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Biomedical subjects

K Krishnan

Publications and source records attributed to K Krishnan.

At least 19 recordsLinked to original sources
PubMed2003

Serologically documented loracarbef (Lorabid)-induced immune thrombocytopenia.

We report here the first case of severe immune thrombocytopenia induced by a second-generation cephalosporin antibiotic, Loracarbef. A 56-year old white female developed acute severe thrombocytopenia associated with acute respiratory symptoms following administration of Loracarbef. She responded to Loracarbef withdrawal and systemic corticosteroid administration. Loracarbef-dependent platelet-reactive antibodies were demonstrable in her serum by flow cytometry.

Autoantibodies↗
PubMed2003

Cancer chemoprevention drug targets.

Cancer chemoprevention is a new approach in the management of cancer. Traditional cytotoxic chemotherapeutic approaches cannot cure most advanced solid malignancies. Chemoprevention can be defined as the use of non-cytotoxic drugs and natural agents to block the progression to invasive cancer. Chemoprevention can either prevent DNA damage that initiates the neoplastic transformation process or reverses the progression of pre-invasive lesions. Epidemiological observations, experimental evidence from animal carcinogenesis models, knock-out models, cancer cell lines and clinical trials have shown the efficacy of this approach. Recent advances in our understanding of carcinogenesis have led to the synthesis of new drugs that target specific receptors. Non-steroidal anti-inflammatory drugs target the prostaglandin pathway. The identification of the role of cyclooxygenase-2 in epithelial carcinogenesis led to the synthesis of selective cyclooxygenase-2 inhibitors (Celecoxib). Celecoxib was subsequently approved for the prevention of colon polyps in familial adenomatous polyposis after the completion of a randomized clinical trial. The large chemoprevention clinical trial with the selective estrogen receptor modulator, tamoxifen, showed the benefit of tamoxifen in the prevention of breast cancer in high-risk women. Retinoids and rexinoids target the retinoid receptors and have a role in chemoprevention of aerodigestive, hepatic and cervical neoplasia. Selenium, an inhibitor of the glutathione peroxidase system, is being tested in the chemoprevention of prostate cancer and lung cancer. The different isoforms of vitamin E (tocopherols) may be chemopreventive. Recent evidence indicates that gamma-tocopherol may be a more powerful chemopreventive than the alpha-tocopherol. The review details the rationale, experimental and clinical evidence and the drug targets of the chemopreventive agents that are currently in various phases of clinical development.

Animals↗
PubMed2002

Computer added locomotion by implanted electrical stimulation in paraplegic patients (SUAW).

Paraplegia means a live long sentence of sensory loss, paralysis and dependence with approximately 1000 new victims in every European country every year and 11.500 new traumatic SCI cases in the US. respectively. Sixty percent are injured before age 30. More than 90% of SCI victims may survive with nearly normal experience of live. Most patients will recover somewhat from SCI over time but no patient who remained plegic for one year regains voluntary motor function after that time period. Despite remarkable efforts and recent achievements in rehabilitation no treatment can be recommended so far to enhance functional recovery and restoring locomotion in paraplegic humans. FES as a technical compensation has become therefore a challenging treatment to restore muscle function and to prevent atrophy and to improve mobility and quality of life at the same time. In paraplegics FES could be the basis to restore locomotion. One of the advantages of an implanted FES version (neuroprosthesis) is that the FES system, electrodes, and cables remain permanently implanted within the body, so that the patient can stay without cables, the programmer attached to the crutches. The SUAW project, supported under BIOMED II Programme by the European Community was aimed to finalize and to put into practice the results of previous research and development. The novel implant with an ASCI-Chip has 16 channels, 8 on each side, 20 mA for monopolar and 2 mA for bipolar stimulation, only one electrode can be stimulated at a given time. Stimulation of 6 muscle groups of both legs are known to be sufficient for locomotion: M. ileopsoas (erector of the body, hip flexor), M. gluteus maximus (hip extensor), M. gluteus medius (lateral hip stabilisator, knee abductor), Mm. hamstrings (knee flexor) stimulated by epimysial electrodes, Mm. sartorius and rectus femoris (knee extensor) stimulated by neural, bipolar electrodes. Patient's selection criteria were: stable spinal cord lesion between T7 and T11, minimum 1 year after the accident without deformity of the spine, the muscle groups for locomotion responding to external FES with the EXOSTIM programmer with the same programme used later for the neuroprosthesis. Two paraplegic male patients, T8, 38 and 31 years old respectively, were operated on by an international group of surgeons according to the protocol in 09/1999, respectively 7/2000. The postop. course was uneventful. Because the threshold of the primary implant was too low regarding scare tissue around the electrodes, this implant was changed in 01/2000 and worked perfectly. Both patients are happy with the success of the novel treatment modalities.

