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Biomedical subjects

A Maheshwari

Publications and source records attributed to A Maheshwari.

At least 19 recordsLinked to original sources
PubMed2006

Oral V2 receptor antagonist (RWJ-351647) in patients with cirrhosis and ascites: a randomized, double-blind, placebo-controlled, single ascending dose study.

BACKGROUND: RWJ-351647 is a selective V2 receptor antagonist that inhibits vasopressin-induced water reabsorption in the kidney. AIM: To investigate the safety and tolerability of RWJ-351647 compared with placebo after single oral dose administration to patients with cirrhosis and ascites, on a stable treatment with furosemide and spironolactone. METHODS: Single oral doses of 1, 2 and 5 mg of RWJ-351647 were administered to 24 patients with ascites on stable concomitant diuretic treatment. RESULTS: RWJ-351647 had a tmax of 1 to 1.1 h and mean half-life of 10.4-17.4 h. There was no affect on the pharmacokinetics of concomitant diuretics. Increases in cumulative urine volume and free water excretion, and a decrease in urine osmolality were noted in a dose-dependent manner reaching the statistical significance at the 5-mg dose. Four patients exhibited a decrease of > 2 kg in weight in the 24 h after dosing. RWJ-351647 was well tolerated, with no evidence of a dose-related increase in adverse events when compared with placebo. No changes in either serum chemistry or plasma AVP (arginine vasopressin) and renin levels were observed despite the observed aquaresis. CONCLUSION: RWJ-351647 is an effective aquaretic causing dose-dependent increases in urine output and free water clearance, when co-administered with conventional diuretics in patients with cirrhosis and ascites.

Administration, Oral↗
PubMed2004

Randomised, double blind, placebo controlled trial of interferon, ribavirin, and amantadine versus interferon, ribavirin, and placebo in treatment naïve patients with chronic hepatitis C.

BACKGROUND AND AIM: In this study, we compared the efficacy of triple therapy (interferon alfa, ribavirin, and amantadine) with standard therapy (interferon alfa and ribavirin) in treatment naïve patients with chronic hepatitis C virus (HCV). METHODS: In this prospective, randomised, double blind, placebo controlled, multicentre study, 85 patients (amantadine group) received a three drug regimen of interferon alfa-2b 3 million units three times per week, ribavirin 1000-1200 mg daily in divided doses, and amantadine 100 mg twice daily, and 86 patients (placebo group) received interferon alfa-2b, ribavirin, and identical placebo. Treatment was discontinued at 24 weeks if patients had detectable HCV RNA by polymerase chain reaction (PCR). All patients were followed for 24 weeks after completion of treatment. The primary end point was undetectable HCV-RNA by PCR at 24 weeks (sustained viral clearance) after completion of treatment. RESULTS: At the end of treatment, HCV RNA clearance was seen in 32.9% of the amantadine group and 38.4% of the placebo group (p=0.3). Sustained virological response was seen in 24.7% of the amantadine group and in 27.9% of the placebo group by intention to treat analysis; response rate was 30.4% and 34.8%, respectively, in those who completed 24 weeks of treatment. Poor response was seen in both groups among cirrhotics, African-Americans, genotype 1, and those with a higher viral load. By multivariate analysis, genotype 1, high viral load, and low serum albumin were the only predictors of poor response. Addition of amantadine to the standard regimen did not result in any unexpected side effects. CONCLUSION: Response to triple therapy of interferon alfa, ribavirin, and amantadine was similar to standard therapy of interferon alfa and ribavirin. Our results suggest that amantadine has no role in the management of HCV.

Adult↗
PubMed2002

Biodegradable polymer-based interleukin-12 gene delivery: role of induced cytokines, tumor infiltrating cells and nitric oxide in anti-tumor activity.

