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Biomedical subjects

P K Bhatnagar

Publications and source records attributed to P K Bhatnagar.

At least 19 recordsLinked to original sources
PubMed2001

Gamma-irradiated onions as a biological indicator of radiation dose.

Post-irradiation identification and dose estimation are required to assess the radiation-induced effects on living things in any nuclear emergency. In this study, radiation-induced morphological/cytological changes i.e., number of root formation and its length, shooting length, reduction in mitotic index, micronuclei formation and chromosomal aberrations in the root tip cells of gamma-irradiated onions at lower doses (50-2000 cGy) are reported. The capabilities of this biological species to store the radiation-induced information are also studied.

Cell Cycle↗
PubMed2001

Calcilytic compounds: potent and selective Ca2+ receptor antagonists that stimulate secretion of parathyroid hormone.

Despite the discovery of many ions and molecules that activate the Ca2+ receptor, there are no known ligands that block this receptor. Reported here are the pharmacodynamic properties of a small molecule, NPS 2143, which acts as an antagonist at the Ca2+ receptor. This compound blocked (IC50 of 43 nM) increases in cytoplasmic Ca2+ concentrations [Ca2+]i elicited by activating the Ca2+ receptor in HEK 293 cells expressing the human Ca2+ receptor. NPS 2143, even when tested at much higher concentrations (3 microM), did not affect the activity of a number of other G protein-coupled receptors, including those most structurally homologous to the Ca2+ receptor. NPS 2143 stimulated parathyroid hormone (PTH) secretion from bovine parathyroid cells (EC50 of 41 nM) over a range of extracellular Ca2+ concentrations and reversed the effects of the calcimimetic compound NPS R-467 on [Ca2+]i and on secretion of PTH. When infused intravenously in normal rats, NPS 2143 caused a rapid and large increase in plasma levels of PTH. Ca2+ receptor antagonists are termed calcilytics and NPS 2143 is the first substance (either atomic or molecular) shown to possess such activity. The pharmacodynamic properties of NPS 2143 together with the recently demonstrated effects of this compound on bone formation support the view that orally active calcilytic compounds might provide a novel anabolic therapy for osteoporosis.

Aniline Compounds↗
PubMed2000

Identification of unique truncated KC/GRO beta chemokines with potent hematopoietic and anti-infective activities.

SK&F 107647, a previously described synthetic immunomodulatory peptide, indirectly stimulates bone marrow progenitor cells and phagocytic cells, and enhances host defense effector mechanisms in bacterial and fungal infection models in vivo. In vitro, SK&F 107647 induces the production of a soluble mediator that augments colony forming cell (CFU-GM) formation in the presence of CSFs. In this paper we purified and sequenced the stromal cell-derived hematopoietic synergistic factors (HSF) secreted from both murine and human cell lines stimulated with SK&F 107647. Murine HSF is an N-terminal 4-aa truncated form of the CXC chemokine, KC, while human HSF was identified as an N-terminal 4-aa truncated form of the CXC chemokine, GRO beta. In comparison to their full-length forms, truncated KC and truncated GRO beta were 10 million times more potent as synergistic growth stimulants for CFU-GM. Enhanced potency of these novel truncated chemokines relative to their full-length forms was also demonstrated in respiratory burst assays, CD11b Ag expression, and intracellular killing of the opportunistic pathogen, Candida albicans. Administration of truncated KC significantly enhanced survival of mice lethally infected with C. albicans. The results reported herein delineate the biological mechanism of action of SK&F 107647, which functions via the induction of unique specific truncated forms of the chemokines KC and GRO beta. To our knowledge, this represents the first example where any form of KC or GRO beta were purified from marrow stromal cells. Additionally, this is the first demonstration of in vivo efficacy of a CXC chemokine in an animal infectious fungal disease model.

Adjuvants, Immunologic↗
PubMed2000

Novel peptidomimetic hematoregulatory compounds.

The activity of a novel series of peptidomimetic hematoregulatory compounds, designed based on a pharmacophore model inferred from the structure activity relationships of a peptide SK&F 107647 (1), is reported. These compounds induce a hematopoietic synergistic factor (HSF) which in turn modulates host defense. The compounds may represent novel therapeutic agents in the area of hematoregulation.

