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Biomedical subjects

M Mayer

Publications and source records attributed to M Mayer.

At least 145 records · Page 8Linked to original sources
PubMed1993

Histamine release after injection of benzodiazepines and of etomidate. A problem associated with the solvent propylene glycol.

Many drugs, especially when given in rapid sequence can cause histamine release. Ten healthy volunteers were premedicated with diazepam 10 mg.70 kg-1 i.v. and lormetazepam 1 mg.70 kg-1 i.v., respectively, 30 min prior to etomidate 0.15 mg.kg-1 i.v. in a single-blind, crossover study. The benzodiazepine lormetazepam and the hypnotic etomidate caused distinct increases in histamine plasma levels in two subjects. Maximal histamine levels after lormetazepam were 2.05 and 2.7 ng.ml-1, and after etomidate 1.85 and 3.2 ng.ml-1, respectively. Both drugs are solved in propylene glycol, a solvent that conveys very high osmolality (lormetazepam 6,750 mosm.kg-1, etomidate 4,900 mosm.kg-1). Clinical symptoms, like tachycardia, hypotension or allergic reactions, associated with similar histamine levels were not seen in either case. This limited histamine release appears to be caused by osmotic damage of tissue and blood cells.

Adult↗
PubMed1993

Direct stimulation of urokinase, plasmin, and collagenase by meperidine: a possible mechanism for the ability of meperidine to enhance cervical effacement and dilation.

Current hypotheses suggest that the degradation of cervical collagen and elastin leads to cervical effacement and dilation during labor. The collagenolytic activity is thought to be initiated through the conversion of latent (pro)collagenase to active collagenase by the plasmin formed from plasminogen or by other proteases similarly formed from their inactive zymogens. We presently demonstrate that meperidine stimulates the activity of several enzymes in the proteolytic cascade leading toward proteolysis of connective tissue proteins. Meperidine in its therapeutic concentration range produces a 26% stimulation of urokinase activity on substrate S-2444, a 39% stimulation of plasmin activity on substrate S-2551, and a 33% stimulation of collagenase activity on 14C-labeled globin substrate. These direct effects on the enzyme activities are noted in vitro with the purified enzymes and were confirmed with several small molecular weight chromogenic substrates and with 14C-globin protein substrate. Oxytocin at levels found during active labor fails to stimulate the in vitro activity of purified urokinase, plasmin, collagenase, trypsin, or tissue-type plasminogen activator. The effect of meperidine on the proteolytic enzymes suggests that its ability to promote cervical effacement and distention during labor may be at least partially due to a meperidine-induced stimulation of cervical proteases.

Cervix Uteri↗
PubMed1993

[The diagnostic role of contrast medium-enhanced MR tomography in the diagnosis of the post-diskectomy syndrome. A prospective study of 109 patients].

In a prospective study, 132 previously operated disc levels in 109 patients with failed back surgery syndrome (FBSS) were examined by MR imaging before and after intravenous application of a contrast agent (0.1 mmol Gd-DTPA/kg). The results were compared with current CT findings in 47 cases. The images were randomized and independently assessed by two experienced radiologists. A second intervention of a total of 30 disc levels was performed in 28 patients. Contrast-enhanced-MR imaging (CE-MRI) improved the differentiation of scar from recurrent disc herniation (RDH) compared to plain MRI and CT. Agreement between the two readers was significantly higher for CE-MRI than for the other two procedures (p < or = 0.001). CE-MRI additionally had the highest diagnostic accuracy (p < or = 0.001). The preoperative diagnosis made by CE-MRI was confirmed in 27 (90%) of the reoperated disc levels. Quantitative evaluation showed that there was no contrast enhancement in RDH as opposed to pronounced enhancement of 122% in scars (p < or = 0.001). Evaluation with respect to scar age revealed a significant difference (p < or = 0.01) in contrast enhancement between scars less and more than 2.5 years old.

Adolescent↗
PubMed1993

Cytokine-mediated regulation of rat ovarian function: interleukin-1 stimulates the accumulation of a 92-kilodalton gelatinase.

