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Biomedical subjects

A Sharma

Publications and source records attributed to A Sharma.

At least 289 records · Page 16Linked to original sources
PubMed2000

Multiple dose pharmacokinetics of oral transmucosal fentanyl citrate in healthy volunteers.

BACKGROUND: Oral transmucosal fentanyl citrate (OTFC) is a solid form of fentanyl that delivers the drug through the oral mucosa. The clinical utility of multiple doses of OTFC in the treatment of "breakthrough" cancer pain is under evaluation. The aim of this study was to test the hypothesis that the pharmacokinetics of OTFC do not change with multiple dosing. METHODS: Twelve healthy adult volunteers received intravenous fentanyl (15 microg/kg) or OTFC (three consecutive doses of 800 microg) on separate study sessions. Arterial blood samples were collected for determination of fentanyl plasma concentration by radioimmunoassay. The descriptive pharmacokinetic parameters (maximum concentration, minimum concentration, and time to maximum concentration) were identified from the raw data and subjected to a nonparametric analysis of variance. Population pharmacokinetic models for all subjects and separate models for each subject were developed to estimate the pharmacokinetic parameters of fentanyl after multiple OTFC doses. RESULTS: The shapes of the profiles of plasma concentration versus time for each dose of OTFC were grossly similar. No change was noted for maximum concentration or time to maximum concentration over the three doses, while minimum concentration did show a significantly increasing trend. Terminal half-lives for intravenous fentanyl and OTFC were similar. A two-compartment population pharmacokinetic model adequately represented the central tendency of the data from all subjects. Individual subject data were best described by either two- or three-compartment pharmacokinetic models. These models demonstrated rapid and substantial absorption of OTFC that did not change systematically with time and multiple dosing. CONCLUSIONS: The pharmacokinetics of OTFC were similar among subjects and did not change with multiple dosing. Multiple OTFC dosing regimens within the dosage schedule examined in this study can thus be formulated without concern about nonlinear accumulation.

Administration, Oral↗
PubMed2000

Multicompartment urea kinetics in well-dialyzed children.

BACKGROUND: We have reported catch-up growth with hemodialysis (HD) of approximately 15 hours/week. Without an equilibrated post-treatment blood urea nitrogen, the variable-volume single-pool (VVSP) model will not account for urea rebound, inflating the estimated HD dose (K(d)t/V). A two-pool model (FVDP) predicts rebound, but requires fixed compartment volumes for the equations to be solvable in closed form, also inflating K(d)t/V. METHODS: We developed an approximate perturbation solution (WKB method) to a variable volume, two-pool (VVDP) model. Estimated model parameters were compared with the results of equilibrated kinetic studies using measured clearance K(d) (N = 17). Once the model was validated, we re-analyzed 292 kinetic studies from our earlier cohort, which was considered well-dialyzed on the basis of growth rates (N = 12, mean annual change in height standard deviation score +0.31, mean follow-up of 26 months). RESULTS: For the VVSP, FVDP, and VVDP models, respectively, the mean errors were (1) K(d)t/V, 0.22 +/- 0.07, 0.29 +/- 0.17, 0.06 +/- 0.07 (ANOVA, P < 0.001); (2) urea distribution volume vol/wt (%), -8.2 +/- 4.2, -9.1 +/- 3.0, -2.2 +/- 3.6 (P < 0.001). Sequential studies confirmed reproducibility, with a coefficient of variation < or = 5%. In the earlier cohort, a comparison of the VVSP and VVDP models yielded the following: (1) K(d)t/V, 1.91 +/- 0.35 vs. 1.76 +/- 0.33 (P < 0.001); (2) normalized protein catabolic rate (nPCR, g/kg/day), 1.56 +/- 0.39 vs. 1.52 +/- 0.38 (P < 0.001); and (3) K(d) (whole blood, mL/kg/min), 4.8 +/- 0.9 vs. 4.4 +/- 0.8 (P < 0.001). CONCLUSION: This VVDP model yields reliable estimates of K(d)t/V and other kinetic parameters using standard blood urea nitrogen sampling. Analysis of patients previously characterized as well-dialyzed on the basis of growth rates clarifies the HD dose needed to sustain normal growth.