Amino Acids↗
PubMed2000

Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats.

Parathyroid hormone (PTH) is an effective bone anabolic agent, but it must be administered parenterally. An orally active anabolic agent would provide a valuable alternative for treating osteoporosis. NPS 2143 is a novel, selective antagonist (a "calcilytic") of the parathyroid cell Ca(2+) receptor. Daily oral administration of NPS 2143 to osteopenic ovariectomized (OVX) rats caused a sustained increase in plasma PTH levels, provoking a dramatic increase in bone turnover but no net change in bone mineral density. Concurrent oral administration of NPS 2143 and subcutaneous infusion of 17beta-estradiol also resulted in increased bone turnover. However, the antiresorptive action of estrogen decreased the extent of bone resorption stimulated by the elevated PTH levels, leading to an increase in bone mass compared with OVX controls or to either treatment alone. Despite the sustained stimulation to the parathyroid gland, parathyroid cells did not undergo hyperplasia. These data demonstrate that an increase in endogenous PTH secretion, induced by antagonism of the parathyroid cell Ca(2+) receptor with a small molecule, leads to a dramatic increase in bone turnover, and they suggest a novel approach to the treatment of osteoporosis.

Animals↗
PubMed1999

Effect of amphotericin B lipid formulation on immune response in aspergillosis.

The immune response against Aspergillus fumigatus has been studied during infection and therapy in order to understand the mechanism of pathogenesis and the effect of treatment with amphotericin B. With this in view an animal model of aspergillosis was developed in Balb/c mice by intravenous injection of an optimized dose of 3. 6x10(6) A. fumigatus spores. Infection due to Aspergillus was well established by histopathological examination and fungal load in the animal. Lesions and eosinophil infiltration was observed in the infected tissues which indicated the involvement of a Type I hypersensitivity response. Evaluation of serological parameters indicated high levels of interleukin-4 (IL-4) and A. fumigatus specific IgG antibodies. The reduction in fungal load and modulation of immune response in the infected mice was studied following treatment with amphotericin B/cholesterol hemisuccinate vesicles (ABCV). The results clearly indicated significant reduction in the fungal load, disappearance of eosinophils and lesions with the appearance of macrophages and neutrophils in the infected lung tissue, a decrease in IL-4 (fourfold) and a concomitant increase of interferon-gamma (IFN-gamma; twofold) with an improvement in general condition of mice. In the non-treated mice, the rise of IL-4 level indicated the association of T(H)2 cell response with susceptibility to infection while the increase of IFN-gamma in the treated group suggested that T(H)1 cell response may be involved in resistance to Aspergillus infection.

Amphotericin B↗
PubMed1999

Large-scale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling.

Linear and convergent routes for the large-scale preparation of the hematoregulatory nonapeptide (Glp-Glu-Asp)2-DAS-(Lys)2 (2, SK&F 107647) were investigated. A convergent approach ('3 + 2'-route employing Boc-and benzyl ester protecting groups) was selected for the preparation of multihundred-gram quantities of 2. Key steps were the preparation and the coupling of tripeptide hydrochloride (HCl.H)2-DAS-(Lys(Z)-OBn)2 (6, DAS-2,7-L,L-diaminosuberic acid) and tripeptide Glp-Glu(OBn)-Asp(OBn)-OH (26). Several coupling reagents were investigated in order to reduce the amount of epimerization of this fragment coupling. TDBTU [O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl-1,1,3,3-tetrameth yluronium tetrafluoroborate] was identified as the condensation reagent of choice. Using this synthetic route > 97% pure final product in an overall yield of 35% calculated on di-Boc protected 2,7-L,L-diaminosuberic acid was prepared.

Indicators and Reagents↗
PubMed1999

Studies on the viability of metacercariae of Fasciola gigantica.

