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Biomedical subjects

A K Bhattacharjee

Publications and source records attributed to A K Bhattacharjee.

At least 37 records · Page 2Linked to original sources
PubMed1999

Vaccines and antibodies in the prevention and treatment of sepsis.

Antibodies to various core glycolipid antigens have been shown to correlate with survival from Gram-negative sepsis. Recent preclinical data also support efficacy of the anti-core glycolipid antibodies in the treatment of sepsis. Failure of some of the previous clinical trials with anti-core glycolipid antibody was probably due to inadequate levels of antibody in those preparations. Future clinical trials must ensure that sufficient amounts of anti-core glycolipid antibodies are present in the circulation of patients with sepsis.

Animals↗
PubMed1999

Stereoelectronic features of the cinchona alkaloids determine their differential antimalarial activity.

For most potent antimalarial activity, the cinchona alkaloids appear to require certain electronic features, particularly a sufficiently acidic hydroxyl proton and an electric field direction pointing from the aliphatic nitrogen atom towards the quinoline ring. These observations are the result of an analysis of molecular electronic properties of eight cinchona alkaloids and an in vivo metabolite calculated using ab initio 3-21G quantum chemical methods in relation to their in vitro IC50 values against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum parasites. The purpose is to provide a profile of the electronic characteristics necessary for potent antimalarial activity for use in the design of new antimalarial agents and to gain insight into the mechanistic path for antimalarial activity. Distinguishing features of the weakly active epiquinine and epiquinidine include a higher dipole moment, a different direction of the electric field, a greater intrinsic nucleophilicity, lower acidity of the hydroxyl proton, a lesser electron affinity of the lowest unoccupied molecular orbitals, and a higher proton affinity than the active cinchona alkaloids. A moderately potent quinine metabolite possesses some, but not all, of the same electronic features as the most potent cinchona alkaloids. Both the positioning of the hydroxyl and aliphatic amine groups and their electronic features appear to play a crucial role for antimalarial potency of the cinchona alkaloids, most likely by controlling the ability of these groups to form effective intermolecular hydrogen bonds.

Animals↗
PubMed1999

Stereoelectronic properties of antimalarial artemisinin analogues in relation to neurotoxicity.

Quantum chemical calculations on the molecular electronic structure of artemisinin (qinghaosu) and eight of its derivatives have resulted in stereoelectronic discriminators that differentiate between analogues with higher and lower neurotoxicities. Detailed ab initio quantum chemical calculations leading to complete optimization of geometry of each of the molecules were followed by calculation of their stereoelectronic properties using the 3-21G split valence basis sets and comparison of the stereoelectronic properties to in vitro neurotoxicity. The least neurotoxic compounds are more polar with an electric field pointing away from the endoperoxide bond and have a higher positive potential on the van der Waals surface of the all carbon-containing ring C, a more stable peroxide bond to cleavage, a less negative electrostatic potential by the endoperoxide, and a single negative potential region extending beyond the van der Waals surface of the molecule. In general, higher intrinsic lipophilicity is associated with greater neurotoxicity.

Animals↗
PubMed1999

Transcranial Doppler findings during balloon test occlusion of the internal carotid artery.

The authors performed transcranial Doppler ultrasonography (TCD) during internal carotid artery (ICA) balloon test occlusion (BTO) and observed changes in mean flow velocity (Vm) in the middle cerebral artery (MCA), and pulsatility index (PI) while monitoring the stump pressure (Sp) of the internal carotid artery (ICA), and neurologic findings. A group of 17 patients requiring possible temporary or permanent occlusion of the ICA in the course of planned procedures first underwent BTO. A patient who either developed neurologic changes or maintained less than 60% of preocclusion Sp or Vm in the ipsilateral MCA during BTO was considered to have a positive test. Eleven patients had negative results, while in six patients, tests were positive. Mean flow velocity showed a decrease after occlusion in all cases but not to a remarkable extent in some patients. Stump pressure decreased in all negative cases after balloon inflation and than tended to increase progressively during 15 minutes of BTO. Pulsatility index tended to decrease gradually during BTO in all negative patients. However, in positive cases, PI and Sp fell steeply. Only one positive case had a neurologic symptom of severe headache. The decreased PI in the MCA reflected autoregulatory dilation of cerebral vessels to compensate for decreased absolute cerebral blood volume following ICA occlusion. Changes in PI are a good indicator for evaluating blood flow during BTO.

