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Biomedical subjects

K Mehta

Publications and source records attributed to K Mehta.

At least 55 records · Page 3Linked to original sources
PubMed1986

Expression of tissue transglutaminase in cultured monocytic leukemia (THP-1) cells during differentiation.

Retinoic acid (RA) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induced differentiation of a human monocytic leukemia cell line, THP-1. RA- or TPA-treated cells stopped proliferating, became adherent to plastic surfaces, and acquired the ability to phagocytose yeast cells, plain sheep RBCs, and IgG-coated sheep RBCs. The morphological and functional changes, induced by RA or TPA, were associated with a 20-50-fold increase in cellular transglutaminase activity. This increase in enzyme activity was found to be due to the induction of a specific intracellular transglutaminase, tissue transglutaminase. The induction of tissue transglutaminase was a specific response of THP-1 cells to differentiation and was not observed with agents that did not induce their morphological or functional differentiation. Dibutyryl cyclic AMP potentiated the RA-induced expression of tissue transglutaminase. A 15-min exposure to TPA was sufficient to induce differentiation and expression of tissue transglutaminase in THP-1 cells. In contrast, RA required a continuous exposure (48 h) to induce similar changes in morphology or enzyme activity. These results support the view that differentiation of cells of the monocytic lineage is associated with an induction and accumulation of the protein cross-linking enzyme tissue transglutaminase.

Bucladesine↗
PubMed1985

Protective effect of liposomal-amphotericin B against C. albicans infection in mice.

The efficacy of free amphotericin B (AmpB) and liposomal-amphotericin B (L-AmpB) in the protection against C. albicans infection in mice was studied. Mice injected with a single dose of L-AmpB (1-4 mg/kg) two days prior to the yeast inoculation had an increased survival time when compared to animals injected with lower doses (0.8 mg/kg) of free AmpB or L-AmpB. L-AmpB (4 mg/kg of body weight) conferred protection against the fungal infection even when administered as a single dose five days prior to the yeast inoculation. A single-dose regimen of free AmpB showed a protective effect only when administered two days prior to the inoculum. When mice were challenged with larger yeast inocula, protection was seen with L-AmpB (4 mg/kg) or with multiple doses of free AmpB (0.8 mg/kg daily x 5) and not with single doses of free AmpB. In this group of mice, only animals treated with L-AmpB were microbiologically free of infection.

Amphotericin B↗
PubMed1985

Liposomal amphotericin B for the treatment of systemic fungal infections in patients with cancer: a preliminary study.

Twelve patients with hematologic malignancies complicated by fungal infections were treated with liposomal amphotericin B (L-AmpB). Nine patients were granulocytopenic; the three additional patients with normal granulocyte counts were immunosuppressed. All patients had biopsy findings or cultural evidence of the progression of their fungal infection while being treated with conventional amphotericin B. Doses of 0.8-1.0 mg/kg of L-AmpB were administered intravenously every 24-72 hr. Three patients had a complete remission, five had a partial remission, and four showed no improvements. A total of 161 doses of L-AmpB were administered. Fever and chills occurred on seven occasions. No hematologic or blood chemistry abnormalities related to L-AmpB treatment were observed.

Adolescent↗
PubMed1985

Selective toxicity and enhanced therapeutic index of liposomal polyene antibiotics in systemic fungal infections.

Incorporation of the polyene antibiotic amphotericin B (AMB) in liposomes results in a marked reduction in drug toxicity with no loss of antifungal potency. Nephrotoxicity, the dose-limiting side effect of AMB, is almost abolished when the drug is utilized in a liposomal carrier. Because of reduced toxicity, high doses of liposomal AMB can be used, resulting in superior therapy of systemic fungal infections in mice. The improved therapeutic index of liposomal AMB versus free AMB is also manifest in infected neutropenic animals. The reduced toxicity of liposomal AMB is due to a fundamental alteration in the interaction of the drug with mammalian cell membranes. AMB transfers effectively from donor liposomes to fungal cell walls and membranes and is thus toxic to fungi. By contrast, AMB does not transfer from liposomes to mammalian cells and thus is not toxic to these cells. Thus, the use of liposomal AMB may offer a marked improvement in the therapy of systemic fungal infection in cancer patients and other immunodebilitated individuals.

Amphotericin B↗
PubMed1985

Prophylaxis of murine candidiasis via application of liposome-encapsulated amphotericin B and a muramyl dipeptide analog, alone and in combination.