The viability of metacercariae of Fasciola gigantica was tested by in vitro and in vivo methods. In vitro testing was based upon the motility of juvenile flukes within the inner cyst as examined under the light microscope. In vivo testing was undertaken through experimental infections of rabbits (two groups) and natural definitive hosts, lambs (one group). In the first group, out of six rabbits each given 25 metacercariae, worm establishment only took place in one rabbit with a single fluke recovery on 60 days post infection. In the second group of six rabbits each given 200 metacercariae, five were infected, with two or three flukes per host. All the lambs given 250 metacercariae became infected showing prevalences of 7.2-40% in comparison with rabbits in which low prevalences (0-4%) were recorded. The results indicated that even viable metacercariae which were already tested in vitro could not readily establish in rabbits. Such variability in worm establishment suggests that immunological and chemotherapeutic studies in rabbits infected with F. gigantica are likely to be unreliable.

Animals↗
PubMed1997

Analysis of HIV seropositive thalassemic children for antibodies specific to Aspergillus fumigatus by luminescent immunoassay.

The applicability of luminescent immunoassay (LIA) in serodiagnosis of fungal infections in multitransfused (MT) thalassemic children seropositive for human immunodeficiency virus (HIV) was investigated. Thirty-one sera samples from HIV infected pediatric patients with thalassemia receiving repeated blood transfusions were analysed for the presence of antibodies specific to Aspergillus fumigatus by LIA. The LIA was standardized using well defined antigens of A. fumigatus. Ten out of 31 (32.2%) of the MT-HIV positive patients were found to have anti-Aspergillus antibodies in their sera by LIA. The ELISA could detect A. fumigatus specific antibodies in 25.8% (8 out of 31) of the patients. Thus, 20% more number of patients turned to be positive for aspergillosis by LIA as compared to ELISA. The difference was found to be statistically significant (p < 0.005). Of the MT-HIV negative patients only 1 out of 33 (3%) showed A. fumigatus specific antibodies by LIA and ELISA both. In age and sex matched control group (n = 25) none of the patients was found to be positive for antibodies to A. fumigatus. LIA was found to have better discriminatory value indicating, thereby, its utility in diagnosis of aspergillosis in compromised patients.

Antibodies, Fungal↗
PubMed1997

Identification of 45 kD antigen in immune complexes of patients of allergic bronchopulmonary aspergillosis.

A glycoprotein antigen with an apparent mw of 45 kD was observed to be predominant in the circulating immune complexes isolated from patients of allergic bronchopulmonary aspergillosis as well as in the immune complexes prepared in vitro. Further characterisation of 45 kD antigen with trypsin showed four immunologically active peptides with mw 43, 36, 33 and 16 kD. Carbohydrate characterization using various lectins (Maackia amurensis agglutinin, Sambucus nigra agglutinin, Peanut agglutinin, Galanthus nivalis agglutinin and Datura stramonium agglutinin) showed presence of both N-linked and O-linked sugar moieties such as mannose, glucose, galactose and N-acetyl glucosamine. Predominant presence of 45 kD antigen in immune complexes, recognition of 45 kD by monoclonal antibodies raised against glycoprotein rich fraction of A. fumigatus and presence of elastinolytic protease activity indicate that 45 kD antigen is probably a potent virulence factor and may be contributing to the pathogenesis of ABPA by its biological as well as immunological activities.

Adult↗
PubMed1996

Structure-activity relationships of novel hematoregulatory peptides.

Hematopoiesis is a lifelong cell renewal process regulated by a family of lineage specific hematopoietic growth factors. Several hematopoietic growth factors such as G-CSF, GM-CSF, and M-CSF have been clinically evaluated for enhancement of host defense in normal and immunocompromised patients and for the treatment of infectious diseases. This paper reports the structure-activity relationships of low molecular weight hematoregulatory peptides based on a nonapeptide (1, SK&F 107647). Like the macromolecular growth factors, these peptides modulate host defense. A molecular target for this class of compounds has not yet been identified. However, the structure-activity relationships established by this study implicate a very specific molecular recognition event that is pivotal for the biological activities of 1 and its analogues.

Amino Acid Sequence↗
PubMed1996

Thrombolysis theraphy in patients with femoropopliteal synthetic graft occulsions.

