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Biomedical subjects

W Warner

Publications and source records attributed to W Warner.

At least 19 recordsLinked to original sources
PubMed2000

Use of intravenous patient-controlled analgesia for the documentation of synergy between tramadol and metamizol.

The quantification of the synergistic interactions (beneficial and adverse) of analgesic drug combinations in humans has been elusive. We propose a new procedure based on analgesic requirements (i.v.-PCA) and pain intensity (VAS-PI). One hundred and one post-hysterectomy patients received at the time of analgesia request (TAR) tramadol (100 mg, group I) or metamizol (1.2 g, group II) alone, or combined in 1:1 (III), 1:0.3 (IV) or 1:3 ratio (V). After 15 min, they received the same treatment by PCA. VAS-PI, analgesic consumption and adverse effects were assessed at TAR, and periodically for 24 h. Data were analysed using interaction indexes and isobolograms. All treatments produced equivalent VAS-PI, per cent efficacy and adverse effects. When drugs were combined in a 1:1 ratio, synergy was present for the analgesic and adverse effects; all other treatments were additive.

Adult↗
PubMed2000

Intestinal inflammation and morphine tolerance alter the interaction between morphine and clonidine on gastrointestinal transit in mice.

BACKGROUND: Morphine and clonidine show synergy or antagonism inhibiting gastrointestinal transit depending on their proportion and level of effect. Their interaction during morphine tolerance and intestinal inflammation were assessed. METHODS: Gastrointestinal transit in mice was evaluated with charcoal and antitransit effects expressed as percent mean values +/- SEM. Tolerance was induced with a morphine pellet (75 mg) implanted for 72 h, and inflammation with intragastric croton oil. Dose-response curves for morphine and clonidine alone and combined at a 1:1 potency ratio were obtained, and doses producing a 50% and 60% inhibition were calculated (ED50, ED60). Interaction was established by isobolograms, interaction indexes, and analysis of variance. RESULTS: In naive and tolerant mice, the combination induced linear dose-response curves up to the ED60 and then reached a plateau. In naive mice, ED50 values were as follows: morphine 1.52 +/- 0.15 mg/kg, clonidine 0.09 +/- 0.008 mg/kg, and combined 0.506 +/- 0.084 mg/kg (0.478 +/- 0.08 mg/kg morphine plus 0.028 +/- 0.004 mg/kg clonidine). During tolerance, ED50 values were as follows: morphine 9.73 +/- 0.8 mg/kg, clonidine 0.09 +/- 0.007 mg/kg, combination 0.131 +/- 0.09 mg/kg (morphine 0. 13 +/- 0.09 mg/kg plus clonidine 0.0013 +/- 0.0005 mg/kg). In both groups, the interaction was synergistic up to the ED60 and antagonistic thereafter; synergy was enhanced during tolerance. During inflammation, ED50 values were as follows: morphine 0.17 +/- 0.04 mg/kg, clonidine 0.015 +/- 0.006 mg/kg, combined 0.62 +/- 0.04 mg/kg (morphine 0.568 +/- 0.04 mg/kg plus clonidine 0.052 +/- 0.004 mg/kg); thus, potencies of morphine and clonidine increased 9.3 and 7.1 times, while the combination remained unaltered. Moreover, inflammation transformed synergy into antagonism. CONCLUSIONS: The interaction between morphine and clonidine was significantly altered during tolerance and inflammation. During tolerance, synergy was present up to 60% effect and then became antagonistic. Inflammation converted synergy to antagonism. A common pathway in signal transduction could partially explain the results.

Analgesics↗
PubMed2000

Influence of immunogenicity on the pharmacokinetics of BMS-191352, a Pseudomonas exotoxin immunoconjugate, in rats and dogs.

BMS-191352 is an immunotoxin construct of modified Pseudomonas exotoxin conjugated to a fragment of the BR96 monoclonal antibody. We have investigated the potential for immunogenicity of BMS-191352 and its influence on the pharmacokinetics in rats and dogs. BMS-191352 was administered intravenously at doses of 0.75, 1.5, and 3 mg m(-2) once every two days for a total of five doses in rats, and 1.2, 2.4, and 4.8 mg m(-2) once every three days for a total of five doses in dogs. Blood samples were collected on days 1 and 9 in rats, and on days 1, 7, and 13 in dogs to monitor pharmacokinetics and anti-BMS-191352 immune response. Plasma concentrations of BMS-191352 and serum anti-BMS-191352 antibody titre were determined using ELISA assays. Pharmacokinetics were assessed using a non-compartmental method. Anti-BMS-191352 antibodies were not observed in rats within the drug administration interval. In all dogs, except one, markedly higher anti-BMS-191352 antibody titres were observed on day 13 compared with days 1 and 7, and its magnitude was independent of BMS-191352 dose. The single dose kinetics of BMS-191352 in rats and dogs were linear and the drug exposures were generally dose proportional. Mean half-life, total body clearance, and volume of distribution were 1.74 h, 3.35 mL min(-1) m(-2), and 0.27 Lm(-2) in rats, respectively, and 4.27 h, 6.28 mL min(-1) m(-2), 1.19 L m(-2) in dogs, respectively. The multiple-dose (day 9) kinetics in rats were similar to the single-dose kinetics. In dogs, the disposition of BMS-191352 on day 7 was similar to that on day 1; however, there was a precipitous reduction in the systemic drug exposure (by 5- to 110-fold) and marked increase in drug clearance on day 13. These changes in the kinetics of BMS-191352 were attributed to the generation of anti-BMS-191352 antibodies. In the one dog that did not develop anti-BMS-191352 antibodies, the pharmacokinetics were unchanged. The pharmacokinetics of BMS-191352 may be perturbed due to an immune response thus restricting the therapeutic utility of the immunotoxin.