The present study was conducted to examine the effect of a lipophilic analog of muramyl dipeptide, 6-O-stearoyl-N-acetylmuramyl-L-alpha-aminobutyryl-D-isoglutamine (6-O-S-Abu-MDP), a macrophage activator, on the prophylactic activity of liposomal amphotericin B (L-AmpB) against disseminated candidiasis in mice. Multilamellar vesicles containing AmpB and (6-O-S-Abu)-MDP were prepared by using dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol (7:3 molar ratio). Hale-Stoner mice (6 to 8 weeks old) were injected with 7 X 10(5) CFU of Candida albicans 336 isolated from a patient. Groups of mice were injected intravenously with different doses of L-AmpB and L-(6-O-S-Abu)-MDP, individually or in combination, 2 days before challenge with C. albicans. The mice were injected with a fixed dose of L-AmpB (1.2 mg/kg in 400 mg of lipid per kg) and various doses of L-(6-O-S-Abu)-MDP (0.6, 1.2, 2, and 4 mg/kg in 400 mg of lipid per kg) or vice versa. Other control groups included untreated mice and those receiving empty liposomes (400 mg of lipid per kg), free AmpB (0.6 mg/kg), or free (6-O-S-Abu)-MDP (4 mg/kg). The mice receiving L-AmpB (1.2 mg/kg) plus L-(6-O-S-Abu)-MDP (0.6 to 4.0 mg/kg) survived up to 25 to 30 days as compared with those injected with L-AmpB alone (15 days) or with L-(6-O-S-Abu)-MDP alone (10 to 15 days). All the mice in other control groups died within 7 to 11 days. The kidney cultures of the mice that received L-AmpB (4 mg/kg) plus L-(6-O-S-Abu)-MDP (1.2 mg/kg) were free of C. albicans infection, unlike those injected with L-AmpB. Variance analysis of these findings indicates a synergistic activity between L-AmpB and L-(6-O-S-Abu)-MDP in the prophylaxis of candidiasis.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

Effect of liposomal amphotericin B on murine macrophages and lymphocytes.

The effect of liposome-encapsulated amphotericin B on mouse macrophages and on T- and B-lymphocyte functions in vitro was compared with that of free amphotericin B. Liposomal amphotericin B was generally less toxic than the free form of the drug. Low concentrations of free amphotericin B completely inhibited the serum-dependent induction of transglutaminase, a marker for macrophage differentiation, and production of superoxide anion by macrophages, whereas encapsulation of the drug within liposomes protected the cells from these adverse effects. Liposomal amphotericin B did not affect the blastogenic response of T cells compared with the free drug, which was inhibitory at high concentrations. Antibody production in vivo was inhibited partially by both free and liposomal amphotericin B. These results thus suggest that encapsulation of amphotericin B in liposomes reduces the immunosuppressive effects exerted by free amphotericin B. This provides further justification for therapeutic use of liposomal amphotericin B in systemic fungal infections (G. Lopez-Berestein, R. Mehta, R. L. Hopfer, K. Mills, L. Kasi, K. Mehta, V. Fainstein, M. Luna, E. M. Hersh, and R. L. Juliano, J. Infect. Dis. 147:939-945, 1983).

Acyltransferases↗
PubMed1985

Interferon-gamma requires serum retinoids to promote the expression of tissue transglutaminase in cultured human blood monocytes.

The culture of HPBM in serum-containing medium induced a large accumulation of the protein cross-linking enzyme, tissue TGase. Immune IFN enhanced the expression of tissue TGase in cultured monocytes. Enzyme-inducing activity, both in normal and IFN-treated cells, was completely blocked by depleting the serum of the lipid fraction. The readdition of retinol at a physiologic concentration (1 micron) to delipidized serum completely restored the enzyme-inducing activity in cultured monocytes. Thus, serum retinoids seem to play an important regulatory role in the expression of tissue TGase gene in differentiating human monocytes.

Acyltransferases↗
PubMed1984

Liposome-encapsulated amphotericin B for treatment of disseminated candidiasis in neutropenic mice.

The relative efficacies of free amphotericin B (Amp B) and liposome-encapsulated Amp B (L-AmpB) in the treatment of established Candida albicans infection in mice rendered neutropenic with cyclophosphamide were studied. AmpB was entrapped in multilamellar liposomes composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol in a molar ratio of 7:3. Infected mice treated with single doses of 3 mg L-AmpB/kg of body weight had an increased survival time compared with those injected with either single (dose, 0.8 mg/kg) or multiple doses (dose, 0.8 mg/kg daily for five days) of free AmpB. When treatment was delayed beyond three days postinfection, neither single nor multiple doses of free AmpB resulted in increased survival, whereas treatment with single-dose L-AmpB (dose, 4 mg/kg) showed efficacy when delayed as much as four days postinfection. Five days postinfection only higher doses (dose, 5.6 mg-11.2 mg/kg) of L-AmpB improved survival time and the renal impairment present in the infected animals. These data provided a rational basis for using high-dose L-AmpB to treat fungal diseases in humans, particularly in neutropenic patients.

Agranulocytosis↗
PubMed1984

Prophylaxis of Candida albicans infection in neutropenic mice with liposome-encapsulated amphotericin B.