Adult↗
PubMed2001

Characterization of age-related changes in body weight and organ weights from birth to adolescence in humans.

The pharmacokinetics and tissue dose of chemicals may differ among individuals of a population, particularly between adults and children. The adult-children differences in pharmacokinetics arise from age-related changes in the physiological, biochemical, and physicochemical determinants of uptake and disposition of chemicals. The objectives of this study were to review the published literature to assemble data on the human body weight and organ weights as a function of age (specifically between birth and 18 yr old) and to analyze these data, in order to develop regression equations for calculating body weight and organ weights of children using age as the dependent function. The specific organs/tissues for which the data on age-related weight were obtained and analyzed include blood, adipose tissues, liver, lungs, brains, heart, kidneys, spleen, the reproductive organs (male: prostate gland, seminal vesicle, testes, and epididymis; female: ovaries, uterus, and uterine tubes), glands (adrenal, pituitary, thymus, pancreas, and thyroid), bone marrow (total and red), intestinal tract, stomach, muscle, skin (epidermis and dermis), and skeleton. In both male and female children, the sum of these organs is systematically lower than the body weight, and this discrepancy may be resolved with the additional availability and consideration of data on hypodermis weight. The equations and data on body weight and organ weights presented in this article should be useful for constructing age-specific, physiologically based pharmacokinetic models for children.

Adolescent↗
PubMed2001

Shear-induced nano-macro structural transition in a polymeric bicontinuous microemulsion.

Bicontinuous microemulsions arise in a narrow concentration range for ternary blends containing two immiscible homopolymers and the corresponding diblock copolymer. Steady shear reveals four distinct regimes of response as a function of shear rate, corresponding to flow-induced transitions in fluid structure. In situ neutron scattering shows flow-induced anisotropy in the nanometer-scale microemulsion structure at moderate shear rates, while higher rates induce bulk phase separation, with micron-size morphology, which is characterized with in situ light scattering and optical microscopy.

Journal Article↗
PubMed2001

Quantitative structure-pharmacokinetic relationship modelling.

This article presents the current methods in quantitative structure-pharmacokinetic relationship (QSPkR) modelling along with examples using chemicals of toxicological significance. The common method involves: (i) collecting pharmacokinetic data or determining pharmacokinetic parameters (e.g. elimination half-life, volume of distribution) by fitting to experimental data; and (ii) associating them with the structural features of chemicals using a Free-Wilson model. Such QSPkRs have been developed for a few series of chemicals but their usefulness is limited to the exposure scenario and conditions under which the experimental data were originally collected. The alternative approach involves the development of quantitative structure-property relationship (QSPR) models for parameters, blood:air partition coefficient, tissue:blood partition coefficient, maximal velocity for metabolism and Michaelis affinity constant, of physiologically-based pharmacokinetic (PBPK) models which are useful for conducting species, route, dose and scenario extrapolations of the tissue dose of chemicals. Mechanistic QSPRs are available for predicting tissue:blood and blood:air partition coefficients from molecular structure information of chemicals, whereas such approaches are not currently available for hepatic metabolism parameters. However, at the present time, the pharmacokinetics of inhaled volatile organic chemicals can be simulated adequately by considering the physiological limits of the hepatic extraction ratio (0-1) and molecular structure-based estimates of partition coefficients in the PBPK model. This current state-of-the-art of structure-based modelling of pharmacokinetics will advance with the development of QSPRs for other chemical-specific parameters of PBPK models. Integrated QSPR-PBPK modelling should facilitate the identification of chemicals of a family that possess desired properties of bioaccumulation and blood concentration profile in both test animals and humans.

Animals↗
PubMed2001

Cholesterol signaling at the endoplasmic reticulum occurs in npc1(-/-) but not in npc1(-/-), LDLR(-/-) mice.