Blood Flow Velocity↗
PubMed1999

Protection of mice against brucellosis by vaccination with Brucella melitensis WR201(16MDeltapurEK).

Human brucellosis can be acquired from infected animal tissues by ingestion, inhalation, or contamination of the conjunctiva or traumatized skin by infected animal products. A vaccine to protect humans from occupational exposure or from zoonotic infection in areas where the disease is endemic would reduce an important cause of morbidity worldwide. Vaccines currently used in animals are unsuitable for human use. We tested a live, attenuated, purine-auxotrophic mutant strain of Brucella melitensis, WR201, for its ability to elicit cellular and humoral immune responses and to protect mice against intranasal challenge with B. melitensis 16M. Mice inoculated intraperitoneally with WR201 made serum antibody to lipopolysaccharide and non-O-polysaccharide antigens. Splenocytes from immunized animals released interleukin-2 (IL-2), gamma interferon, and IL-10 when cultured with Brucella antigens. Immunization led to protection from disseminated infection but had only a slight effect on clearance of the challenge inoculum from the lungs. These studies suggest that WR201 should be further investigated as a vaccine to prevent human brucellosis.

Animals↗
PubMed1999

Predicting mosquito repellent potency of N,N-diethyl-m-toluamide (DEET) analogs from molecular electronic properties.

Specific molecular electronic properties of 30 N,N-diethyl-m-toluamide (DEET) analogs demonstrate functional dependence with their reported duration of protection against mosquito bites, thus providing predictors of insect repellent efficacy. No single electronic property is sufficient to predict repellent efficacy as measured by protection time, rather a set of specific electronic properties is required. Thus, the values of the van der Waals surface electrostatic potential by the amide nitrogen and oxygen atoms, the atomic charge at the amide nitrogen atom, and the dipole moment must all be in optimal ranges for potent repellency. The electronic properties were calculated using the AM semi-empirical quantum chemical method using commercial software. These easily calculable predictors of repellent efficacy should be useful in predicting the relative efficacy of newly designed compounds, thus guiding the selection of new repellents for testing.

Animals↗
PubMed1999

Evaluation of surrogate markers of impending death in the galactosamine-sensitized murine model of bacterial endotoxemia.

BACKGROUND AND PURPOSE: When evaluating vaccines for efficacy against gram-negative endotoxemia, the challenge has historically required death of a large percentage of test subjects. We attempted to identify surrogate markers of impending death to allow for early euthanasia without interfering with experimental data collection. METHODS: Galactosamine-sensitized mice (n = 140) were inoculated intraperitoneally with various dosages of endotoxin, and development of clinical signs of disease--body temperature, body weight, hunched posture, ruffled coat, inability to ambulate, and loss of consciousness--was evaluated. RESULTS: Wide fluctuations in body temperature (+/- 4 degrees C) were observed in survivors and nonsurvivors. Posture, coat, and body weight were not accurate predictors of death. Only inability to ambulate, with a positive predictive value of 100% (11 of 11), accurately predicted death in the experimental mice of this study. CONCLUSION: Using this surrogate marker, loss of ability to ambulate, 11 of 13 mice that developed this sign could have been euthanized early, preventing anywhere from 2 to 22 h of potential distress prior to death.

Animals↗
PubMed1998

Functional correlation of molecular electronic properties with potency of synthetic carbinolamine antimalarial agents.

Specific calculated molecular electronic properties of structurally diverse synthetic aromatic carbinolamines containing phenanthrene, quinoline, and N-substituted biphenyl rings are associated with antimalarial potency allowing use of these electronic features in the prediction of antimalarial efficacy, thus aiding the design of new antimalarial agents. These electronic features include the magnitude and location of 3-dimensional molecular electrostatic potentials, lowest unoccupied molecular orbitals, and highest occupied molecular orbitals. Stereoelectronic properties were calculated using quantum chemical AM1 methods on the optimized geometry of the lowest energy or most populated conformer in both gaseous and aqueous environments. In the phenanthrene carbinolamines, the aliphatic nitrogen atom and the hydroxyl proton are intrinsically more nucleophilic and less electrophilic, respectively, than in the non-phenanthrene compounds. Hydrogen bonding ability and the electrophilic nature of the aromatic ring appear to be two important features responsible for interaction with receptor molecules.

