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Biomedical subjects

H Gyllenhammar

Publications and source records attributed to H Gyllenhammar.

At least 37 records · Page 2Linked to original sources
PubMed1989

Alternating combination chemotherapy (VMCP/VBAP) is not superior to melphalan/prednisone in the treatment of multiple myeloma patients stage III--a randomized study from MGCS.

86 previously untreated patients with multiple myeloma stage III entered a randomized trial comparing combination chemotherapy (VMCP/VBAP) (n = 42) with intermittent oral melphalan and prednisone (MP) treatment (n = 44). The treatment gropus were well comparable with regard to major prognostic factors. There was no statistically significant difference in the response rates, 52% (VMCP/VBAP) vs 61% (MP); in the response duration times, median 19 months vs 22 months, or in the survival times, median 24 months vs 28 months. However, survival of patients older than 65 years was significantly shorter in the VMCP/VBAP group (median 15 months) compared to the MP group (median 23 months) (p = 0.03). No significant difference in non-hematological or hematological toxicity was noted. The study further supports the notion that MP therapy should be used as primary standard treatment for patients with multiple myeloma.

Adult↗
PubMed1989

Induction treatment with alpha-interferon in multiple myeloma: an interim report from MGCS.

A randomized study comparing melphalan/prednisone (M/P) therapy with MP + natural alpha-IFN in untreated patients with multiple myeloma stages II and III started April 1, 1986. By March 1989, 78 patients were evaluable in the MP group and 80 in the MP/IFN group. 48% of the MP patients achieved a response and 66% in the MP/IFN group (p = 0.04). Stage II patients responded better to MP/IFN (76%) than MP alone (47%) (p = 0.02), while no statistically significant difference was noted for stage III patients. 90% of the IgA myelomas responded to MP/IFN and 52% to MP (p = 0.02). Both for IgG and BJ myelomas the response rates of MP/IFN were higher than of MP, although the differences were not statistically significant. The observation period is still short. There was no difference in total survival between the two treatment groups. However, in patients less than or equal to 65 years a tendency to a longer survival was seen for those receiving the IFN combination (p = 0.12).

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Mechanisms for luminol-augmented chemiluminescence from neutrophils induced by leukotriene B4 and N-formyl-methionyl-leucyl-phenylalanine.

Neutrophils stimulated with formyl-methionyl-leucyl-phenylalanine (fMLP) or leukotriene B4 (LTB4) generated kinetically distinctive luminol augmented chemiluminescence (LCL). Inhibitors of .O2- [superoxide-dismutase (SOD) or tiron], H2O2 (catalase), myeloperoxidase, MPO, (NaN3), HOCl (taurine) and .OH (mannitol) hampered LCL dose-dependently with similar characteristics for both stimuli. In cell free systems it was found that .O2- (generated in the xanthine/xanthine-oxidase reaction) or H2O2 produced LCL. Superoxide dismutase inhibited .O2- -induced LCL dose dependently. The MPO + H2O2 system, which generated more pronounced LCL than either component alone, was inhibited by catalase and taurine but not by SOD. When neutrophils, treated with luminol, but where extracellular luminol had been removed, were stimulated with fMLP or LTB4, they produced less than 2% of the LCL where luminol was present in the medium. When neutrophil LCL and superoxide formation by the cytochrome C method were assessed in parallel experiments, in all instances the peak LCL response coincided with the linear phase in that response. Thus, LCL, induced by LTB4 and the corresponding fMLP peak, are extracellular events with similar chemical backgrounds, closely related to generation of reactive oxygen species. Consequently, the kinetical differences in LCL between fMLP and LTB4 suggest that LTB4, by yet unknown mechanisms, activates the NADPH oxidase more rapidly than fMLP.

Drug Synergism↗
PubMed1989

Correlation between neutrophil superoxide formation, luminol-augmented chemiluminescence and intracellular Ca2+ levels upon stimulation with leukotriene B4, formylpeptide and phorbolester.

When neutrophils were stimulated with leukotriene B4 (LTB4) .O2- -production and elevation of intracellular Ca2+ were initiated more rapidly than after stimulation with N-formyl-methionyl-leucyl-phenylalanine. Phorbol myristate acetate (PMA) induced a substantially more protracted superoxide (.O-2) production. Luminol augmented chemiluminescence (LCL) reflected the kinetic characteristics accurately. The primary distinguishing attribute of LTB4-induced responses were an initial high rate of activation and a rapid termination. Thus, LTB4-induced neutrophil Ca2+-inflow and .O2- -formation may be initiated by mechanisms similar in part to those for formylpeptides; however it does not possess the ability to maintain this activation. The kinetic properties of neutrophil activation may be studied with LCL, irrespective of the exact nature of the LCL-generating oxidants formed by neutrophils.