It is known that the mammalian ovary possesses a complete interleukin-1 (IL-1) system replete with ligands, receptors, and a receptor antagonist. To further assess the hypothesis that IL-1 may play an intermediary role in gonadotropin-triggered ovulation, we have set out to determine whether IL-1 is capable of promoting ovarian collagenase biosynthesis, an established component of the ovulatory cascade. Untreated cultured whole ovarian dispersates from immature (25 day old) rats constitutively elaborated several collagenolytic species as assessed in a gelatin matrix. A major 72 kilodalton (kDa) gelatinase (GL) was particularly apparent. Treatment with IL-1 beta produced selective dose- and cell density-dependent increments in the accumulation of a 92-kDa GL species. Administration of an IL-1 receptor antagonist neutralized the IL-1-induced stimulation of the 92-kDa GL in a dose-dependent fashion thereby supporting the presumption that the IL-1 effect is receptor mediated. Studies of comparable cellular densities of granulosa or enriched theca-interstitial cultures demonstrated the IL-1 induced 92-kDa GL to be highly expressed in the enriched theca-interstitial but not in the isolated granulosa cell preparations. Treatment with transforming growth factor-beta 1, a putative regulator of IL-1 action, significantly attenuated IL-1-induced 92-kDa GL accumulation thereby suggesting a potential regulatory paracrine/autocrine role for this agent in ovarian gelatinase economy. Initial characterization revealed the 92-kDa GL species to be a metalloproteinase present in its proenzyme zymogenic form. Taken together, our present findings reveal the ovarian expression of a constitutive 72-kDa GL and of an IL-1-stimulated 92-kDa GL the accumulation of which is particularly marked in enriched theca-interstitial preparations. These observations, along with the demonstration of the gonadotropin-dependent preovulatory induction of ovarian IL-1 gene expression, provide strong indirect support for the view that IL-1 may be the centerpiece of an intraovarian regulatory loop concerned with the promotion of the ovulatory cascade.

Animals↗
PubMed1993

Gonadotropin-mediated inhibition of proteolytic enzymes produced by human trophoblast in culture.

We investigated the effect of gonadotropins on protease that were suggested to be implicated in the invasive activity of the trophoblast. hCG levels ranging from 10 x 10(3) to 333 x 10(3) IU/L produced a dose-dependent inhibition of the in vitro globinolytic activity of the purified proteases trypsin, chymotrypsin, and urokinase, but failed to inhibit plasmin, collagenase, elastase, and tissue-type plasminogen activator. Likewise, FSH inhibited purified trypsin and urokinase, but not plasmin or tissue-type plasminogen activator. Culture medium conditioned with human trophoblast displayed serine protease and urokinase-like activities; exposure of the cultured trophoblast to exogenous hCG markedly suppressed serine protease and urokinase activities in the conditioned medium. A short treatment of the conditioned medium with trypsin abolished the hCG-mediated inhibition of urokinase activity. The present findings offer an explanation for earlier observations that hCG reduced collagenase activity in trophoblasts without affecting the level of collagenase-specific mRNA. The present results are also consistent with the concept that hCG, by its direct ability to inhibit certain serine proteases and urokinase in trophoblast, suppresses a protease-mediated conversion of procollagenase to active collagenase. The ability of hCG to prevent initiation of the collagenolytic cascade suggests that gonadotropins may regulate the transient invasive activity of the trophoblast.

Aprotinin↗
PubMed1993

High levels of human chorionic gonadotropin retard first trimester trophoblast invasion in vitro by decreasing urokinase plasminogen activator and collagenase activities.

