angioplasty-induced narrowing (P<0.05), and the mean intima-to-media ratio showed a 39% (P<0.006) protection for the tranilast-treated rats. Histological analysis of the mean intima-to-media ratio demonstrated that tranilast provided 36% (P<0. 01) protection in the intima-to-media ratio. Further, treatment with tranilast showed a 52% reduction in collagen density of the intimal layer and a 70% reduction in collagen density of the medial layer of the injured arteries. CONCLUSION: The data obtained by in vivo MRI, ex vivo MRI, histology and collagen analysis demonstrate that tranilast provided significant beneficial effects in inhibiting neointimal formation in the rat carotid artery model. Also this study, to the best of our knowledge, is the first to harness complimentary information from various technologies, including lumen patency by in vivo MRI, neointimal formation by ex vivo MRI and conventional histomorphometry, and histological analysis for collagen density, to provide a comprehensive understanding of the pathology in this disease model.

Analysis of Variance↗
PubMed1999

Comparing treatment variances in repeated measures bioavailability trials.

In repeated measures bioavailability/bioequivalence studies involving two formulations, the underlying measurements, such as the area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (Cmax), typically have a block compound-symmetric covariance matrix. To test the equality of the variances in such a covariance matrix, we derive in this paper an exact test and four asymptotic tests. We compare these tests using simulation to determine those that have good performance in terms of controlling the type I error rate as well as providing good power. We provide an example to demonstrate the proposed method.

Biological Availability↗
PubMed1999

Use of diffusion-weighted MRI and neurological deficit scores to demonstrate beneficial effects of isradipine in a rat model of focal ischemia.

The neuroprotective effects of isradipine, a 2,4-dihydropyridine calcium channel blocker, has been well studied in the rat model of focal ischemia (induced by middle cerebral artery occlusion, MCAO). The present study was designed to evaluate whether isradipine pretreatment caused early (0-3 h after stroke) ischemic changes in diffusion- weighted magnetic resonance imaging (DWI) and if such changes were predictive of previously documented protection in brain infarction. An initial dose-response study using neurological deficit scores and estimates of protection from brain infarction (by histology) showed that isradipine reduced cortical infarctions compared to vehicle-treated animals at most doses (between 1.25 and 5 mg/kg/day s.c. for 6 days) with the best results obtained at 5 mg/kg/day, where a 78.5% reduction was observed. This dose was utilized to perform the DWI study. Early quantitative estimates of infarct size, as measured by DWI at 1, 2 and 3 h after MCAO, were similar to those obtained with late histology at 24 h. These data indicate that in pretreatment protocols, DWI can be used to quantitatively predict areas at risk of permanent damage. This work also demonstrates that neurological deficits, developing from the damaged forebrain following focal stroke, may provide an index of isradipine's neuroprotective activity.

Animals↗
PubMed1998

Application of serial in vivo magnetic resonance imaging to evaluate the efficacy of endothelin receptor antagonist SB 217242 in the rat carotid artery model of neointima formation.

BACKGROUND: Alleviating vascular restenosis after percutaneous transluminal angioplasty remains a formidable challenge. Although multiple factors have been implicated in the pathophysiology of this vascular remodeling disorder, only limited therapeutic success has been achieved. Endothelin (ET)-1 has recently been implicated in the pathogenesis of neointimal growth. We report the in vivo efficacy of SB 217242, a nonpeptide dual ET(A)/ET(B) receptor antagonist with high oral bioavailability, in the rat carotid artery balloon angioplasty model. METHODS AND RESULTS: The lumen volumes of carotid arteries were estimated serially with magnetic resonance imaging (MRI) at baseline and at day 7 and day 14 after balloon catheter-induced denudation of the carotid arterial wall in the rat. Histomorphometric analysis was performed at day 14 after surgery to quantitate intimal hyperplasia. Statistical analysis was performed with ANOVA followed by post hoc Newman-Keuls multiple comparison test. In comparison to vehicle-treated animals, a 20% protection (P<0.05) from reduction was shown in the estimated lumen volume with long-term administration of SB 217242 (15 mg/kg BID p.o.). Histologic analyses indicated a 42% decrease (P<0.05) in neointimal growth. The MRI lumen volumes had a significant correlation with the corresponding histologic indices. CONCLUSIONS: Serial MRI provides the opportunity to assess the progression of vascular lumen volume in vivo after balloon angioplasty. MRI measurements can, in conjunction with in vitro histologic measurements, contribute to the understanding of the actions of pharmacologic agents in experimental models of neointima formation. With the use of serial MRI and histologic measurements, it is demonstrated that protection from both lumen volume reduction and neointima formation is obtained in this model by use of a potent, nonpeptide dual ET(A)/ET(B) receptor antagonist, SB 217242. Furthermore, this study provides additional support to the implication of ET-1 in the pathophysiology of neointima formation.

Angioplasty, Balloon↗
PubMed1997

Design of potent and selective human cathepsin K inhibitors that span the active site.

Potent and selective active-site-spanning inhibitors have been designed for cathepsin K, a cysteine protease unique to osteoclasts. They act by mechanisms that involve tight binding intermediates, potentially on a hydrolytic pathway. X-ray crystallographic, MS, NMR spectroscopic, and kinetic studies of the mechanisms of inhibition indicate that different intermediates or transition states are being represented that are dependent on the conditions of measurement and the specific groups flanking the carbonyl in the inhibitor. The species observed crystallographically are most consistent with tetrahedral intermediates that may be close approximations of those that occur during substrate hydrolysis. Initial kinetic studies suggest the possibility of irreversible and reversible active-site modification. Representative inhibitors have demonstrated antiresorptive activity both in vitro and in vivo and therefore are promising leads for therapeutic agents for the treatment of osteoporosis. Expansion of these inhibitor concepts can be envisioned for the many other cysteine proteases implicated for therapeutic intervention.

Binding Sites↗