Adolescent↗
PubMed2000

Relationship between N1 evoked potential morphology and the perception of voicing.

Auditory evoked potential (AEP) correlates of the neural representation of stimuli along a /ga/-/ka/ and a /ba/-/pa/ continuum were examined to determine whether the voice-onset time (VOT)-related change in the N1 onset response from a single to double-peaked component is a reliable indicator of the perception of voiced and voiceless sounds. Behavioral identification results from ten subjects revealed a mean category boundary at a VOT of 46 ms for the /ga/-/ka/ continuum and at a VOT of 27.5 ms for the /ba/-/pa/ continuum. In the same subjects, electrophysiologic recordings revealed that a single N1 component was seen for stimuli with VOTs of 30 ms and less, and two components (N1' and N1) were seen for stimuli with VOTs of 40 ms and more for both continua. That is, the change in N1 morphology (from single to double-peaked) coincided with the change in perception from voiced to voiceless for stimuli from the /ba/-/pa/ continuum, but not for stimuli from the /ga/-/ka/ continuum. The results of this study show that N1 morphology does not reliably predict phonetic identification of stimuli varying in VOT. These findings also suggest that the previously reported appearance of a "double-peak" onset response in aggregate recordings from the auditory cortex does not indicate a cortical correlate of the perception of voicelessness.

Adult↗
PubMed2000

Neurophysiologic correlates of cross-language phonetic perception.

This study examined neurophysiologic correlates of the perception of native and nonnative phonetic categories. Behavioral and electrophysiologic responses were obtained from Hindi and English listeners in response to a stimulus continuum of naturally produced, bilabial CV stimuli that differed in VOT from -90 to 0 ms. These speech sounds constitute phonemically relevant categories in Hindi but not in English. As expected, the native Hindi listeners identified the stimuli as belonging to two distinct phonetic categories (/ba/ and /pa/) and were easily able to discriminate a stimulus pair across these categories. On the other hand, English listeners discriminated the same stimulus pair at a chance level. In the electrophysiologic experiment N1 and MMN cortical evoked potentials (considered neurophysiologic indices of stimulus processing) were measured. The changes in N1 latency which reflected the duration of pre-voicing across the stimulus continuum were not significantly different for Hindi and English listeners. On the other hand, in response to the /ba/-/pa/ stimulus contrast, a robust MMN was seen only in Hindi listeners and not in English listeners. These results suggest that neurophysiologic levels of stimulus processing reflected by the MMN and N1 are differentially altered by linguistic experience.

Cerebral Cortex↗
PubMed2000

Genetic diversity of Vibrio cholerae in Chesapeake Bay determined by amplified fragment length polymorphism fingerprinting.

Vibrio cholerae is indigenous to the aquatic environment, and serotype non-O1 strains are readily isolated from coastal waters. However, in comparison with intensive studies of the O1 group, relatively little effort has been made to analyze the population structure and molecular evolution of non-O1 V. cholerae. In this study, high-resolution genomic DNA fingerprinting, amplified fragment length polymorphism (AFLP), was used to characterize the temporal and spatial genetic diversity of 67 V. cholerae strains isolated from Chesapeake Bay during April through July 1998, at four different sampling sites. Isolation of V. cholerae during the winter months (January through March) was unsuccessful, as observed in earlier studies (J. H. L. Kaper, R. R. Colwell, and S. W. Joseph, Appl. Environ. Microbiol. 37:91-103, 1979). AFLP fingerprints subjected to similarity analysis yielded a grouping of isolates into three large clusters, reflecting time of the year when the strains were isolated. April and May isolates were closely related, while July isolates were genetically diverse and did not cluster with the isolates obtained earlier in the year. The results suggest that the population structure of V. cholerae undergoes a shift in genotype that is linked to changes in environmental conditions. From January to July, the water temperature increased from 3 degrees C to 27.5 degrees C, bacterial direct counts increased nearly an order of magnitude, and the chlorophyll a concentration tripled (or even quadrupled at some sites). No correlation was observed between genetic similarity among isolates and geographical source of isolation, since isolates found at a single sampling site were genetically diverse and genetically identical isolates were found at several of the sampling sites. Thus, V. cholerae populations may be transported by surface currents throughout the entire Bay, or, more likely, similar environmental conditions may be selected for a specific genotype. The dynamic nature of the population structure of this bacterial species in Chesapeake Bay provides new insight into the ecology and molecular evolution of V. cholerae in the natural environment.