The efficacy of liposome-encapsulated amphotericin B in the prophylaxis of disseminated Candida albicans infections in neutropenic mice was studied. The administration of liposome-encapsulated amphotericin B was associated with protection against infection with C. albicans when used at doses of greater than or equal to 2 mg of amphotericin B per kg of body weight. Neither empty liposomes nor free amphotericin B showed prophylactic efficacy.

Agranulocytosis↗
PubMed1984

Phagocytosis inhibits the expression of tissue transglutaminase in mouse peritoneal macrophages.

Culture of mouse peritoneal macrophages in serum-containing medium produces a rapid and marked induction of tissue transglutaminase. Concurrent endocytosis of a variety of particles via specific and nonspecific routes suppresses or completely abolishes the induction of the enzyme. The suppression is dose-dependent and is reversible. The rate of recovery from the inhibitory effect, however, depends on the nature of the particles internalized. The inhibitory effect is due to the inhibition of the synthesis of tissue transglutaminase.

Acyltransferases↗
PubMed1984

Stimulation of macrophage protease secretion via liposomal delivery of muramyl dipeptide derivatives to intracellular sites.

We have observed that murine macrophages can be activated for enhanced neutral protease secretion by exposing the cells to muramyl dipeptides (MDPs). A lipophilic derivative of nor-MDP is more efficacious than the parent hydrophilic nor-MDP. The efficacy and potency of the lipophilic and more prominently the hydrophilic drugs can be increased (10-10(3) fold) by encapsulating them in lipid vesicles (liposomes); however the encapsulation of drug causes a delay in the onset of activation. The enhanced effectiveness of liposomal MDPs seems in part, to be due to increased uptake, slow release and thus potentiated action of the drug at intracellular sites as emphasized by studies with [3H]-MDP. Appropriate distribution of the drug to intracellular compartments of the cell also seems to be an important factor in the activation process. The internalization of a relatively large amounts (greater than 5 ng/10(6) cells) of nor-MDP results in 'down regulation', that is reduced protease secretion, as compared to effects produced by internalization of lesser amounts of the drug. The macrophage activating effects of liposomal MDPs do not seem to require the processing of liposomes in the lysosomal compartment; thus lysosome-blocking agents, such as chloroquine and dextran sulphate, do not affect the induction of protease secretion.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1983

Induction of tissue transglutaminase in mouse peritoneal macrophages.

Tissue transglutaminase accumulates rapidly and to very high levels (1-2% of cellular protein) in mouse peritoneal macrophages cultured in mouse serum. The induction is due to accelerated synthesis of the enzyme (150-fold increase) that occurs within 90 min of exposure of the cells to a heat-labile constituent of serum or plasma. The induction is reversible and is not reproduced by known activators of macrophage function such as lipopolysaccharide, muramyl dipeptide, and tuftsin. In animals, elevated levels of tissue transglutaminase are also found in inflammatory macrophages elicited by thioglycolate broth.

Acyltransferases↗
PubMed1983

Effects of sterols on the therapeutic efficacy of liposomal amphotericin B in murine candidiasis.

Incorporation of amphotericin B (AMP-B) into phospholipid vesicles (liposomes) has been shown previously to decrease AMP-B toxicity while retaining the antifungal efficacy of the drug. In this report, the role of sterols in the formulation of liposomes as well as in their effectiveness in the treatment of murine candidiasis have been investigated. The presence of ergosterol or cholesterol at different lipid ratios did not augment the encapsulation efficiency of AMP-B as compared with vesicles containing phospholipids alone. There was no significant difference in the survival time of mice infected with Candida albicans treated with sterol-containing vesicles compared with those treated with sterol-free vesicles. These findings suggest that the sterol-free liposomes might be of advantage for delivering AMP-B because of its simple formulation, lack of toxicity, and ease of preparation.

Amphotericin B↗
PubMed1983

Treatment and prophylaxis of disseminated infection due to Candida albicans in mice with liposome-encapsulated amphotericin B.

The toxicology of liposome-encapsulated amphotericin B in mice and its efficacy in the treatment and prophylaxis of systemic candidiasis in these animals were studied. The toxicology studies indicated that the maximal tolerated dose of free amphotericin B was 0.8 mg/kg of body weight and the 50% lethal dose (LD50) was reached at 1.2 mg/kg, while neither the maximal tolerated dose nor the LD50 for the liposomal amphotericin B was reached at a dose of 12 mg/kg. No abnormalities in blood chemistry or histology were observed in the animals injected with encapsulated amphotericin B, while the administration of free amphotericin B was associated with nephrocalcinosis and renal parenchymal edema. The encapsulated drug was as effective as the free drug when used in similar concentrations, while the animals treated with higher concentrations of liposomal amphotericin B (4 mg/kg) had a longer survival time. Thus, an improved therapeutic index resulted by encapsulating amphotericin B in liposomes.

Amphotericin B↗