Antimalarials↗
PubMed1998

Covalent polymyxin B conjugate with human immunoglobulin G as an antiendotoxin reagent.

Polymyxin B (PMB) is a cyclic decapeptide antibiotic which also binds and neutralizes endotoxin. Unfortunately, PMB can be considerably nephrotoxic at clinically utilized doses, thereby limiting its utility as a therapeutic antiendotoxin reagent. We sought to change the pharmacokinetics and toxicity profile of PMB by covalently linking it to a human immunoglobulin G (IgG) carrier. Conjugates of PMB with IgG were prepared by EDAC [1-ethyl-3-(3-dimethylaminopropyl) carbodiimide]-mediated amide formation. Analysis by dot enzyme-linked immunosorbent assay with an anti-PMB monoclonal antibody showed that the purified conjugate contained bound PMB. The IgG-PMB conjugate reacted with lipid A and J5 lipopolysaccharide in Western blot assays in a manner comparable to that of whole antiserum with anti-lipid A reactivity; unconjugated IgG had no reactivity. The PMB bound in the conjugate retained its endotoxin-neutralizing activity compared to that of unbound PMB as evidenced by its dose-dependent inhibition of tumor necrosis factor release by endotoxin-stimulated human monocytes in vitro; unconjugated IgG had no activity. By this assay, the PMB-IgG conjugate was determined to have approximately 3.0 microg of bound functional PMB per 100 microg of total protein of conjugate (five molecules of PMB per IgG molecule). The PMB-IgG conjugate was also bactericidal against clinical strains of Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae relative to unconjugated IgG with MBCs of <4 microg of conjugate per ml for each of the tested strains. The conjugate appeared to be nontoxic at the highest doses deliverable and provided statistically significant protection from death to galactosamine-sensitized, lipopolysaccharide-challenged mice in a dose-dependent fashion when administered prophylactically 2 h before challenge. However, neither free PMB nor the PMB-IgG conjugate could protect mice challenged with endotoxin 2 h after administration. This suggests that these reagents can play a role in prophylaxis but not in therapy of sepsis. These experiments demonstrated that the PMB-IgG conjugate retains bound yet functional PMB as evidenced by its endotoxin-neutralizing activity both in vitro and in vivo. Further work is required to define the role that this or related conjugate compounds may play in the prophylaxis of endotoxin-mediated disease.

Anti-Bacterial Agents↗
PubMed1998

Endotoxin-neutralizing protein protects against endotoxin-induced endothelial barrier dysfunction.

Bacterial lipopolysaccharide induces tyrosine phosphorylation of paxillin, actin reorganization, and opening of the transendothelial paracellular pathway through which macromoles flux. In this study, lipid A was shown to be the bioactive portion of the lipopolysaccharide molecule responsible for changes in endothelial barrier function. We then studied whether endotoxin-neutralizing protein, a recombinant peptide that is derived from Limulus antilipopolysaccharide factor and targets lipid A, could block the effects of lipopolysaccharide on protein tyrosine phosphorylation, actin organization, and movement of 14C-bovine serum albumin across bovine pulmonary artery endothelial cell monolayers. In the presence of serum, a 6-h exposure to lipopolysaccharide (10 ng/ml) increased transendothelial 14C-albumin flux compared to the simultaneous media control. Coadministration of endotoxin-neutralizing protein (> or =10 ng/ml) with lipopolysaccharide (10 ng/ml) protected against lipopolysaccharide-induced barrier dysfunction. This protection was dose dependent, conferring total protection at endotoxin-neutralizing protein/lipopolysaccharide ratios of > or =10:1. Similarly, endotoxin-neutralizing protein was capable of blocking the lipopolysaccharide-induced endothelial cell responses that are prerequisite to barrier dysfunction, including tyrosine phosphorylation of paxillin and actin depolymerization. Finally, endotoxin-neutralizing protein cross-protected against lipopolysaccharide derived from diverse gram-negative bacteria. Thus, endotoxin-neutralizing protein offers a novel therapeutic intervention for the vascular endothelial dysfunction of gram-negative sepsis and its attendant endotoxemia.

