Living & learning with allergy: a European perception study on respiratory allergic disorders.

BACKGROUND: Knowledge of allergy patients' perception of own disease is inadequate, and understanding of the impact of local environment, including family and health-care system, on patients' management of disease is insufficient. We examined the potential of telephone-based survey techniques for establishing this knowledge in 10 European countries. METHODS: A two-phased questionnaire developed by use of focus groups in seven countries was translated into 10 languages. To ensure that the true values of the populations were restored in randomly selected populations, 75,343 telephone numbers selected for screening represented balanced national distributions of households. RESULTS: Eight thousand two hundred and sixty-eight respiratory allergy sufferers were identified by the telephone screening process. 85.4% accepted to participate in the survey and 89.6% completed both phases comprising 34 questions and rating of 49 statements. Data for each country were weighted in terms of age, sex and the recorded allergy prevalence within age intervals. CONCLUSIONS: The telephone survey technique allowed for establishment of random representative samples, and application of mathematical weighting procedures assured that the true national values were restored in the data set. As all interviews were performed in a standardised manner we conclude that the telephone-based survey methodology enables national representative data set to be established and compared.

[Effectiveness and tolerability of the glucocorticoid mometasone furoate given as nasal spray in seasonal allergic rhinitis]. / A glükokortikoid mometazon furoát orrspray formában való adásának hatása szezonális allergiás rhinitisben.

The clinical effect and tolerance of momethasone furoate (MF) glucocorticoid nasal spray (MFNS) were studied in 14-70 year-old patients suffering from seasonal allergic rhinitis. The patients administered daily one (morning) dose, 100 micrograms each, of MF into both nostrils, for a period of 14 days. They did not use other medicines affecting nasal symptoms. Nasal symptoms (nasal discharge, nasal obstruction, nasal itching, sneezing) and non-nasal symptoms (lacrimation, eye itching/burning sensation, palatal itching, ear itching, general itching), scored 0 to 3, and serving as a basis for evaluating the effect, were registered before treatment (day 1) and at visits on 3, 7 and 14th day. Of the 196 patients involved in the open multicentric study, 188 completed the study. The total average nasal symptom scores decreased, already after 3 days of treatment, from 8.7 to 4.1 and to 1.6 by the 14th day. Decrease of non-nasal symptoms was also conspicuous, however, lacrimation persisted in 57 of 188 cases, while eye itching--mainly in moderate and mild form--in 90 cases. The general condition of rhinitis before the treatment was evaluated by the examiners as severe or very severe in 155 cases (82%), as symptom-free (99 cases) on day 14 in, and mild (71 cases), in 170 cases (90%). The therapeutic effect was considered by both, patients and physician, as excellent, in 106 (56%) and 115 (61%) cases, resp. and as good in 63 (34%) and 56 cases (30%). Side-effects were mostly mild and transitory. Treatment was not discontinued due to side-effect in any of the cases. Based on the results, MFNS, administered in a single daily dose of 200 micrograms, has proved to be an effective and safe glucocorticoid preparation, also easy to use locally, in the treatment of allergic rhinitis.

Ro 25-6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro.

The interaction of Ro 25-6981 with N-methyl-D-aspartate (NMDA) receptors was characterized by a variety of different tests in vitro. Ro 25-6981 inhibited 3H-MK-801 binding to rat forebrain membranes in a biphasic manner with IC50 values of 0.003 microM and 149 microM for high- (about 60%) and low-affinity sites, respectively. NMDA receptor subtypes expressed in Xenopus oocytes were blocked with IC50 values of 0.009 microM and 52 microM for the subunit combinations NR1C & NR2B and NR1C & NR2A, respectively, which indicated a >5000-fold selectivity. Like ifenprodil, Ro 25-6981 blocked NMDA receptor subtypes in an activity-dependent manner. Ro 25-6981 protected cultured cortical neurons against glutamate toxicity (16 h exposure to 300 microM glutamate) and combined oxygen and glucose deprivation (60 min followed by 20 h recovery) with IC50 values of 0.4 microM and 0.04 microM, respectively. Ro 25-6981 was more potent than ifenprodil in all of these tests. It showed no protection against kainate toxicity (exposure to 500 microM for 20 h) and only weak activity in blocking Na+ and Ca++ channels, activated by exposure of cortical neurons to veratridine (10 microM) and potassium (50 mM), respectively. These findings demonstrate that Ro 25-6981 is a highly selective, activity-dependent blocker of NMDA receptors that contain the NR2B subunit.

[Acute kidney failure caused by rhabdomyolysis]. / Rhabdomyolysis kapcsán kialakult akut veseelégtelenség.