It remains controversial whether deficiency of the Niemann-Pick C1 (npc1) protein results in altered cholesterol signaling at the endoplasmic reticulum (ER). In this report, we have measured the processed, nuclear form of sterol regulatory element binding protein (SREBP)-1 in livers of npc1 wild-type, heterozygous, and homozygous deficient mice, alone, and in combination with deficiencies of the low density lipoprotein receptor (LDLR) or the multiple drug resistant (mdr)1a, P-glycoprotein. Cleavage of SREBPs to activated forms normally occurs when the ER is deficient in cholesterol. A large decrease in processed SREBP-1 was evident in fasted npc1(-/-) mice and npc1(-/-), mdr1a(-/-) mice, with no decrease evident in npc1(-/-), LDLR(-/-) mice. These results suggest that the increase in cellular cholesterol which occurs in npc1(-/-) and in npc1(-/-), mdr1a(-/-) mice includes the sites responsible for cholesterol signaling, while the similar increase in cholesterol found in npc1(-/-), LDLR(-/-) mice does not.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2001

Molecular structure-based prediction of human abdominal skin permeability coefficients for several organic compounds.

Mechanistically based predictions of skin permeability coefficients (Kp) derived solely on the basis of molecular structure information of organic compounds have not been reported previously. The objective of the present study was to predict the human abdominal Kp of structurally unrelated organic compounds using a mechanistic equation that takes into account compound-specific and species-specific determinants of Kp and relates the compound-specific determinants directly to molecular structure information. The method consisted of obtaining predictions based on a modified form of the conventional equation used to describe Kp (= P x D/L, where P, D, and L represent the stratum corneum:water partition coefficient, diffusion coefficient, and path length of diffusion). The value of P was predicted from the n-octanol:water partition coefficient (Po:w) computed from molecular structure information as well as the lipid, protein, and water contents in stratum corneum. The value of D was predicted according to the conventional Einstein-Stoke equation using the molar volume (Vmolar) of compounds computed from molecular structure information as well as data on viscosity of the stratum corneum components. Finally, the value of L was estimated in accordance with the characteristics of the diffusion pathways in the stratum corneum (i.e., transcellular and intercellular pathways). The average ratio of predicted Kp to the corresponding mean experimental values obtained from the literature was 1.25 (SD = 0.68, r = .95) for 47 structurally unrelated organic compounds (volatile organics and drugs), which were characterized by the presence of less than 2 hydrogen bonding groups and Vmolar < 231 cm3/mol. The present study is the first initiative that permits prediction of the human Kp of organic compounds by using molecular structure information as the sole chemical-specific input in a mechanistic equation.

Abdomen↗
PubMed2001

Blood:air partition coefficients of individual and mixtures of trihalomethanes.

The objective of the present study was to determine the rat blood:air partition coefficients (P(b:a)) of chloroform, bromodichloromethane, dibromochloromethane and bromoform present in vitro individually or as mixtures. The experimentally determined P(b:a) of chloroform, bromodichloromethane, dibromochloromethane and bromoform present individually corresponded to (mean +/- SD, n = 8) 21.3 +/- 1.8, 41.8 +/- 6.2, 97.5 +/- 4.1, and 187 +/- 7.4, respectively. The P(b:a) of these trihalomethanes (THMs) showed a decreasing trend during mixed in vitro exposures to 0.138 +/- 0.002 or 0.273 +/- 0.002 micromol of each of the four THMs. In general, the P(b:a) determined during mixed exposures differed by < or = 15% of the average P(b:a) determined for THMs present individually. The results of this study suggest that an alteration of P(b:a) of the individual THMs is unlikely to occur at the blood concentrations of THMs observed during mixed exposures in rats.

Animals↗
PubMed2001

Prostaglandin inhibitors and the chemoprevention of noncolonic malignancy.

Much has been learned about the role of NSAIDs as cancer preventives through epidemiologic and experimental studies. The pathways of carcinogenesis in the gastrointestinal tract are initiated by many different genetic, environmental, infective, and lifestyle factors. It is possible that the final common pathway of all these malignancies may have some common features. It is conceivable that head and neck, esophageal, gastric, and colorectal epithelial carcinogenesis all are influenced by or require COX-2 up-regulation as a step toward transformation. Intuitively, it is possible that selective COX-2 inhibitors may have a preventive role in all these epithelial malignancies. Today's challenge is to translate this information into clinical trials to define what role, if any, COX inhibition might play in the prevention of these malignancies.

Adenocarcinoma↗
PubMed2001

Bonding agent is a decisive factor in determining the marginal leakage of dental composites subjected to thermal cycling: an in vitro study.