Calcium↗
PubMed1989

Substance P activates and modulates neutrophil oxidative metabolism and aggregation.

The substance P (SP) fragment SP(7-11) induced chemiluminescence (CL) and aggregation in human neutrophils at high concentrations (greater than or equal to 10 microM), whereas the entire molecule SP(1-11) was less potent and the SP(1-4) fragment was inactive. At these concentrations SP and its fragments also inhibited CL and aggregation evoked by subsequent addition of formyl-methionyl-leucyl-phenylalanine (fMLP), an effect that may depend on desensitization. However, at lower concentrations (1-10 nM) SP was able to prime human neutrophils to enhanced CL and enzyme release stimulated by fMLP. These findings indicate that, in addition to direct activation of CL and aggregation, SP also modulates neutrophil function and can thus amplify the release of potentially cytotoxic substances, a possible mechanism for nervous system involvement in rheumatoid arthritis.

Cell Aggregation↗
PubMed1989

Linoleic acid-deficient rat neutrophils show decreased bactericidal capacity, superoxide formation and membrane depolarization.

Essential fatty acid deficiency (EFAD) is associated with depressed inflammatory responses, e.g. neutrophil chemotaxis, which may be related to reduced generation of the arachidonate metabolite LTB4, a potent mediator for neutrophil activation. In this study we show that neutrophils from EFAD rats exhibited impairments of membrane depolarization and superoxide anion formation upon stimulation with a formylpeptide, FMLP, or when challenged with living Staphylococcus aureus (but not when activated with phorbol myristate acetate). Likewise, bactericidal capacity for S. aureus was depressed. However, ionomycin and FMLP stimulated intracellular Ca2+ elevations, phagocytic capacity, and conformational alterations as well as spreading were similar to control neutrophils. Thus, EFAD confers discrete functional abberations in neutrophils likely to be due to perturbation of arachidonate metabolism and/or membrane function.

Animals↗
PubMed1989

Effects of extracellular pH on neutrophil superoxide anion production, and chemiluminescence augmented with luminol, lucigenin or DMNH.

When neutrophils were stimulated with f-met-leu-phe (fMLP) or phorbol myristate acetate (PMA) chemiluminescence (CL) augmented with luminol, lucigenin or 7-dimethylamino-naphthalene-1,2-dicarbonic acid hydrazide (DMNH) showed a strong dependence on the pH of the medium. CL increased in an exponential fashion when pH was increased from 6.5-9.2. All three luminescent intermediaries showed this pH-dependency but luminol was affected most. Unstimulated CL showed a similar increase with pH. Also neutrophil superoxide anion production (in the cytochrome C reduction assay) increased with pH, but not to the same extent as CL. CL induced by xanthine-oxidase plus hypoxanthine increased likewise with pH, and that increase was more pronounced than what was observed from the same reaction in the cytochrome C assay. The lucigenin-amplified neutrophil CL showed the best correlation to the superoxide production from neutrophils. Thus, several effects underlie the variation of CL with pH but the pH dependency of the luminescent intermediaries contribute substantially, which must be considered.

Acridines↗
PubMed1988

Leukotriene B4 triggers highly characteristic and specific functional responses in neutrophils: studies of stimulus specific mechanisms.

By using human neutrophils we studied the on-off phenomenon for leukotriene B4 (LTB4) -induced functional responses compared with fMetLeuPhe (fMLP). LTB4 induced rapidly appearing and disappearing neutrophil chemiluminescent (CL), superoxide anion formation, aggregatory and membrane depolarizing responses, whereas fMLP responses were slower both in onset and termination. Increases of intracellular calcium concentrations (as reflected by quin2 and fura-2 fluorescence) were of similar magnitude for both stimuli; however, LTB4 responses were more rapidly terminated and fMLP responses were biphasic. When intracellular calcium fluxes, calmodulin or protein kinase C activities were inhibited by quin2, trifluoperazine, verapamil or 3,4,5-trimethoxybenzoic acid 8-diethylamino)octyl ester (TMB-8), profound changes were noted for chemiluminescent and aggregation kinetics induced by fMLP, whereas kinetics of LTB4 responses were less affected. When drugs were used to modulate cAMP levels, or to inhibit cyclo- and lipoxygenase metabolites of arachidonic acid, no effects on response kinetics were observed. Cytochalasin B both amplified and delayed responses although chemiluminescent responses to fMLP were amplified more than those to LTB4. Despite those effects cytochalasin B did not enhance peak fura-2 or quin2 responses to either fMLP or LTB4. Thus, LTB4 rapidly initiates functional responses in neutrophils, and stimulus-specific response patterns are already discernable during the mobilization of calcium, and can be modulated by interference with calcium-dependent reactions.