DNA Fingerprinting↗
PubMed2000

Cloning and functional expression of human retinal kir2.4, a pH-sensitive inwardly rectifying K(+) channel.

To identify novel potassium channel genes expressed in the retina, we screened a human retina cDNA library with an EST sequence showing partial homology to inwardly rectifying potassium (Kir) channel genes. The isolated cDNA yielded a 2,961-base pair sequence with the predicted open reading frame showing strong homology to the rat Kir2. 4 (rKir2.4). Northern analysis of mRNA from human and bovine tissues showed preferential expression of Kir2.4 in the neural retina. In situ hybridization to sections of monkey retina detected Kir2.4 transcript in most retinal neurons. Somatic hybridization analysis and dual-color in situ hybridization to metaphase chromosomes mapped Kir2.4 to human chromosome 19 q13.1-q13.3. Expression of human Kir2. 4 cRNA in Xenopus oocytes generated strong, inwardly rectifying K(+) currents that were enhanced by extracellular alkalinization. We conclude that human Kir2.4 encodes an inwardly rectifying K(+) channel that is preferentially expressed in the neural retina and that is sensitive to physiological changes in extracellular pH.

Amino Acid Sequence↗
PubMed2000

Effect of glycemic control and vitamin E supplementation on total glutathione content in non-insulin-dependent diabetes mellitus.

Thirty patients with non-insulin-dependent diabetes mellitus were selected for the study. 15 age-matched healthy volunteers served as controls. Serum malonaldehyde, total glutathione, and vitamin E levels were estimated before and after glycemic control and after 4 weeks of vitamin E supplementation. Both total glutathione and vitamin E levels increased after glycemic control and showed an increase after vitamin E supplementation. Malonaldehyde levels lowered after glycemic control, but remained higher than controls. Since vitamin E supplementation significantly decreased oxidative stress in the present study, it may play a role in reducing free-radical-induced oxidant injury in diabetes mellitus.

Blood Glucose↗
PubMed2000

Pharmacokinetics and safety of duloxetine, a dual-serotonin and norepinephrine reuptake inhibitor.

The pharmacokinetics and safety of duloxetine were evaluated in a single-blind, placebo-controlled, escalating multiple-dose study in 12 healthy male subjects. In the treatment group (n = 8), duloxetine was administered orally at a starting dose of 20 mg twice daily (bid) and escalated at weekly intervals to 30 mg bid, then to 40 mg bid. The observed plasma concentration-time data at all three dose levels were adequately described by a one-compartment model with a first-order absorption rate constant. The mean oral clearance, apparent volume of distribution, and half-life values were 114 L/h (range: 44 to 218 L/h), 1943 L (range: 803 to 3531 L), and 12.5 h (range: 9.2 to 19.1 h), respectively. Somnolence, nausea, and dry mouth were observed following the initial dose, but they resolved with continuing drug administration. Duloxetine was not associated with clinically significant changes in blood pressure (BP) or heart rate (HR) measured in the standing position. However, in recumbent position, small increases in systolic (< or = 9 mmHg) and diastolic (< or = 5 mmHg) BP and small decreases in HR (< or = 6 beats/min) were observed. Abrupt discontinuation of duloxetine was associated with a small increase in mean HR (< or = 12 beats/min). In 3 subjects, abrupt discontinuation was also associated with transient sleep disturbance. No clinically important changes in electrocardiograms, cardiac intervals, clinical laboratory tests, and neurological functions were observed. These results indicate that duloxetine exhibits linear pharmacokinetics with respect to dose and duration of treatment and that a multiple oral dose regimen starting at 20 mg bid and gradually escalating up to 40 mg bid was generally well tolerated.