Rhabdomyolysis developed in the muscles of the left lower extremity of a 43 year old man leading to myoglobinuria and acute renal failure. The diagnosis of rhabdomyolysis was strengthened by muscle and renal biopsy. The renal functions were restituted after peritoneal dialysis performed four times (12 hours each) within two weeks. The possible role of alcohol or Dalgol intoxication as well the disturbed circulation in the development of rhabdomyolysis is discussed. Authors point out the benefit of peritoneal dialysis in acute renal failure caused by rhabdomyolysis.

Relation of renal thromboxane A2 production to urine flow, electrolyte excretion and plasma renin activity in control state and drug induced hypotension.

The functional importance of renal TxB2 generation in the maintenance of elevated arterial blood pressure in essential hypertension was followed in 22 patients, using the method of sustained blood pressure decrease by i.v. sodium nitroprusside infusion. Linear correlation between urinary excretion of TxB2, urine flow, and sodium excretion could be established in both control and hypotensive periods. Presumably, changes in urinary excretion of TxB2 reflect a secondary intrarenal counterregulatory response.

The background of hysteretic properties of the human umbilical arterial wall. Smooth muscle contraction and hysteresis of the pressure-radius curves.

Incongruency between the upward and downward routes of pressure-radius curves, a phenomenon called hysteresis, was studied on 124 human umbilical arterial segments. Such characteristic phenomena were found which are unusual if one compares them to the viscotic hysteresis of the unliving material. After a stay at low distending pressure, the loop of the forthcoming pressure-radius cycle became exceptionally wide. The width of the loop was relatively independent of the rate of pressure change. Equilibrium points were not always inside the loop. Addition of a smooth muscle contracting agent increased the width of the loop. At low pressure the segments contracted spontaneously and the shortened elements kept the shortened length for some time even at higher distending pressure. All phenomena found in connection with hysteresis can be explained if we suppose that some of the contractile elements contract during cyclic stretching relatively easily at low distending pressures. Due to the "catchlike" properties of this contraction, the shortened elements could resist against higher distending forces on the upward route and this way a delay in the dilatation process occurred. This made upward and downward routes different.

A simple model describing the elastic properties of human umbilical arterial smooth muscle.

Elastic properties of cylindrical segments of 71 normal double and 4 single human umbilical arteries were studied. This specimen is rich in vascular smooth muscle in comparison with other great arteries. Outer diameter versus intraluminal pressure characteristic curves were taken with decreasing pressures in vitro in different contraction states. Tangential force and circumferential incremental elastic modulus were computed. A sum of 222 curves was analysed. The investigations showed that if we take tangential force and outer radius values measured at the same pressure levels but in different contraction states, then a similar proportional change in tangential force will induce a similar proportional passive change in the outer radius, to some extent independently of the degree of active tangential shortening of the segment. For example to induce a 10% passive decrease of the outer radius from values measured at 100 mm Hg intraluminal pressure, tangential force had to be decreased by 76.7 +/- 9.9% in single relaxed arteries, and by 79.6 +/- 0.8% in normal double relaxed segments. These values corresponded to intraluminal pressure levels of 26.4 +/- 4.9 mm Hg and 23.1 +/- 0.9 mm Hg, respectively. In 30% active spontaneous shortening to reach the same 10% passive decrease in outer radius from the value measured at 100 mm Hg, tangential force had to be decreased by 75.2 +/- 1.9% which corresponded to 29.6 +/- 20 mm Hg. The same values in 5-HT induced contraction, 30% active shortening were 76.7 +/- 2.0% and 28.4 +/- 2.6 mm Hg, respectively. In addition to the similarity of relative changes in tangential force, the pressure levels were to some extent also similar. These data suggest that elastic elements in the human umbilical arterial smooth muscle may be organized in such a way as to ensure similar prestretch of similar elastic elements at similar pressures independently of the degree of active shortening of the circumference.

Acylmorphinans. A novel class of potent analgesic agents.

A series of novel 2- and 3-acylmorphinans (8-14) was synthesized in our search for a potent analgesic agent with low addiction potential. The compounds were evaluated for antinociceptive potency and receptor binding affinity. Among these compounds, the levorotatory 3-acetyl-N-(cyclopropylmethyl)morphinan (12) was found to be an orally active analgesic, comparable in potency to morphine (1), yet only weakly able to substitute for morphine (1) in morphine-dependent rats.

Potential synthetic codeine substitutes: (-)-3-O-aryl-N-methylmorphinans.