Trophoblast cells of the blastocyst and of the first trimester placenta penetrate the endometrial basement membrane during the process of implantation and placental development. However, this invasive capacity seems to be restricted to the fetomaternal interface, as few trophoblast cells can be identified in the decidua, and trophoblasts rarely penetrate the maternal blood vessels. We have shown that the high invasive ability of first trimester human trophoblasts in vitro depends on collagenase activated by plasmin generation. In our study we used invasive first trimester trophoblast cells in conjunction with as in vitro amnion invasion assay to assess the role of hCG in the invasive process. hCG inhibited trophoblast invasion capacity in a dose-dependent fashion but exerted no effect on the ability of the trophoblasts to attach to the basement membrane. The activity of collagenase by trophoblasts (determined by zymography) was down-regulated by hCG, again in a dose-dependent manner. In contrast, hCG had no effect on production of the tissue inhibitor of metalloproteinases. Similar inhibitory effects of hCG on urokinase-plasminogen activator (uPA) and the activity of trophoblast-conditioned media were shown (measured by degradation of S-2444). The hCG effect on collagenase production was not mediated by the expression of procollagenase messenger RNA (mRNA), the expression of the mRNA encoding tissue inhibitor of metalloproteinase, or the expression of uPA mRNA, suggesting posttranscriptional control of hCG action. High levels of hCG attenuated the activity of commercial uPA but had no effect on commercial collagenase activity. These observations suggest that hCG may play a role in the trophoblast invasion process by inhibition of uPA activity, in turn decreasing collagenase activity and thereby reducing trophoblast cell invasion.

Cell Adhesion↗
PubMed1993

A non-enzymatic reaction in the late biosynthesis of the decarestrictine family.

In the late biosynthesis of the decarestrictines, inhibitors of the de novo formation of cholesterol isolated from the culture broth of Penicillium simplicissimum (FH-A 6090), a common pentaketide precursor undergoes post-polyketide modifications leading to the different members of the decarestrictine family. Besides subsequent enzymatically catalyzed reactions an unexpected non-enzymatic conversion was found to be the key step in the biosynthetic sequence. Under acidic conditions during fermentation the decarestrictines A1 and A2 (3 and 4) are converted into the main product decarestrictine D (2) and the new decarestrictines N (5) and O (6), whose physico-chemical data are reported. Mechanistic aspects of the non-enzymatic reaction as well as a more detailed picture of the biosynthetic relationships of the decarestrictine family are described. By the application of pH-static fermentations these results were successfully used to manipulate the secondary metabolite pattern of strain FH-A 6090 directing the fermentation process to produce desired members of the decarestrictine family.

Anticholesteremic Agents↗
PubMed1993

[Pharmacodynamics and clinical adverse effects of mivacurium. The effect of oral premedication with H1/H2 antagonists].

Duration of neuromuscular block may be prolonged by H1/H2 antagonists. This study was designed to determine the influence of H1/H2 antagonist treatment on onset, duration and recovery after mivacurium chloride (MIV), a new nondepolarizing neuromuscular blocking agent with a relatively short duration of action, which is metabolized by human plasma cholinesterase (PChE). METHODS. After approval from the hospital ethical committee and written informed consent, 48 ASA I-II patients of either sex (ages 18-65 years, weight 45-100 kg) were included in this double blind study and randomly allocated to four groups of 12 each: group A, 0.105 mg/kg MIV (1.5 x ED95) and H1/H2 antagonist; group B, 0.105 mg/kg MIV and placebo; group C, 0.21 mg/kg MIV (3 x ED95) and H1/H2 antagonist; Group D 0.21 mg/kg MIV and placebo. Premedication consisted of 2 mg lormetazepam p.o., 300 mg ranitidine and 0.1 mg/kg dimetindene, or placebo p.o. Anaesthesia was induced with thiopentone (5-7 mg/kg) and maintained with N2O/O2 at a 65/35 ratio, enflurane (0.8-1.5%) and supplements of fentanyl. The ulnar nerve was stimulated with supramaximal 2 Hz train-of-four (TOF) every 10 s. Neuromuscular twitch response was recorded with EMG. Onset time (time from end of injection to maximal or total block), maximal block (%), T125 (time from end of injection to 25% recovery) were recorded after each dose, and recovery index (T1 from 25% to 75% recovery) and TOF70 (time from end of injection to TOF ratio of 70%), after the last dose. RESULTS. The four groups did not differ with respect to age, weight or height. There was no difference in the pharmacodynamics of mivacurium between the groups receiving H1/H2 antagonists and those receiving placebo. Following 1.5 x ED95 the onset was at 3.7 +/- 1.2 (H1/H2) and 3.8 +/- 0.9 min (placebo), respectively. Clinical duration (T125) was 13.1 +/- 3.4 and 12.8 +/- 3.4 min. 3 x ED95 led to a significant faster onset and longer duration (P < or = 0.05). Onset was at 1.9 +/- 0.7 (H1/H2) and 2.1 +/- 0.5 min (placebo), respectively, and clinical duration 19.1 +/- 6.1 and 19.3 +/- 3.8 min. Duration of repetitive doses (10.1 +/- 5.3 min), recovery index (6.8 +/- 2.9 min) and interval from last dose to spontaneous recovery (22.4 +/- 7.0 min) did not differ between groups. Three patients in group D (placebo and 0.21 mg/kg MIV) had haemodynamic changes of over 20% from baseline. Flush and erythema were significantly less pronounced after H1/H2 premedication than after placebo (4 vs 12 pts). CONCLUSIONS. Our results suggest that time of onset and clinical duration of effects of MIV are not altered by dimetindene and ranitidine. The duration depends more heavily on the dose of MIV. The recovery of neuromuscular function, once it has begun, is prolonged neither by MIV nor by H1/H2 antagonists. As MIV is mainly broken down by PChE, it is evident that its duration of action is more prolonged by atypical PChE activity than by interaction with other drugs. Oral H1/H2 premedication may diminish haemodynamic side-effects and clinical signs of histamine release.