BACKGROUND: The aim of this study was to evaluate the efficiency of thrombolysis in the presence of an occluded femoropopliteal synthetic graft. PATIENTS AND METHODS: Over a 3-year period, 46 occluded femoropopliteral grafts were treated with urokinase and reconstruction. The cases were divided into three groups: group 1 (n=25), complete thrombolysis followed by reconstruction or angioplasty or both; group 2 (n=5), complete thrombolysis alone; and group 3 (n=16), failure of thrombolysis requiring reconstruction or leading to amputation. Patients were completely observed after treatment for more than 1 year. RESULTS: There are no fatal complications among patients with thrombolytic therapy. In group 1, the 3-year patency rates were 12% and the 3-year limb salvage rates were 77%. In group 2, the 3-year patency rates and the limb salvage rates were 20% and 80%, respectively. The group 3 patency rates and the limb salvage were 8% and 40%, respectively. The best results were achieved in patients who had thrombolysis followed by reconstruction (group 1) and in those who had thrombolysis alone (group 2). limb salvage was poor in patients with failure of lytic therapy regardless of the reconstruction (P<0.01). CONCLUSION: The use of intra-arterial urokinase followed by secondary vascular reconstructive procedures was studied. The patient with synthetic graft occlusion still has a reasonably favorable prognosis for long-term limb salvage when thrombolysis is successful.

Aged↗
PubMed1996

Metabolism, uptake, and transepithelial transport of the diastereomers of Val-Val in the human intestinal cell line, Caco-2.

PURPOSE: The purpose of this study was to determine whether the binding of the diastereomers of Val-Val to the apical oligopeptide transporter(s) could be correlated with their cellular uptake and transepithelial transport. METHODS: The Caco-2 cell culture system was used for all experiments. The binding of the diastereomers of Val-Val was evaluated by determining their ability to inhibit [3H]cephalexin uptake. The stability of the diastereomers was determined in a homogenate of Caco-2 cells and in the apical bathing solution over Caco-2 cell monolayers. The cellular uptake and transepithelial transport properties of the individual diastereomers were studied using Caco-2 cell monolayers. RESULTS: 10 mM concentrations of L-Val-L-Val, L-Val-D-Val, D-Val-L-Val and D-Val-D-Val inhibited cellular uptake of [3H]cephalexin (0.1 mM) by 92%, 37%, 70%, and 18%, respectively. When the cellular uptake of Val-Val diastereomers (1 mM) were evaluated, the intracellular concentrations of L-Val-D-Val and D-Val-L-Val were 15 and 50 times higher, respectively, than that of D-Val-D-Val. The cellular uptake of L-Val-D-Val and D-Val-L-Val was inhibited by Gly-Pro (10 mM) ( > 95%), whereas Gly-Pro had no effect on the cellular uptake of D-Val-D-Val. L-Val-L-Val was not detected in the Caco-2 cells, probably due to its metabolic lability. When the transepithelial transport of the Val-Val diastereomers (1 mM) was determined, L-Val-D-Val, D-Val-L-Val and D-Val-D-Val transport rates were similar. The transepithelial transport of L-Val-D-Val and D-Val-L-Val was inhibited by Gly-Pro (10 mM) 36% and 30%, respectively, while Gly-Pro inhibited carnosine (1 mM) transepithelial transport by 65%. Gly-Pro had no effect on the transepithelial transport of D-Val-D-Val. CONCLUSIONS: These results suggest that the major transepithelial transport route of L-Val-D-Val, D-Val-L-Val and D-Val-D-Val is passive diffusion via the paracellular route. The binding of Val-Val diastereomers to the oligopeptide transporter(s) is a good predictor of their cellular uptake, however, the binding is not a good predictor of their transepithelial transport. It appears that the stereochemical requirements for the transporter that mediates efflux of the peptide across the basolateral membrane may be different from the requirements for the apical transporter that mediates cellular uptake.

Biological Transport↗
PubMed1996

Treatment of experimental gram-negative and gram-positive bacterial sepsis with the hematoregulatory peptide SK&F 107647.