Adrenergic Uptake Inhibitors↗
PubMed2000

Na+/H+ exchanger: an emerging therapeutic target in cardiovascular disorders.

Six isoforms of Na(+)/H(+) exchanger (NHE) have been identified to date. The NHE-1 isoform is expressed on the plasma membrane of cardiomyocytes and is involved in the regulation of intracellular pH and cell volume under normal physiological conditions. Myocardial ischemia-reperfusion is reported to strongly activate NHE-1. NHE-1 activation is postulated to contribute to myocardial injury by Ca(2+) overload. Several amiloride analogs non-selectively inhibit all isoforms of NHE and have been demonstrated to confer cardioprotection against ischemia-reperfusion injury in a number of experimental models with infarction, contractility, enzyme release and arrhythmias as endpoint. Recently, several selective inhibitors of the NHE-1 isoform have been synthesized and tested for their cardioprotective effect in animal models of ischemia-reperfusion injury. Cariporide and eniporide are currently being evaluated in phase II clinical trials for their antiischemic efficacy. NHE activity is reported to be altered in lymphocytes and vascular smooth muscle cells of spontaneously hypertensive rats and hypertensive patients. However, further research is required to clarify the role of NHE in the pathogenesis of hypertension. Several mitogenic stimuli are reported to activate NHE. Results of studies evaluating the effect of NHE inhibitors on postinfarction-induced cardiac remodeling in animals are promising. Further investigations are being carried out to highlight the involvement of NHE in cardiac hypertrophy. Based on the available data, it can be suggested that NHE has emerged as a useful target site in myocardial ischemia and may become a novel site for pharmacological modulation in hypertension and cardiac hypertrophy.

Journal Article↗
PubMed2000

Function and composition of pulmonary surfactant and surfactant-derived fatty acid profiles are altered in young adults with cystic fibrosis.

STUDY OBJECTIVES: To determine whether chronic lung inflammation in young adult patients with cystic fibrosis (CF) alters the composition and function of surfactant and surfactant components in bronchoalveolar secretions. DESIGN: A prospective, descriptive study. SETTING: An adult CF center in a tertiary health-care center. PARTICIPANTS: Thirteen normal volunteer (NV) subjects recruited via local advertising and 15 CF patients recruited from the CF center. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: We performed BAL and measured surfactant-associated protein A (SP-A) via enzyme-linked immunosorbent assay in BAL fluid (BALF), and quantitated total phospholipid, phospholipid subclass, and fatty acid subclass content of extracted BALF. We also determined the protein and phospholipid content, SP-A content, and functional characteristics of surfactant isolated from BALF via high-speed centrifugation. The phospholipid-to-protein ratio (milligram/milligram) of surfactant isolated by centrifugation (mean +/- SEM) was 1.01 +/- 0.07 for NV subjects and 2.62 +/- 0.42 for CF patients (p = 0.0001). Minimal surface tension was < 1 dyne.s.cm(-5) in all samples from NV subjects, but 21.9 +/- 0.73 dyne.s.cm(-5) for surfactant from CF patients. Immunoblotting of isolated surfactant revealed a marked decrease in SP-A for CF patients, compared to NV subjects. However, mean concentrations of SP-A in BALF that had not been subjected to high-speed centrifugation to isolate surfactant were not significantly different for CF patients (4.7 +/- 0.8 microgram/mL) vs NV subjects (4.6 +/- 0.2 microgram/mL). Additionally, phospholipid-to-protein ratios (0.32 +/- 0.04 for NV subjects vs 0.10 +/- 0.02 for CF patients; p < 0.0001) in extracted uncentrifuged BALF, and SP-A-to-protein ratios (microgram/milligram) in BALF were significantly depressed (74 +/- 8 for NV subjects vs 16 +/- 3 for CF patients; p < 0.0001). The phospholipid and fatty acid subclass profiles of extracted CF BALF vs NV BALF revealed a decreased mean phosphatidylcholine-to-sphingomyelin ratio (20.7 +/- 10.0 vs 55.2 +/- 8.7; p = 0.002), increased oleic acid content (12.1 +/- 2.3 nmol/mL vs 3.2 +/- 0.9 nmol/mL; p < 0.01), and increased arachidonic acid content (2.2 +/- 0.5 nmol/mL vs 0.6 +/- 0.3 nmol/mL; p < 0.05) for CF patients. CONCLUSIONS: Altered phospholipid-to-protein ratios and phospholipid subclasses, altered surfactant-derived fatty acid profiles, high minimal surface tension, and decreased association of SP-A with lipid components of isolated surfactant indicate that surfactant components are considerably altered and dysfunctional in lower respiratory tract secretions of CF patients. Surfactant composition and function are altered in CF, and the pattern of phospholipid and surfactant-derived fatty acid subclass alterations in CF are characteristic of ongoing lung injury and may depress surfactant function.