Aminoquinolines↗
PubMed1988

Effects of fasting on disease activity, neutrophil function, fatty acid composition, and leukotriene biosynthesis in patients with rheumatoid arthritis.

Fourteen patients with rheumatoid arthritis (RA) were studied before, during, and after a 1-week total fast. Disease activity decreased, as did the neutrophil release of lysozyme induced by the ionophore A23187. The ability of zymosan-activated RA patient serum to aggregate control neutrophils was reduced, together with serum concentrations of C3. The relative contents of arachidonic acid and eicosapentaenoic acid were increased in serum, platelets, and neutrophils, whereas levels of linoleic acid and linolenic acid were unchanged. Fasting also reduced the release of leukotriene B4 from neutrophils. We thus conclude that a reduced ability to generate cytotaxins, reduced release of enzyme, and reduced leukotriene formation from RA neutrophils, together with an altered fatty acid composition of membrane phospholipids, may be mechanisms for the decrease of inflammatory symptoms that results from fasting.

Adult↗
PubMed1988

Effects of lipoxins A and B on functional responses of human granulocytes.

The effects of synthetic lipoxin A and B (LXA and LXB) as well as several of their isomers were assessed as inducers of functional responses of human granulocytes. LXA stimulated migration at 1 nM and exhibited a variable effect as inducer of chemiluminescence at concentrations greater than or equal to 1 microM. Both migration and chemiluminescence evoked by LXA proved to be highly stereospecific, since e.g. 6S-LXA was less active than LXA. Neither synthetic LXA nor several of its stereoisomers provoked degranulation, aggregation, membrane potential changes or intracellular calcium fluxes. In addition, LXB and its isomers did not stimulate aggregation, degranulation or chemiluminescence. Pretreatment of granulocytes with LXA did not modify subsequent challenges with leukotriene B4. Together, these results indicate that granulocyte responses to LXA are highly stereospecific and are mediated by other mechanisms than those evoked by leukotriene B4.

Calcium↗
PubMed1988

Rat neutrophil function, and leukotriene generation in essential fatty acid deficiency.

Since the essential fatty acid linoleic acid is the precursor of arachidonic acid and thus of leukotrine B4 (LTB4), essential fatty acid deficiency (EFAD) may result in decreased synthesis of this stimulator of neutrophil granulocyte functions. Peritoneal and blood neutrophils from rats fed a diet with only 0.3% of energy requirements as linoleic acid and exhibiting biochemical evidence of EFAD showed substantial functional impairments compared to neutrophils from rats maintained on a diet with 3% of the energy requirement as linoleic acid. Oxidative burst activation (assessed by chemiluminescence), chemotaxis and aggregation were impaired upon stimulation with formylpeptides or the ionophore A23187. In contrast, these functions were intact on stimulation with exogenous LTB4. Chemiluminescence was slightly but not significantly enhanced in EFAD rat neutrophils compared to controls when stimulated with phorbol myristate acetate (PMA). There were no differences between EFAD and control peritoneal neutrophils in the number of f-met-leu-phe (fMLP) receptors, or in their affinity for the ligand, assessed with fML(3H)P. The fraction of responding cells also were similar, assessed with dichlorofluorescein diacetate fluorescence. Moreover, the endogeneous LTB4 production in response to A23187 or fMLP was decreased by 57.7% and 63.5%, respectively, in EFAD peritoneal neutrophils. Thus, EFAD was associated with reductions of LTB4 production and neutrophil responsiveness to A23187 and formylpeptides but not to LTB4 or PMA, which supports the hypothesis that endogeneous LTB4 may contribute to the activation of neutrophil functions involved in inflammation and host defense.