The marginal leakage at the dentine/composite interface in Class II composite restorations subjected to thermal cycling has been effectively evaluated using the silver staining technique. The presence of a bonding agent at the dentine/composite interface is found to improve adhesion. Scanning electron and optical microscopic observations of sectioned specimens reveal that applying a second coat of bonding agent on the dentinal surface helps in reducing microleakage compared to a single coat application, in all three radiopaque composite/bonding agent systems studied (Z100/Single Bond, Spectrum TPH/Prime & Bond 2.1 and Chitra/Chitrabond 1.0). Thermal cycling during in vitro studies was found to provide a more appropriate representation of the adhesive behaviour of the composite in clinical situations.

Adhesiveness↗
PubMed2001

In vitro human tissue models in risk assessment: report of a consensus-building workshop.

Advances in the technology of human cell and tissue culture and the increasing availability of human tissue for laboratory studies have led to the increased use of in vitro human tissue models in toxicology and pharmacodynamics studies and in quantitative modeling of metabolism, pharmacokinetic behavior, and transport. In recognition of the potential importance of such models in toxicological risk assessment, the Society of Toxicology sponsored a workshop to evaluate the current status of human cell and tissue models and to develop consensus recommendations on the use of such models to improve the scientific basis of risk assessment. This report summarizes the evaluation by invited experts and workshop attendees of the current status of such models for prediction of human metabolism and identification of drug-drug interactions, prediction of human toxicities, and quantitative modeling of pharmacokinetic and pharmaco-toxicodynamic behavior. Consensus recommendations for the application and improvement of current models are presented.

Cell Culture Techniques↗
PubMed2001

A PBPK modeling-based approach to account for interactions in the health risk assessment of chemical mixtures.

The objectives of the present study were: (1) to develop a risk assessment methodology for chemical mixtures that accounts for pharmacokinetic interactions among components, and (2) to apply this methodology to assess the health risk associated with occupational inhalation exposure to airborne mixtures of dichloromethane, benzene, toluene, ethylbenzene, and m-xylene. The basis of the proposed risk assessment methodology relates to the characterization of the change in tissue dose metrics (e.g., area under the concentration-time curve for parent chemical in tissues [AUCtissue], maximal concentration of parent chemical or metabolite [Cmax], quantity metabolized over a period of time) in humans, during mixed exposures using PBPK models. For systemic toxicants, an interaction-based hazard index was calculated using data on tissue dose of mixture constituents. Initially, the AUCtarget tissue (AUCtt) corresponding to guideline values (e.g., threshold limit value [TLV]) of individual chemicals were obtained. Then, the AUCtt for each chemical during mixed exposure was obtained using a mixture PBPK model that accounted for the binary and higher order interactions occurring within the mixture. An interaction-based hazard index was then calculated for each toxic effect by summing the ratio of AUCtt obtained during mixed exposure (predefined mixture) and single exposure (TLV). For the carcinogenic constituents of the mixture, an interaction-based response additivity approach was applied. This method consisted of adding the cancer risk for each constituent, calculated as the product of q*tissue dose and AUCtt. The AUCtt during mixture exposures was obtained using an interaction-based PBPK model. The approaches developed in the present study permit, for the first time, the consideration of the impact of multichemical pharmacokinetic interactions at a quantitative level in mixture risk assessments.

Air Pollutants, Occupational↗
PubMed2001

The HOX homeodomain proteins block CBP histone acetyltransferase activity.

Despite the identification of PBC proteins as cofactors that provide DNA affinity and binding specificity for the HOX homeodomain proteins, HOX proteins do not demonstrate robust activity in transient-transcription assays and few authentic downstream targets have been identified for these putative transcription factors. During a search for additional cofactors, we established that each of the 14 HOX proteins tested, from 11 separate paralog groups, binds to CBP or p300. All six isolated homeodomain fragments tested bind to CBP, suggesting that the homeodomain is a common site of interaction. Surprisingly, CBP-p300 does not form DNA binding complexes with the HOX proteins but instead prevents their binding to DNA. The HOX proteins are not substrates for CBP histone acetyltransferase (HAT) but instead inhibit the activity of CBP in both in vitro and in vivo systems. These mutually inhibitory interactions are reflected by the inability of CBP to potentiate the low levels of gene activation induced by HOX proteins in a range of reporter assays. We propose two models for HOX protein function: (i) HOX proteins may function without CBP HAT to regulate transcription as cooperative DNA binding molecules with PBX, MEIS, or other cofactors, and (ii) the HOX proteins may inhibit CBP HAT activity and thus function as repressors of gene transcription.

Amino Acid Motifs↗
PubMed2001

Reactive and clonal thrombocytosis: proinflammatory and hematopoietic cytokines and acute phase proteins.