Administration, Oral↗
PubMed1993

[Postoperative pain therapy. The efficacy of a serotonin antagonist (GR 38032F;ondansetron) and the prostaglandin synthesis inhibitor lysin acetylsalicylate (Aspisol)].

Serotonin is one of the many neurotransmitters involved in nociception. Serotonin antagonists may therefore reduce postoperative pain. In the present study we examined whether the new 5-HT3 receptor antagonist GR 38032F (ondansetron) reduced postoperative pain after minor surgery and compared its effectiveness with that of lysin acetyl salicylate (Aspisol). METHODS. A series of 100 patients of both sexes who were undergoing minor surgery were enrolled in this study. Patients who did not need analgesic medication within the first 3 h after surgery were regarded as "dropouts", and the rest were studied for 24 h. In a preliminary study (n = 19) patients received ondansetron i.v. in increasing dosages (6, 12, 24, 48, 96 and 128 micrograms.kg-1) to evaluate the analgesic potency of this drug. In the main double-blind, randomized, study (n = 81), three groups were formed, and patients received 50 micrograms.kg-1 or 100 micrograms.kg-1 ondansetron i.v. or saline only i.v. Analgesia was evaluated by visual analogue (VAS) and verbal rating scales (VRS). If pain persisted patients received 1.8 g lysin acetylsalicylate (LAS) i.v. RESULTS. There were 6 (out of 19) patients in the preliminary study and 36 (out of 81) patients in the main study who were dropouts; that is to say they did not require any analgesic medication within the first 3 h, but 12 of these dropouts needed analgesic medication more than 3 h after end of surgery. Pain was reduced by 82% from baseline in 7 out of 13 patients in the preliminary study (11 men, 2 women). In the main study (n = 45, 28 men, 17 women) 100 micrograms.kg-1 ondansetron did not show a better analgesic effect than 50 micrograms.kg-1, and there was no significant difference between ondansetron and saline. VAS showed a reduction in pain from 6.9 +/- 2.0, 6.8 +/- 1.5 and 6.6 +/- 1.8 to 4.1 +/- 2.4, 3.4 +/- 2.2 and 3.4 +/- 2.1 in the 50 micrograms.kg-1, 100 micrograms.kg-1 and saline groups, respectively, within 60 min after i.v. application. VRS diminished from 2.5 +/- 0.5, 2.5 +/- 0.6 and 2.4 +/- 0.5 to 1.7 +/- 0.7, 1.5 +/- 0.8 and 1.5 +/- 0.7, respectively. There were 26 patients who experienced no pain relief in response to ondansetron or placebo and who therefore received LAS, and 21 of these then experienced significant pain reduction. CONCLUSION. Pain after minor surgery does not appear to be a major problem. For 42 out of 100 patients no analgesics were needed within the first 3 h after end of surgery. Ondansetron was no more effective than placebo in reducing postoperative pain. Lysin acetylsalicylate, however, may be an effective alternative to opioids for the treatment of postoperative pain.

Adult↗
PubMed1993

[Congenital myasthenia with esophageal involvement].