ADP Ribose Transferases↗
PubMed1996

Interaction of morphine and clonidine on gastrointestinal transit in mice.

BACKGROUND: Combinations of drugs are frequently used to achieve effective analgesia while minimizing side effects. Although the analgesic effects of morphine and clonidine seem to be synergistic, few studies have investigated other effects. Their role in inhibiting gastrointestinal transit was evaluated using different methods of analysis. METHODS: Percentage inhibition of transit induced by morphine, clonidine, or their combination was measured in mice that had been given an intragastric charcoal meal. Dose-response curves were obtained for each drug individually; for morphine:clonidine at 1:3, 1:1, and 1:0.33 ratios; and for morphine in the presence of 0.0138 mg/kg clonidine. The interaction was evaluated by isobolograms, combination indexes, and fixed-dose analysis. RESULTS: Each drug and their combinations inhibited transit in a dose-related manner. Combinations of morphine and clonidine produced interaction that depended on the ratio and level of response. The interaction analyzed by isobolograms and combination indexes showed that combinations in 1:1 and 1:3 proportions were synergistic at the median effective doses or less and were antagonistic at larger doses. Fixed-dose analysis using different ratios showed similar results. The effects of the combination (median effective dose at 1:1 ratio) were antagonized by efaroxan but not by naloxone, suggesting a predominant role of alpha-2-mediated effects. CONCLUSIONS: Investigations into drug interactions should include several levels of response and combinations at different ratios. Isobolographic analysis permits the statistical evaluation of results without making assumptions about mechanisms of action of the drugs or their interactions. In this study, the combination of morphine and clonidine should produce synergy, antagonism, or no interaction depending on the relative doses and the level of effect.

Adrenergic alpha-Antagonists↗
PubMed1992

On the mechanism of the interaction of ketamine and halothane in vitro.

1. Electrically induced contraction of guinea pig ileum myenteric plexus-longitudinal muscle was inhibited by ketamine and halothane with IC50s of 2.1 x 10(-4) M and 1.8 v/v% respectively. 2. The inhibitory action of ketamine was partially antagonized by naloxone and the selective kappa antagonist nor-binaltorphimine. 3. The actions of ketamine and halothane were synergistic at high levels of response (above 30% inhibition). 4. The actions of ketamine and halothane became antagonistic after treatment with pertussis toxin. 5. The interaction of ketamine and halothane was similar to the interaction of morphine and halothane.

Animals↗
PubMed1990

Synergistic interaction of morphine and halothane in the guinea pig ileum: effects of pertussis toxin.

The effects of pertussis toxin on the actions of morphine and halothane in the guinea pig ileum are described. Both morphine and halothane produce a dose-related inhibition of electrically induced muscle contraction. The IC50 of morphine was unchanged by the toxin (2.1 and 2.2 X 10(-7) M in control and toxin-pretreated animals). However, the IC50 of halothane was increased from 2.1 to an extrapolated value of 9.1 vol/vol% by pertussis toxin. At high levels of inhibition the interaction between morphine and halothane was synergistic and was converted to additive in the presence of the toxin. These results demonstrate that in the myenteric longitudinal muscle preparation the effects of halothane, but not those of morphine, are mediated by the substrate for pertussis toxin, possibly a Gi membrane protein. The present study provides significant evidence that the effects of halothane on neuronal tissue are dependent upon an interaction with a specific membrane protein.

Animals↗
PubMed1990

Effects of azepexole on opioid receptors and endogenous opioid release in the guinea pig ileum.