BACKGROUND: We quantitated proinflammatory and thrombopoietic cytokines in reactive thrombocytosis (RT) and clonal thrombocytosis (CT) to identify a cytokine profile that might aid in the distinction of these two disorders. METHODS: Serum levels of cytokines relevant to platelet biology--interleukins 3, 6, 11, and 1beta; thrombopoietin; tumor necrosis factor alpha; and C-reactive protein (CRP)--were measured by enzyme-linked immunosorbent assay in healthy subjects and in patients with CT and RT. RESULTS: Interleukin-6 and CRP levels were higher in RT patients than in controls or CT patients. Interleukin 1beta levels were higher in the RT group than in the CT and control groups. CONCLUSIONS: In RT, IL-6, IL-1beta, and CRP levels are elevated. In both RT and CT, IL-11 is elevated, but thrombopoietin levels are not.

Adult↗
PubMed2001

Colonic mucosal prostaglandin E2 and cyclooxygenase expression before and after low aspirin doses in subjects at high risk or at normal risk for colorectal cancer.

UNLABELLED: Development of potential cancer chemopreventive drugs involves the systematic evaluation of these drugs in preliminary Phase I and II studies in human beings to identify the optimal drug dose, drug toxicity, and surrogate end point biomarker modulation. OBJECTIVES: We tested the hypothesis that aspirin, at a single, once-daily 81-mg dose, will reduce colonic mucosal concentration of prostaglandin estradiol (E2) in individuals at high risk for colorectal cancer development similar to our prior observations in a young normal-risk population. METHODS: Aspirin was administered at a dose of 81 mg once daily for 28 days in a cohort of 92 matched high-risk and normal-risk colorectal cancer subjects. Prostaglandin E2 and cyclooxygenase expression were assayed from distal sigmoid biopsies from all of the subjects before and after treatment. RESULTS: The mean prostaglandin E2 for normal-risk subjects before aspirin treatment was 11.3 +/- 1.7 pg/microg (mean +/- SE) tissue protein and after aspirin treatment was 4.9 +/- 0.91 pg/microg tissue protein (P < 0.0001). In high-risk subjects, mean pretreatment prostaglandin E2 was 14.4 +/- 1.7 pg/microg tissue protein and after aspirin treatment was 4.7 +/- 0.70 pg/microg tissue protein (P < 0.0001). Aspirin treatment did not alter cyclooxygenase-1 protein expression. CONCLUSIONS: Aspirin treatment at a dose of 81 mg reduces colorectal mucosal prostaglandin E2 concentration after 28 daily doses. Risk for colorectal carcinoma did not modify colorectal mucosal baseline or post-aspirin prostaglandin E2, or cyclooxygenase expression. Colorectal mucosal prostaglandin concentration may be used as a "drug-effect surrogate biomarker," that is, a surrogate to assess sufficient delivery and tissue effect of a chemopreventive agent.

Adult↗
PubMed2000

Physiologically based modeling of the maximal effect of metabolic interactions on the kinetics of components of complex chemical mixtures.

The objective of this study was to predict and validate the theoretically possible, maximal impact of metabolic interactions on the blood concentration profile of each component in mixtures of volatile organic chemicals (VOCs) [dichloromethane (DCM), benzene (BEN), trichloroethylene (TCE), toluene (TOL), tetrachloroethylene (PER), ethylbenzene (EBZ), styrene (STY), as well as para, ortho-, and meta-xylene (p-XYL, o-XYL, m-XYL)] in the rat. The methodology consisted of: (1) obtaining the validated, physiologically based toxicokinetic (PBTK) model for each of the mixture components from the literature, (2) substituting the Michaelis-Menten description of metabolism with an equation based on the hepatic extraction ratio (E) for simulating the maximal impact of metabolic interactions (i.e., by setting E to 0 or 1 for simulating maximal inhibition or induction, respectively), and (3) validating the PBTK model simulations by comparing the predicted boundaries of venous blood concentrations with the experimental data obtained following exposure to various mixtures of VOCs. All experimental venous blood concentration data for 9 of the 10 chemicals investigated in the present study (PER excepted) fell within the boundaries of the maximal impact of metabolic inhibition and induction predicted by the PBTK model. The modeling approach validated in this study represents a potentially useful tool for screening/identifying the chemicals for which metabolic interactions are likely to be important in the context of mixed exposures and mixture risk assessment.

Administration, Inhalation↗