The objective of this study was to investigate the role of induced cytokines, tumor infiltrating cells and nitric oxide (NO) in anti-tumor activity upon intratumoral injection of free and condensed plasmid DNA encoding murine interleukin-12 (pmIL-12) into BALB/c mice bearing subcutaneous tumors. Poly[alpha-(4-aminobutyl)-L-glycolic acid] (PAGA) was used for complex formation with pmIL-12 in presence of 5% (w/v) glucose. Upon characterization, PAGA/pmIL-12 (3/1, +/-) complexes were found to be most effective in gene transfer and were used consistently throughout this study. The levels of mIL-12 p70 and induced cytokines were determined by ELISA in the supernatant of the cultured tumors of the CT-26 subcutaneous tumor bearing BALB/c female mice 48 h after intratumoral injection of PAGA/pmIL-12 complexes and naked pmIL-12. The levels of IL-12, IFN-gamma, TNF-alpha and NO were higher for the PAGA/pmIL-12 complexes than those for the naked pmIL-12, PAGA alone and 5% glucose injected groups. The relative presence of natural killer (NK) cells, CD4(+) T cells, and antigen presenting cells, such as macrophages and dendritic cells determined using immunohistochemistry was higher for PAGA/pmIL-12 complexes compared with naked pmIL-12. The presence of CMV promoter in plasmid encoding IL-12 cDNAs did not induce any type I interferon response. There was a significant improvement in the survival rate and the inhibition of tumor growth after repeated injections of PAGA/pmIL-12 complexes.

Adenocarcinoma↗
PubMed2002

Immune-mediated neutropenia in the neonate.

Alloimmune neonatal neutropenia, neonatal autoimmune neutropenia and autoimmune neutropenia of infancy have remained nebulous entities with difficulties in both clinical and laboratory identification. These disorders are reviewed in this article.

Adrenal Cortex Hormones↗
PubMed2001

Intratumoral delivery of p2CMVmIL-12 using water-soluble lipopolymers.

Our objective was to design a water-soluble lipopolymer (WSLP) and an interleukin-12 (IL-12) expression plasmid for enhanced delivery of the IL-12 gene. We synthesized WSLP using branched polyethylenimine (PEI) of 1800 Da and cholesteryl chloroformate, and constructed p2CMVmIL-12, encoding the IL-12 subunits p35 and p40, each under the transcriptional control of a separate cytomegalovirus (CMV) promoter. The percentage of cholesterol conjugated to PEI was about 47% and the average molecular weight of WSLP was approximately 2000 Da. The mean particle size of WSLP/p2CMVmIL-12 complexes formulated in 5% glucose was 26 to 62 nm and xi potential was 8 to 60 mV. The WSLP/p2CMVmIL-12 complexes were nontoxic to CT-26 colon carcinoma cells at the N/P ratio (nitrogen atoms of WSLP/phosphate of plasmid DNA) of 20 and below; PEI25000/pDNA complexes were highly toxic. WSLP/p2CMVmIL-12 complexes demonstrated higher transfection in CT-26 cells compared with the DNA formulations prepared using PEI of molecular weights 1800, 10,000 and 25,000 Da. Transfection efficiency increased with an increase in N/P ratios from 5 to 15, then there was no significant increase in transfection up to the N/P ratio of 30/1. There was an increase in the level of IL-12 when free or complexed p2CMVmIL-12 was compared with free or complexed pIRESmIL-12 in which the p35 and p40 subunits were linked to the internal ribosome entry sites (IRES). At 48 hours post-injection of WSLP/p2CMVmIL-12 complexes into BALB/c mice bearing CT-26 subcutaneous tumors, the levels of IL-12, IFN-gamma, and nitric oxide (NO) in the supernatant of the cultured tumors were higher for the WSLP/p2CMVmIL-12 complexes than for the naked p2CMVmIL-12, WSLP, and 5% glucose injected groups. There was a significant improvement in the survival rate and the inhibition of tumor growth after a single injection of WSLP/p2CMVmIL-12 complexes. We have designed an effective, nontoxic WSLP and an IL-12 expression plasmid with two CMV promoters.

Animals↗
PubMed2001

Roberts-SC phocomelia syndrome.