Adult↗
PubMed2000

Comparison of chromosome damage induced by three zinc compounds using human leukocyte culture.

The degree of chromosome damage induced by three compounds of zinc (zinc chloride, zinc sulfate, zinc acetate) was compared in human leucocytes in vitro. Three concentrations of each salt, 3.0 x 10(-5)M, 3.0 x 10(-4)M, and 1.5 x 10(-3)M, were added to leukocyte cultures. The cells were harvested after 48 and 72 h and chromosome spreads were prepared following a colchicine-hypotonic-fixation-air drying-Giemsa staining schedule. The end point screened was chromosome aberrations. All three salts were lethal at the highest concentration. The degree of chromosome damage was directly proportional to the concentrations used for zinc sulfate and zinc acetate but not for zinc chloride.

Adult↗
PubMed2000

Study of IgM aggregation in serum of patients with macroglobulinemia.

The effect of solvent conditions on the aggregation of IgM in serum specimens from patients with macroglobulinemia was studied by a turbidimetric procedure. Aggregation of IgM varied considerably among the samples and was affected by a number of experimental parameters. In general, IgM aggregation was more pronounced under acidic conditions and in solvents with low ionic strength. The presence of water-miscible organic solvents also promoted aggregation. Based on these studies, it was concluded that the major force involved in the formation of immunoglobulin aggregates in the serum of patients with macroglobulinemia was electrostatic, rather than hydrophobic, interactions. A number of additives known to prevent protein aggregation were evaluated for their effectiveness in inhibiting IgM aggregation. The only additives that were shown to inhibit or reduce IgM aggregation were charged molecules, such as arginine, sodium chloride, ethylenediamintetraacetic acid and quaternary ammonium beta-cyclodextrin. Some of these charged additives were also effective in dissociating the IgM aggregates once they were formed, even in the presence of detergent.

Anions↗
PubMed2000

Expression profile and chromosomal location of cDNA clones, identified from an enriched adult retina library.

PURPOSE: To delineate the profile of genes expressed in the adult human retina and assign chromosomal location of cDNA clones. METHODS: The end-sequence of random clones from an enriched human retinal cDNA library was analyzed by NCBI database search. Expression profile was established by northern blot analysis, database search, or both. Selected cDNA clones were localized to human chromosomes by somatic cell hybrid analysis, in situ hybridization to metaphase chromosomes, or both. Chromosomal location was also obtained by searching the databases. RESULT: One hundred and thirty-seven clones were isolated from the subtracted retinal library. Fifty-one clones were identical with 35 known human genes in GenBank, and 24 clones corresponded to 23 uncharacterized human expressed sequenced tags (ESTs), novel genes, or both. The remaining 59 clones were not pursued further because they contained bacterial sequences or repetitive elements. Several clones indicated a restricted pattern of expression with high levels of transcripts in the retina. Chromosomal location of novel retinal ESTs is also reported. CONCLUSIONS: This study provides a profile of genes expressed in the adult human retina. One round of subtraction eliminated most constitutively expressed genes and permitted partial normalization of the retinal library. Twenty-three novel genes were identified. The combined information obtained from expression analysis and chromosomal localization of retinal cDNAs should be valuable in identifying candidate genes for diseases involving retinal dysfunction.