BACKGROUND: Mild disorders associated with persistent neonatal myasthenia gravis may not be recognized for several months. Esophageal dysfunction in this type of myasthenia has never been studied. CASE REPORT: A gastroesophageal reflux was diagnosed during the first weeks of life in a girl; she was not treated. At 8 month-old, she was admitted for febrile convulsions; the pyrexia was due to urinary tract infection by Escherichia coli. 4 days later, the infant displayed weakness of the eyelids and extraocular muscles. The proximal muscles of the arms were also weak. Neostigmine, 0.3 mg subcutaneously, completely removed the symptoms in a few minutes. Neuromuscular transmission tests showed a progressive decrease in eyelid muscle response on repetitive stimulation of the nerve, with a pattern of post-synaptic defects that was corrected by edrophonium chloride injection. Neither the girl nor her mother had acetylcholine receptor antibodies. Overnight monitoring of the distal esophagus pH showed numerous episodes of acid reflux, essentially after the meal. Manometry disclosed abnormalities of both the striated and smooth muscles of the esophagus that were corrected with neostigmine. The girl was given neostigmine and was in good condition one year later. CONCLUSION: Myasthenia could worsen and/or trigger a gastroesophageal reflux by decreasing esophageal clearance and lower esophageal sphincter pressure.

Female↗
PubMed1992

Stimulation of plasmin activity by oleic acid.

The amidolytic activity of plasmin with the chromogenic substrate H-D-valyl-L-leucyl-L-lysine p-nitroanilide (S-2251) is stimulated by oleic acid in a dose-dependent and saturable fashion. The activity of plasmin on S-2251 in the presence of oleic acid followed a sigmoidal kinetic pattern, with an almost 4-fold stimulation of activity at 60 microM-oleic acid. Half-maximal stimulation occurred at an oleic acid level of 19.5 microM. The amino acid analogue 6-aminohexanoic acid (AHA), which is known to bind to lysine-binding sites in plasmin, suppressed the stimulatory effect of oleic acid in a concentration-dependent manner; at 0.3 mM-AHA, about 70% of the oleic acid-dependent enhancement of plasmin activity was abolished. The l/v versus 1/[S] plot for plasmin changed in the presence of oleic acid from a linear to a non-linear curve, suggesting positive co-operativity. 14C-labelled oleic acid bound to plasmin, and the bound ligand was displaced by an excess of unlabelled oleic acid. Oleic acid also produced a marked (40-fold) stimulation of the plasminogen-dependent cleavage of S-2251 by urokinase. A half-maximal effect on plasminogen activation was obtained at 40 microM-oleic acid. The present findings suggest that the ability of oleic acid to stimulate plasmin activity and to enhance the conversion of plasminogen to plasmin depends on the interaction of oleic acid with specific lysine-binding sites in plasmin.

Aminocaproic Acid↗
PubMed1992

Direct inhibition of proteases and cervical plasminogen activator by antibiotics.

OBJECTIVES: Preterm premature rupture of the fetal membranes and premature delivery are sometimes linked to genital tract infection and activation of proteolytic enzymes that degrade the extracellular matrix. The possible beneficial effect of antibiotics in prevention of preterm premature rupture of fetal membranes and retardation of the onset of labor in some patients with clinical or subclinical infection was explained via their antibacterial efficacy. The aim of this study was to determine the effect of antibiotics on proteolytic enzymes as a possible explanation for the ability of antibiotics to retard preterm labor. STUDY DESIGN: The direct effect of four antibiotics on the proteolytic activities of purified collagenase, elastase, plasmin, trypsin, and chymotrypsin and on streptokinase and human cervical plasminogen activator was measured. RESULTS: The macrolide antibiotic erythromycin and the beta-lactam antibiotics penicillin G, cloxacillin, and ampicillin exerted, in most of the tested combinations with the different proteases, inhibitory effects on the proteolytic activities. CONCLUSION: The present finding that antibiotics directly inhibit proteases may offer an explanation for the beneficial response to antibiotic therapy in some cases of idiopathic preterm labor even in absence of pathogenic bacterial infection.

Ampicillin↗
PubMed1992

Does etomidate cause haemolysis?