The interactions of the opioid and adrenergic systems were investigated in the guinea pig myenteric plexus longitudinal muscle preparation. Morphine and azepexole (a highly selective alpha 2-adrenergic agonist) inhibit the electrically induced contractions with ED50 of 1.9 X 10(-7) M and 3.1 X 10(-6) M, respectively. The effect of morphine but not that of azepexole was competitively antagonized by naloxone. Stimulation of the preparation at 10 Hz was used to induce endogenous opioid release that was unaffected by azepexole. The authors' findings indicate that the effects of morphine and azepexole are additive, but that there is no direct interaction between the opioid and adrenergic receptors in the ileum. These observations provide some additional insight into the ability of alpha 2-agonists to enhance the effects of opioids and inhalation anesthetics.

Adrenergic alpha-Agonists↗
PubMed1990

Effect of pertussis toxin on the interaction of azepexole and halothane.

The effect of pertussis toxin on the interaction of azepexole and halothane was determined on the guinea pig ileum. Both azepexole and halothane inhibited electrically induced contractions with IC50 values of 3.3 X 10(-6) M and 1.5 V/V%, respectively. The two drugs interacted synergistically at concentrations producing inhibition greater than 50%. Pretreatment with pertussis toxin reduced the potency of each agent individually and abolished the synergistic interaction. The results demonstrate that the effects of halothane and azepexole involve a pertussis-sensitive G protein, thus suggesting that the effects of volatile anesthetics are mediated in part by this group of membrane associated proteins.

Adrenergic alpha-Agonists↗
PubMed1989

Congenital pseudarthrosis of the tibia. Long-term follow-up study.

Review of the literature reveals how difficult it is to assess the results of treatment of pseudarthrosis of the tibia. There is disagreement as to when the result can be considered final. This study reviewed the long-term results of treatment to determine if skeletal maturity could be considered the definitive end point of treatment or if the results deteriorate past skeletal maturity. In addition, the effect of neurofibromatosis on pseudarthrosis of the tibia is analyzed. Forty-one patients were reviewed. Only 25 had sufficient follow-up data to be included in this study. Eighteen of the 25 had neurofibromatosis. The results were classified according to criteria developed by Morrissy et al. At skeletal maturity, there were ten good results, three fair results, and three poor results, with nine patients having had amputation. At long-term follow-up evaluation (average 36 years; range five to 62 years), one patient with a fair result had elected amputation. About one half of the patients with neurofibromatosis required amputation. This study suggests that the results at skeletal maturity are reliable indicators of long-term results.

Adolescent↗
PubMed1988

Droperidol enhances fentanyl and sufentanil, but not morphine, analgesia.

1. The effect of droperidol pre-treatment on the analgesic potency of morphine, fentanyl and sufentanil was assessed in mice. 2. Acetic acid writhing test and tail immersion test were used to measure the analgesic response. 3. The neuroleptic augments the effects of sufentanil and fentanyl. 4. Thus, the dose-response curves for fentanyl and sufentanil were shifted to the left and the ED50 of the analgesics lowered in droperidol pre-treated animals. 5. However, morphine analgesia was not influenced by droperidol. 6. The results suggest that combination of sufentanil or fentanyl with droperidol may be better than morphine to produce neuroleptanalgesia and anesthesia.

Analgesics, Opioid↗
PubMed1988

Synergistic interaction of morphine and halothane in the guinea pig ileum.

The present study describes the effects of halothane on morphine activity in the myenteric plexus-longitudinal muscle preparation of the guinea pig ileum. Morphine and halothane produced a dose-related inhibition of the electrically induced muscle contractions with IC50 of 1.9 X 10(-7) and 1.7 V/V%, respectively. The effects of morphine, but not halothane, were antagonized by naloxone. The IC50 of morphine was decreased in the presence of halothane (0.8-3.0 V/V%). Hill coefficients derived from dose-response curves were less than one for morphine or halothane alone, while it was 1.4 for the combination. The pA2 values (a measure of affinity of the antagonist for the opioid receptor) for naloxone in the absence and presence of halothane (1.6%) were 9.4 and 9.1, respectively. These results indicate that 1) halothane increases the potency of morphine in the guinea pig ileum at clinically relevant concentrations, 2) the interaction between the agents is synergistic, and 3) halothane does not modify the binding of naloxone to opioid receptors, but may affect membrane or intracellular processing of the receptor signal.

Animals↗
PubMed1987

Effects of temperature on the interaction of morphine with opioid receptors.

The electrically stimulated guinea pig ileum preparation was used to determine the effects of temperature on the affinity of morphine for opioid receptors. The potency of morphine (expressed as the concentration which produces 50% inhibition--IC50) was significantly decreased at 30 degrees C (IC50 41.0 x 10(-8) mol litre-1) and increased at 40 degrees C (IC50 5.1 x 10(-8) mol litre-1) when compared with its potency at 37 degrees C (IC50 8.8 x 10(-8) mol litre-1). Experiments carried out in the presence of naloxone (a competitive opioid antagonist) indicated that the affinity of opioid receptors for this antagonist was not affected by temperature. Further studies using B-funaltrexamine (a mu-specific, non-reversible opioid antagonist) revealed an increase in morphine receptor affinity when temperature was increased from 30 to 37 degrees C. The data demonstrated that the potency of morphine increased with temperature; the affinity of naloxone for opioid receptors was unaltered by temperature; and the affinity of morphine for mu-receptors reached an optimal value within the range 30-37 degrees C.