Blotting, Northern↗
PubMed2000

Comparative pharmacodynamics of keliximab and clenoliximab in transgenic mice bearing human CD4.

Keliximab and clenoliximab are monkey/human chimeric CD4 monoclonal antibodies (mAbs) of the IgG1 and IgG4 isotypes, respectively. The pharmacokinetics (PK) and pharmacodynamics (PD) of these mAbs were evaluated in transgenic mice bearing human CD4 molecules on their T cells after a single i.v. administration at three dose levels (5-125 mg/kg). The PK of keliximab and clenoliximab were similar, dose-dependent, and adequately described by a two-compartment model with saturable elimination from both compartments. The enumeration of circulating CD4(+) T cells and density of CD4 on their surface were determined as the PD effects. An indirect response model was proposed to characterize the PD effects. With the increase in mAb dose, the maximum intensity (R(max)) of PD effects was increased, and the time to reach R(max) shifted to later times. At all three dose levels, keliximab caused a relatively rapid decline in the number of circulating CD4(+) T cells, which then recovered gradually. In contrast, clenoliximab at the lowest dose (5 mg/kg) did not produce a significant effect on CD4(+) T cell counts compared with the placebo group. At high doses, clenoliximab caused a significant decrease in the number of CD4(+) T cells. Keliximab appeared to be more potent and efficient in depleting CD4(+) T cells. Both mAbs produced similar down-modulation of CD4 at corresponding dose levels. The findings of this study are consistent with the results of a recent clinical trial that emphasize the importance of this transgenic mouse model for evaluating PK/PD to support clinical development of anti-human CD4 mAbs.

Animals↗
PubMed2000

Identification of an appropriate strategy to control anemia in adolescent girls of poor communities.

OBJECTIVES: To obtain baseline data on hemoglobin (Hb) levels of adolescent girls belonging to the low-socio-economic groups; investigate the comparative efficacy of once 'weekly' and 'daily' administration of iron-folate tablets with respect to impact on the Hb levels; and find out the effect of added ascorbic acid supplementation on the efficacy of iron-folate administration with respect to increment in Hb levels. DESIGN: Randomized experimental. SETTING: Adolescent girls of poor communities in urban areas of Delhi and rural parts of Bharatpur (Rajasthan). METHODS: The baseline investigations included measurements of height, weight, and Hb levels. The Hb levels of the participating subjects were measured again after 3 months and 6 months of supplementation. RESULTS: 61.9% of the subjects in the urban and 85.4% in the rural area were anemic. The response of Hb levels to daily iron/folate supplementation was better in comparison to once-weekly supplementation. The increment in Hb levels of subjects due to addition of vitamin C to iron/folate supplementation was more than that with supplementation of iron/folate alone. CONCLUSIONS: Considering compliance, feasibility and cost-factors, a public-health approach consisting of once-weekly distribution of iron/folate supplementation through schools and welfare centers is better and can be recommended as an appropriate strategy for combating anemia in adolescent girls of poor communities in developing countries like India.

Adolescent↗
PubMed2000

Acute alcoholic myopathy, rhabdomyolysis and acute renal failure: a case report.

A case of middle aged male who developed swelling and weakness of muscles in the lower limbs following a heavy binge of alcohol is being reported. He had myoglobinuria and developed acute renal failure for which he was dialyzed. Acute alcoholic myopathy is not a well recognized condition and should be considered in any intoxicated patient who presents with muscle tenderness and weakness.

Acute Kidney Injury↗