Animals↗
PubMed1988

Recombinant human leukocyte interferon modulates neutrophil function in vitro.

Recombinant human interferon-alpha 2 (rIFN-alpha A) was evaluated as a modulator of neutrophil functions. Neutrophils treated with rIFN-alpha A for 1 h in vitro showed reduced chemiluminescence (CL) and aggregation in response to phagocytosis. In contrast, when certain soluble stimuli [f-met-leu-phe (fMLP) or leukotriene B4] were used, rIFN-alpha A treatment conferred a doubling of CL. This was paralleled by a similar increase in superoxide anion production and a 56% increase of release of beta-glucuronidase and lysozyme. The NBT test showed that IFN treatment did not increase the number of responding neutrophils. However, there was a significant increase in the displaceable binding of fML[3H]P. Enzyme release, aggregation, and CL in response to other soluble stimuli, the ionophore A23187 and phorbol myristate acetate were unaffected by IFN treatment. Likewise, chemotaxis was not affected. Thus, phagocytosis-associated events and aggregation were hampered by rIFN-alpha A whereas secretory responses to receptor-dependent soluble stimuli were augmented. The mechanism for the latter is most likely dependent on the observed modulation of binding of fMLP to its receptor.

Cell Migration Inhibition↗
PubMed1988

High doses of natural alpha-interferon (alpha-IFN) in the treatment of multiple myeloma--a pilot study from the Myeloma Group of Central Sweden (MGCS).

alpha-interferon (alpha-IFN) is a biological response modifier with a dose-dependent activity. The present study on the treatment of patients with multiple myeloma with high doses of natural alpha-IFN was designed to meet this dose-dependent concept. 50 previously untreated patients with IgA and BJ myelomas and a s-Creatinine less than or equal to 200 mumol/l entered the study. Various treatment schedules were tested. The initial plan was to give the patients 30 X 10(6) U alpha-IFN daily. This dosage, however, gave unacceptable toxicity. Step-by-step decreasing dose schedules were given to the patients, 10 X 10(6) U of alpha-IFN daily for 7 consecutive d repeated every 3rd week was found to be the maximal tolerable dose that could be given to most patients. 36% (95% confidence levels: 22%-50%) of the patients responded: 41% of the IgA myelomas and 23% of BJ myelomas. Median time to response was 1.5 months and median response duration was 20 months. Impaired general condition and central nervous system and gastrointestinal-related toxicity were the main adverse reactions. Hematological side-effects were mild.

Aged↗
PubMed1987

The effects of lipoxin A and lipoxin B on functional responses of human granulocytes.

Lipoxin A and lipoxin B (LXA and LXB) are formed from arachidonic acid by leukocyte 5- and 15-lipoxygenases. We have assessed the effects of synthetic lipoxins on functional responses of human granulocytes. LXA stimulated migration at 1 nM. The effect was highly stereospecific, since e.g. 6S-LXA and LXB were less active than LXA. Neither synthetic LXA nor several of its stereoisomers provoked degranulation or aggregation. LXB and its isomers did not induce any of these functional responses. These results indicate that migratory granulocyte responses to LXA are highly stereospecific.

Cell Aggregation↗
PubMed1987

Lucigenin chemiluminescence in the assessment of neutrophil superoxide production.

Lucigenin-amplified chemiluminescence (LUCL) was induced by .O2- (from the xanthine/xanthine-oxidase reaction) but not, as with luminol-augmented CL (LCL), by myeloperoxidase (MPO) and only weakly by H2O2 or the H2O2-MPO-Cl- system. Neutrophil LUCL induced by fMet-Leu-Phe (fMLP) was dose-dependently inhibited by scavengers of .O2- but not by NaN3, catalase, mannitol or taurine. Response patterns of several soluble stimuli (leukotriene B4 (LTB4), platelet-activating factor (PAF), fMLP, A23187 and phorbol-myristate-acetate (PMA)) were assessed with LUCL. PMA-induced LUCL was protracted, A23187 showed intermediary kinetics whereas fMLP and PAF both showed rapid peak responses at 30-50 s. However, LTB4 was the most rapid initiator of LUCL (7-12 s). The kinetics of fMLP- or PMA-induced neutrophil .O2- production, assessed with the cytochrome C reduction method, correlated well with LUCL. Thus it is suggested that LUCL provides a specific method for studying the kinetic properties of neutrophil .O2- production where stimulus-specific response patterns can be distinguished.

Acridines↗