A severely growth retarded baby was born at 38 weeks gestation. He had multiple craniofacial anomalies, microbrachycephaly, phocomelia in the upper limbs and renal cysts visible on ultrasound. He died of recurrent apneas. The autopsy showed left sided multicystic dysplastic kidney and absence of one testis. Cytogenetic studies did not reveal any abnormality. The phenotypic features match those described in the Roberts-SC phocomelia syndrome. A literature review revealed that 50% of these patients have chromosomal defects and antenatal detection is possible on ultrasound and by chromosome analysis of the amniocytes.

Abnormalities, Multiple↗
PubMed2001

Early onset mixed Morganella and Klebsiella sepsis in a neonate.

A premature baby girl was delivered vaginally to a mother who had an otherwise normal pregnancy, and spontaneous premature onset of labour. She had early onset neonatal sepsis with pneumonia. The baby's blood culture as well as the amniotic membrane culture grew Morganella and Klebsiella. She recovered on appropriate antibiotics. This is only the second reported case of early onset neonatal sepsis due to Morganella. The literature is reviewed.

Anti-Bacterial Agents↗
PubMed2001

The rate of terminal nucleotide loss from a telomere of the mosquito Anopheles gambiae.

Using a single copy pUChsneo transgene insertion at the Anopheles gambiae 2L telomere, this chromosome end was monitored by genomic Southern blots for forty-four mosquito generations. During this time, the chromosome end lost terminal nucleotides at an apparently constant rate of 55 bp/generation, which can be accounted for by incomplete DNA replication and does not imply exonuclease activity. No telomere elongation events were detected, suggesting that a previously described gene conversion event at this transgene does not occur very frequently. Moreover, no evidence for elongation by transposable elements was found, as described in Drosophila melanogaster. These results are consistent with the proposal that gene conversion between complex terminal satellite repeats that are present at natural telomeres, represents the major telomere elongation mechanism in A. gambiae. Such recombination events between repetitive sequences would occur more frequently than between the single copy pUChsneo transgene on the 2L homologues.

Animals↗
PubMed2001

Folate-PEG-folate-graft-polyethylenimine-based gene delivery.

Folate-polyethylene glycol-folate-grafted-polyethylenimine (FPF-g-PEI) was synthesized by linking folic acid to both ends of a mono-functional PEG and then grafting to PEI. The graft ratio was determined using Beer's law by measuring the UV absorbance at 363 nm. The pH profile, diameter and shape of the carriers were determined. Transfection efficiencies were optimized in normal smooth muscle cells (SMC) and CT-26 colon adenocarcinoma cells using plasmid DNA encoding luciferase reporter gene. Free folic acid was shown to inhibit transfection with FPF-2.3 g-PEI at neutral charge ratio. Relative toxicity between PEI and the modified carrier was measured using MTT colorimetric assay. Therapeutic potential of pmIFN-gamma complexed with these polymeric carriers in terms of gene expression was determined at protein and mRNA levels using ELISA and RT-PCR. FPF-g-PEI was determined to have 2.3 folate-PEG-folate (FPF) linear polymers grafted to each PEI molecule. The average molecular weight was measured to be approximately 33,500 Mw and the pH profile was characteristic of endosomal disruption capacity. Atomic Force Microscopy (AFM) and Dynamic Laser Light Scattering (DLLS) indicated FPF-2.3 g-PEI and PEI (at 2 w/w ratio) efficiently condensed plasmid DNA resulting in oblique spheroid polyplexes with a mean diameter of approximately 150 nm. FPF-2.3 g-PEI was superior to PEI in terms of cytotoxicity and transfection efficiency in cancer cells. Smooth muscle cells showed no specificity for folate tethered complexes, where PEI/pLuc complexes yielded higher efficiencies.

Carrier Proteins↗
PubMed2000

Soluble biodegradable polymer-based cytokine gene delivery for cancer treatment.