Actins↗
PubMed1997

Conformational and electrostatic properties of naphthazarin, juglone, and naphthoquinone: an ab initio theoretical study.

Conformational features of naphthazarin, juglone, and naphthoquinone have been examined via ab initio (Hartree-Fock) SCF calculations at 3-21G level. The results suggest a planar structure for all the three molecules and internally hydrogen-bonded structure for naphthazarin and juglone to be their preferred conformation. The optimized structural features are essentially the same as their crystal geometries. Molecular electrostatic potential (MEP) calculations using ab initio SCF methods ranging from 3-21G to 6-31G levels have been performed to visualize their three-dimensional pharmacophoric patterns and topography. The results indicate that two factors--(i) the depth, extent, and relative location of negative potential around hydroxyl and quinonoid oxygens, and (ii) a gradual loss of negative potential over the molecular plane due to the presence and orientation of the hydroxyl groups in the phenolic part of the molecules--are crucial for recognition interaction of the compounds with their receptors. Aqueous solvation seems to have significant influence on the MEP profiles of the molecules. Although intrinsic nucleophilicity increases for all the compounds, including the different conformers, due to aqueous solvation, the intrinsic electrophilicity shows remarkable decrease for all. It appears that the acidic nature of the hydrogens in these compounds and conformers decreases sharply along with shifts of positions while going from the gas phase to the aqueous phase. These observations may help to explain the mechanism of action(s) of the anthracyclin family of cytotoxic antibiotics.

Antineoplastic Agents↗
PubMed1996

Molecular electronic properties of a series of 4-quinolinecarbinolamines define antimalarial activity profile.

A detailed computational study on a series of 4-quinolinecarbinolamine antimalarials was performed using the semiempirical Austin model 1 (AM1) quantum chemical method to correlate the electronic features with antimalarial activity and to illuminate more completely the fundamental molecular level forces that affect the function and utility of the compounds. Ab initio (3-21G level) calculations were performed on mefloquine, the lead compound in this series, to check the reliability of the AM1 method. Electron density in specific regions of the molecules appears to play the pivotal role toward activity. A large laterally extended negative potential in the frontal portion of the nitrogen atom of the quinoline ring and the absence of negative potential over the molecular plane are crucial for the potent antimalarials. These electrostatic features are likely to be the modulator of hydrophobicity or lipophilicity of the compounds and, hence, determine their activities. The magnitude of the positive potential located by the hydroxyl hydrogen atom also correlates with potent antimalarial activity. Two negative potential regions occur near the hydroxyl oxygen and piperidyl nitrogen atoms. The two negative potential regions and the positive potential located by the hydroxyl hydrogen atom are consistent with intermolecular hydrogen bonding with the cellular effectors. The present modeling study should aid in efficient designing of this class of antimalarial agents.

Animals↗
PubMed1996

A noncovalent complex vaccine prepared with detoxified Escherichia coli J5 (Rc chemotype) lipopolysaccharide and Neisseria meningitidis Group B outer membrane protein produces protective antibodies against gram-negative bacteremia.

Earlier studies showed that purified IgG from sera of rabbits immunized with a boiled Escherichia coli J5 (Rc chemotype) whole cell vaccine protected neutropenic rats against gram-negative bacterial sepsis. In the present study, de-O-acylated J5 lipopolysaccharide (J5 DLPS) as a noncovalent complex with Neisseria meningitidis group B outer membrane protein (GBOMP) elicited anti-J5 LPS antibodies in rabbits. IgG prepared from immune rabbit sera protected neutropenic rats against lethal challenge with Pseudomonas aeruginosa 12:4:4 (Fisher Devlin immunotype 6). Sixteen of 26 rats treated with the postimmune serum IgG were protected compared with none of 20 rats treated with the control rabbit serum IgG (P < .001). In vitro binding studies showed binding of anti-J5 IgG to several gram-negative bacteria. These results indicate that a subunit vaccine made of J5 DLPS as a noncovalent complex with GBOMP may protect against gram-negative bacteremia.

Animals↗
PubMed1996

Outer membrane protein of Neisseria meningitidis as a mucosal adjuvant for lipopolysaccharide of Brucella melitensis in mouse and guinea pig intranasal immunization models.