SK&F 107647, a novel synthetic low-molecular-weight peptide, has demonstrated potent antiinfective activities in murine models of fungal and viral infection. To determine if the hematoregulatory activities of SK&F 107647 could offer protection over conventional antibiotic therapy or as a single agent in animal models of bacterial sepsis, rats were implanted intraperitoneally with a live bacteria-containing fibrin-thrombin clot. Rats pretreated subcutaneously or orally with SK&F 107647 and then infected with either a gram-negative (Escherichia coli) or a gram-positive (Staphylococcus aureus) bacteria-containing clot demonstrated significantly improved survival over control formulation-treated animals. Treated animals showed increased effector cell activation, measured by CD11b expression on neutrophils and monocytes, and up to 1000-fold reduction in the number of E. coli recovered from blood. Thus, the hematoregulatory activities of SK&F 107647 can increase natural host resistance to infections caused by both gram-negative and gram-positive bacteria.

Adjuvants, Immunologic↗
PubMed1996

Aspergillus fumigatus specific antibodies in multitransfused children with human immunodeficiency virus (HIV) infection in relation to serum levels of Interleukin-2, gamma Interferon and tumour necrosis factor.

Anti-Aspergillus fumigatus antibodies (IgG and IgE class) and serum levels of cytokines (gamma Interferon, Interleukin-2 and tumour necrosis factor-alpha) were studied in multitransfused (MT) children in relation to human immunodeficiency virus (HIV) infection. The specific antibodies to Aspergillus fumigatus were present in 25 per cent of MT children seropositive for HIV as compared to only 2 per cent among HIV-negative MT children (X2 = 14, P < 0.001). Estimation of serum cytokines level in MT children showed that the asymptomatic HIV-infected children had elevated levels of gamma interferon (Y-IFN) and tumor necrosis factor-alpha (TNF-alpha) without any alteration of Interleukin-2 (IL-2) level, compared to HIV-negative group. However, clinically diagnosed cases of AIDS in the HIV-infected group showed elevation of all the three cytokines levels as compared to HIV negative group, as well as asymptomatic HIV infected group. Presence or absence of concomitant A. fumigatus infection did not lead to alteration of Y-IFN and IL-2 level in the HIV infected group, while TNF-alpha levels were markedly raised in the cases with evidences of presence of A. fumigatus specific antibodies irrespective of whether the group belonged to asymptomatic HIV infection or clinically proven cases of AIDS. The significance of these altered cytokines profile with respect to occurence of A. fumigatus infection in HIV-positive MT children has been discussed.

Acquired Immunodeficiency Syndrome↗
PubMed1996

The impact of thrombolytic therapy on arterial and graft occlusions: a critical analysis.

BACKGROUND: The indications for intraarterial thrombolytic therapy of lower extremity native arterial and synthetic graft occlusions prior to vascular reconstructions requires further refinement before firm conclusions can be made. STUDY DESIGN: A retrospective review of 55 patients undergoing 81 lytic treatments with high dose urokinase from February 1989 to February 1993 was performed. The cases were divided into three groups: Group I: successful thrombolysis with residual defects followed by surgical reconstruction or percutaneous transluminal angioplasty (PTA); Group II: successful thrombolysis alone; and Group III: failure of thrombolysis requiring reconstruction or leading to amputation. No effort was made to analyze the particular type of reconstruction. Follow-up ranged from 1 to 1627 days (4 years and 5 1/2 months). RESULTS: One, two, and three year patency rates were 47%, 24%, and 8% for Group I; 57%, 46%, and 46% for Group II; and 24%, 10%, and 10% for Group III respectively. The one, two and three year limb salvage rates were 92%, 76%, and 76% for Group I; 82%, 82%, and 82% for Group II; and 48%, 37%, and 37% for Group III respectively. Forty-one complications occurred in 35 of the 81 (43%) lytic treatments. CONCLUSIONS: Intraarterial thrombolytic therapy can be regarded as a possible consideration in the initial management of acute lower extremity arterial and synthetic graft occlusions especially in patients with multiple prior vascular reconstructions. Unsuccessful thrombolysis results in a poor outcome despite surgical reconstruction in the majority of cases.

Aged↗