Etomidate is currently presented as a solution with propylene glycol as solvent. This organic solvent has an extremely high osmolality and is probably responsible for some of the side effects of this drug. In order to detect haemolysis, an indication for cell damage, we have measured serum haptoglobin concentrations in 12 healthy male volunteers after administration of etomidate 0.3 mg kg-1. Six subjects received etomidate in propylene glycol (EtoPG) with an osmolality of 4965 mosmol kg-1 and six received etomidate in lipid emulsion (EtoLip, 400 mosmol kg-1). Haptoglobin concentrations in the EtoPG group decreased by 44% and 43% from baseline values at 2 and 4 h after administration, respectively, and were significantly smaller than after administration of EtoLip. After 24 h, haptoglobin concentrations had not reached baseline values.

Adult↗
PubMed1992

Onset and recovery of rocuronium (Org 9426) and vecuronium under enflurane anaesthesia.

We have studied the onset, duration of action and recovery index of twice the ED90 of rocuronium (Org 9426) (0.6 mg kg-1) and of vecuronium (0.08 mg kg-1) in patients during enflurane anaesthesia. Rocuronium had a significantly shorter mean onset time of 1.8 (SD 0.4) min, compared with vecuronium 3.4 (0.8) min. Clinical duration (time for the first twitch in the train-of-four to recover to 25% of control) was similar for both drugs (29 (10) min vs 31 (12) min). Spontaneous recovery times (TOF ratio 70%) did not differ significantly between rocuronium (47 (10) min) and vecuronium (44 (11) min).

Adolescent↗
PubMed1992

Brain MRI and electrophysiologic abnormalities in preclinical and clinical adrenomyeloneuropathy.

We describe the neurophysiologic abnormalities in 17 patients with clinical adrenomyeloneuropathy (AMN), an adult phenotype of X-linked adrenoleukodystrophy (ALD). These abnormalities also allowed the early recognition of the AMN phenotype in three asymptomatic boys with biochemically proven ALD. In 14/16 adult AMN patients, there were cerebral white matter abnormalities on MRI which were severe and comparable with cerebral ALD in four of the patients.

Addison Disease↗
PubMed1992

Osmolalities of propylene glycol-containing drug formulations for parenteral use. Should propylene glycol be used as a solvent?

Propylene glycol (PG) is a widely used vehicle for water-insoluble drugs. Injection of drugs formulated with this solvent often results in pain, thrombosis, or thrombophlebitis that can be reduced by premedication with local anesthetics or opioids. Because osmolality and pH that are unphysiologic may cause these adverse effects, we assessed the contribution of PG to the osmolality of parenteral drug formulations. Osmolality of PG measured in distilled water showed that PG content and osmolality were directly related: 2% wt/vol PG, 264 mOsm/L; 100% PG, 15, 200 mOsm/L. The osmolalities of commercially available preparations of drugs dissolved in PG ranged from 365 mOsm/L (2% PG content) to 12,800 mOsm/L (83.46% PG), with most above 1000 mOsm/L. Replacement of PG by a solvent with lower osmolality in Germany has effectively reduced the incidence of side effects for one drug. Until PG can be replaced in drugs, we recommend diluting drugs in a large volume of saline solution; this may help to minimize the undesirable effects of this solvent.

Anesthesiology↗
PubMed1992

Antigliadin antibody, D-xylose, and cellobiose/mannitol permeability tests as indicators of mucosal damage in children with coeliac disease.

A dual sugar (cellobiose/mannitol) permeability test using an iso-osmolar solution was performed, to compare its ability to predict small-bowel mucosal damage in children affected by coeliac disease with the determination of serum levels of D-xylose and antigliadin antibody. Eighty-three children (67 on gluten-containing diet and 16 on gluten-free diet) were investigated. The D-xylose and the serum antigliadin antibody test predicted accurately 70% and 78% of the small-bowel biopsy results, respectively, whereas the cellobiose-mannitol permeability test predicted 93%. These data confirm the superiority of the permeability test over the D-xylose test, although the former cannot be advocated as a substitute for jejunal biopsy. Our results suggest a complementary use of the permeability test and the antigliadin antibody measurement as screening tests for coeliac disease before applying more invasive procedures.

Adult↗