Animals↗
PubMed1985

Alterations in calcium metabolism in phorbol ester-treated mouse peritoneal macrophages.

Phorbol 12-myristate 13-acetate (PMA)-treated macrophages exhibited a two-fold increase in the rate of 45Ca++ efflux and over a three-fold increase in the size of the exchangeable calcium pool, resulting in almost a seven-fold increase in the slow phase of calcium efflux. The calcium antagonist 8-(N,N-diethylamino) octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8) by itself did not affect calcium efflux in macrophages; but abolished the PMA-induced increase in the rate of calcium efflux. The divalent cationphore A23187 increased the rate constant of the fast phase of calcium efflux two-fold when applied alone or when applied with PMA. These effects might be linked to ionophore enhancement and TMB-8 inhibition of PMA-induced macrophage chemotaxis and spreading (previously reported in Cell Calcium 3:503-514 and Cancer Research 43:3385-3391). No change in calcium efflux was observed if cells were exposed to PMA only during the efflux experiment suggesting that a prolonged exposure to PMA is required to elicit changes in calcium flux. Increased 45Ca++ remained in treated cells at each time point perhaps reflecting the PMA-induced increase in exchangeable calcium.

Animals↗
PubMed1982

Incentive spirometer for bedside studies.

We evaluated an incentive spirometer (IS) for monitoring changes in lung function in hospitalized patients. Accuracy and reproducibility of IS measurements of known volumes were adequate (r = 0.87). Flow dependency was demonstrated but was not significant in the clinically useful range. Reproducibility of IS measurements in five normal subjects was good, with a small training effect uncovered. In 15 patients with asthma and chronic obstructive lung disease, change in IS values closely correlated with spirometrically measured changes in volume and flows (best correlation: IS versus FEV1/FVC%, r = 0.98) and in peak flow. The performance of the IS as tested and its availability in most hospitals outweigh its limitations. We advocate its use as an adjunct in monitoring progress of hospitalized patients with obstructive lung disease.

Asthma↗
PubMed1981

Effects of ionophore A23187 on calcium fluxes from cultured adrenal cells.

The effect of the calcium ionophore A23128 on calcium fluxes from Y-1 adrenal cortical cells was investigated. Conditions were chosen which are known to result in an inhibition of steroidogenesis (6 . 10(-6) M ionophore and 3 . 10(-4) M extracellular calcium). Calcium efflux from Y-1 cells exhibited two distinct phases. A fast phase which was insensitive to the mitochondrial poison sodium azide and a slow, azide-sensitive phase. The ionophore brought about a rapid increase in the rate of calcium efflux and an 84% reduction in the size of the calcium pool which was associated with the slow efflux phase as well as a reduction in its rate constant. A decrease in the size of the rapidly exchanging calcium pool was also detected. Ethanol, the solvent which was used for the ionophore, slightly increased the rate constant of the rapidly exchanging pool. Conditions which resulted in diminished steroidogenic capacity also brought about a reduction in the size of an energy dependent, intracellular pool. The data is interpreted as being consistent with a hypothesis that the ionophore-induced inhibition of steroidogenesis may be causatively related to the loss of intracellular calcium or to the mechanism which brings about the loss.

Adrenal Glands↗
PubMed1978

Effects of ruthenium red, A23187 and D-600 on steroidogenesis in Y-1 cells.

The effects of the calcium antagonists ruthenium red and D-600 and the cation ionophore A23187 on steroidogenesis were investigated. Steroidogenesis triggered by corticotrophin and cyclic AMP was inhibited by each of the agents. Incubation of Y-1 cells with an excess of ethyleneglycol-bis-(beta-amino-ethylether)-N,N'-tetraacetic acid (EGTA) abolished the steroidogenic response to corticotrophin while the response to cyclic AMP was unaffected. The ability of ruthenium red and D-600 (1 . 10(-5) M), and A23187 (6 . 10(-6 M) to inhibit a response which does not require the presence of extracellular calcium (cyclic AMP induced steroidogenesis) suggests that they are altering intracellular calcium. Neither of the calcium antagonists nor the cation ionophore inhibited the steroidogenic response to exogenous pregnenolone, thereby suggesting that the cells were still viable. Only when A23187 was used in the presence of a 15-fold increase in extracellular calcium (4.8 mM) was the response to pregnenolone diminished. The data are interpreted as a further indication that, in intact cells, intracellular calcium plays a role in the steroidogenic pathway.

Adrenocorticotropic Hormone↗