A mucosal vaccine against brucellosis consisting of the lipopolysaccharide (LPS) of Brucella melitensis complexed with the outer membrane protein (GBOMP) of group B Neisseria meningitidis was tested in small-animal models of intranasal immunization. Mice given two doses of the vaccine developed high levels of immunoglobulin G (IgG) and IgA antibodies specific for B. melitensis LPS in lung lavages and specific IgG and IgA antibody-secreting cells in the lungs and spleen. Similarly, in guinea pigs immunized twice intranasally, IgG and IgA LPS-specific antibodies were detected in lung lavages, and specific antibody-secreting cells were isolated from the spleen and cervical nodes. In mice immunized with LPS only, pulmonary responses consisted mostly of IgM antibodies, while guinea pigs given LPS alone developed local antibody of all three isotypes, but at lower levels compared to animals given the complex vaccine. Both mice and guinea pigs also developed high levels of serum IgG and moderate levels of IgA as a result of intranasal immunization with the complex vaccine. The serum antibodies in both cases were found to cross-react with the LPS of B. abortus, which shares an immunogenic epitope with B. melitensis LPS. In mice given the complex vaccine, there was a prominent serum IgG1 response that was absent in the mice given LPS alone. In conclusion, the N. meningitidis GBOMP was an effective mucosal adjuvant for secretory IgA and IgG responses in the lungs of both mice and guinea pigs. The IgG1 subclass response in mice suggests that GBOMP may have favored a Th2 type of response to the LPS. A vaccine capable of stimulating high levels of antibody at local sites has the potential to protect against brucellae, since these pathogens gain entry to the host via mucosal routes.

Adjuvants, Immunologic↗
PubMed1994

Affinity-purified Escherichia coli J5 lipopolysaccharide-specific IgG protects neutropenic rats against gram-negative bacterial sepsis.

Antibodies were raised in rabbits by immunization with the heat-killed J5 mutant of Escherichia coli O111 (Rc chemotype). Serum antibodies were separated into purified IgG and IgM by sequential affinity chromatography on protein G-Sepharose and anti-rabbit IgG-Sepharose columns. J5 lipopolysaccharide (LPS)-specific IgG was prepared by affinity chromatography of purified IgG on a J5 LPS-EAH Sepharose 4B affinity column. Purified IgM, IgG, and J5 LPS-specific IgG protected neutropenic rats against lethal challenge with Pseudomonas aeruginosa 12:4:4 (Fisher Devlin immunotype 6). Nine of 16 rats treated with the IgM fraction were protected (P < .001). Thirteen of 20 rats treated with the purified IgG and 6 of 8 treated with J5 LPS-specific IgG were protected compared with none of 25 treated with IgG made from the preimmune serum of the same rabbit (P < .001). These results demonstrate that purified J5 LPS-specific IgG protects against the lethal consequences of gram-negative bacteremia.

Animals↗
PubMed1990

Antibodies to meningococcal H.8 (Lip) antigen fail to show bactericidal activity.

Purified H.8 (Lip) antigen was coupled to tresyl-activated Sepharose 4B and used in affinity columns to purify anti-Lip antibodies from convalescent patient sera and from immune rabbit sera. Affinity-purified anti-Lip antibodies isolated from two convalescent patient sera contained 1000 and 1280 ELISA units of antibody and included antibodies of IgG, IgA, and IgM isotypes. An anti-Lip mouse monoclonal ascites (2-1-CA2) had 28,400 ELISA units of antibody. Bactericidal assays were performed using three different case strains of Neisseria meningitidis group B, namely 44/76, 8532, and 8047. Neither preparation of purified human anti-Lip antibodies had detectable bactericidal activity against strains 44/76 and 8532, but one of the two had a titer of 1:4 against strain 8047. Anti-Lip antibodies that were purified from immune rabbit serum and contained 1600 ELISA units of anti-Lip antibodies also failed to show detectable bactericidal activity. The rabbits were immunized with purified Lip antigen and showed specific antibody levels of 2000-2200 units by ELISA, but even the unfractionated sera had little or no bactericidal activity against the test strains. The high titer mouse monoclonal ascites had no bactericidal activity against the test strains. The poor bactericidal activity associated with monoclonal and polyclonal antibodies to the Lip antigen suggest that in spite of other attractive properties it may not be useful as a meningococcal vaccine.

Animals↗