Transgene expression and tumor regression after direct injection of plasmid DNA encoding cytokine genes, such as mIL-12 and mIFN-gamma, remain very low. The objective of this study is to develop nontoxic biodegradable polymer-based cytokine gene delivery systems, which should enhance mIL-12 expression, increasing the likelihood of complete tumor elimination. We synthesized poly[alpha-(4-aminobutyl)-l-glycolic acid] (PAGA), a biodegradable nontoxic polymer, by melting condensation. Plasmids used in this study encoded luciferase (pLuc) and murine interleukin-12 (pmIL-12) genes. PAGA/plasmid complexes were prepared at different (+/-) charge ratios and characterized in terms of particle size, zeta potential, osmolality, surface morphology, and cytotoxicity. Polyplexes prepared by complexing PAGA with pmIL-12 as well as pLuc were used for transfection into cultured CT-26 colon adenocarcinoma cells as well as into CT-26 tumor-bearing BALB/c mice. The in vitro and in vivo transfection efficiency was determined by luciferase assay (for pLuc), enzyme-linked immunosorbent assay (for mIL-12, p70, and p40), and reverse transcriptase-polymerase chain reaction (RT-PCR) (for Luc and mIL-12 p35). PAGA condensed and protected plasmids from nuclease degradation. The mean particle size and zeta potential of the polyplexes prepared in 5% (w/v) glucose at 3:1 (+/-) charge ratio were approximately 100 nm and 20 mV, respectively. The surface characterization of polyplexes as determined by atomic force microscopy showed complete condensation of DNA with an ellipsoidal structure in Z direction. The levels of mIL-12 p40, mIL-12 p70, and mIFN-gamma were significantly higher for PAGA/pmIL-12 complexes compared to that of naked pmIL-12. This is in good agreement with RT-PCR data, which showed significant levels of mIL-12 p35 expression. The PAGA/pmIL-12 complexes did not induce any cytotoxicity in CT-26 cells as evidenced by 3-¿4, 5-dimethylthiazol-2-yl¿-2,5-diphenyltetrazolium bromide assay and showed enhanced antitumor activity in vivo compared to naked pmIL-12. PAGA/pmIL-12 complexes are nontoxic and significantly enhance mIL-12 expression at mRNA and protein levels both in vitro and in vivo.

Absorbable Implants↗
PubMed2000

Acute MI. Age-related presentations and treatment options.

At least 60% of all acute myocardial infarctions (AMIs) occur in patients age 65 and older and about one-third in patients older than age 75. The presentation of AMI is modified by age-related changes in endothelial function, smooth muscle cell activity, diastolic function, and responses to circulating catecholamines. Atypical presentations are common in the older patient and require the physician to maintain a high index of suspicion for AMI. ECG findings of ST-segment depression make many older patients ineligible for reperfusion by thrombolytic therapy. Acute and post-MI medical therapies are underused in the older population and should be individualized, based on the presence of comorbid conditions.

Age Factors↗
PubMed2000

Diagnostic utility of estimation of mycobacterial antigen A60 specific immunoglobulins in serum and CSF in adult neurotuberculosis.

An ELISA assay based on mycobacterial antigen A60 (Anda, Biologicals France) was used to detect specific immunoglobulins (IgM, IgA and IgG) in 48 cases of adult neurotuberculosis (24 TBM; 24 Tuberculoma) and in 48 controls (24 diseased controls; 24 healthy controls). Serum was analysed in all the subjects whereas CSF was assayed only in TBM cases and diseased controls. The cut off values used for IgM, IgG and IgA in this study were 1.500 ODI (optical density index) at 1:100 dil, 250 units/ml and 150units/ml respectively in serum; and 1.500 ODI at 1:10 dil, 10 units/ml and 10 units/ml respectively in CSF. The mean titres of all three antibodies were found to be significantly higher in cases as compared to controls. In cases of TBM, in serum, the percentage positivity for IgM, IgG, IgA and combination of IgG or IgA were 41.67, 87.50 87.50 and 95.83 respectively. The corresponding figures in CSF were 62.50, 75.0, 66.67 and 79.16 for IgM, IgG, IgA and 'IgA or IgM' respectively. In tuberculoma cases, in serum, the figures were 37.50, 75.0, 75.0 and 83.33 respectively. Overall, a high sensitivity and specificity were obtained in cases of TBM (Serum: ST = 95.83%: SP = 87.50%; CSF ST = 79.16%. SP = 100%) and Tuberculoma cases (serum: ST = 83.33% SP = 87.50%) employing the combined antibody estimations.

Adult↗