A series of novel O-aryl-N-methylmorphinans (7-19) were synthesized by the Ullmann reaction from levorphanol (4) in our search for a synthetic codeine (2) substitute with reduced addition liability. The compounds were evaluated for antinociceptive potency and receptor binding affinity. Among these compounds, (-)-3-phenoxy-N-methylmorphinan (7) is an orally active analgesic comparable in potency to codeine (2), which exhibits decreased physical dependence liability and longer duration of action.

Synthesis and pharmacology of metabolically stable tert-butyl ethers of morphine and levorphanol.

3-O-tert-Butylmorphine (5) was prepared from 6-O-acetylmorphine (3) via alkylation with N,N-dimethylformamide di-tert-butyl acetal, followed by hydrolytic removal of the 3-(dimethylamino)-2-propenoate group. The same process was used to prepare the tert-butyl ether of levorphanol (6), (-)-3-tert-butoxy-N-methylmorphinan (8). Both 5 and 8 exhibited in vitro affinity for the opiate receptor comparable to codeine and had analgesic properties in the writhing test. Only 5 exhibited activity in the tail-flick procedure and neither compound showed significant antitussive activity.

Levorphanol: a simplified radioimmunoassay for clinical use.

A recently reported radioimmunoassay (RIA) procedure (Res. Comm. Chem. Pathol. Pharmacol 29, 535, 1980) developed for the quantitation of the narcotic analgesic, levorphanol, in dog plasma has been simplified for clinical use using the original antiserum to an albumin conjugate of (-)-3-hydroxy-N-carboxymethylmorphinan. Due to the absence of and/or insignificant concentrations of the cross-reactive metabolite, nor-levorphanol, in human plasma, the new simplified procedure allows for the specific quantitation of levorphanol directly in clinical plasma samples, thereby circumventing the extraction and chromatographic steps of the original procedure. The direct procedure has a limit of sensitivity of 1 ng/ml of levorphanol using a 20 microliter sample of plasma and is ideally suited for the routine determination of steady state plasma concentrations of levorphanol in patients receiving various therapeutic doses of the drug. In two subjects studied the apparent half-lives of elimination of levorphanol from plasma were 10 and 16 hr. The characteristics and use of another antiserum to levorphanol, obtained by immunization of rabbits with an albumin conjugate of (-)-3-O-carboxymethyl-N-methylmorphinan, is discussed.

(-)-2-Hydroxy-n-cyclopropylmethylmorphinan: radioimmunoassay and phamacokinetic profile.

The pharmacokinetic profile of (-)-2-hydroxy-N-cyclopropylmethylmorphinan (HCMM), a narcotic antagonist and analgesic, has been evaluated in man following administration of 25 to 50 mg of the drug orally and 10 to 15 mg intramuscularly. A specific radioimmunoassay procedure was developed for the determination of HCMM in plasma and urine. The drug had a mean "apparent" elimination half-life in plasma of about 11 hr following both routes of administration. A mean of 47% of the oral dose was excreted in the urine as unconjugated and conjugated HCMM and only 5% of the dose was excreted as intact HCMM. In one subject studied, the plasma levels of conjugated HCMM were as much as 5-fold higher than the levels of unconjugated drug. Although there was considerable intersubject variability following both routes of administration, the overall pharmacokinetic parameters suggest that oral and intramuscular doses are bioequivalent.

Dextromethorphan: radioimmunoassay and pharmacokinetics in the dog.

A specific radioimmunoassay (RIA) for the determination of the widely used non-narcotic antitussive agent, dextromethorphan (DM) in plasma and urine has been developed using an antiserum to DM which was obtained from rabbits following immunization with an albumin conjugate of (+)-3-methoxymorphinan-17-succinyloxyethyl. Specificity of the RIA was achieved by selective extraction of DM from its known metabolites into hexane at pH 6.5 with 86% recovery. Employing tritium labelled-DM as the radioligand the RIA had a limit of sensitivity of about 4 ng/ml of plasma using a 0.5 ml sample. Following I.V. administration of 2 mg/kg of DM to two dogs, the plasma levels of intact DM declined biexponentially; the terminal exponential phase having a half-life of 2.5-3.9 hr. The volume of distribution of the central compartment ranged from 5-6.4 l/kg while the metabolic clearance rate ranged from 2.5-2.6 1/hr/kg. Oral administration of 10 mg/kg of DM in gelatin capsule resulted in peak plasma levels of 50 and 92 ng/ml at 2 hr post-drug. Following both routes of administration, less than 3.5% of the dose was excreted in the urine as intact DM indicating almost complete biotransformation and/or alternate routes of excretion. In one human subject who received 0.5 mg/kg of DM P.O. in a syrup, the plasma levels were less than 1 ng/ml.

Metabolism of the enantiomers of 2-hydroxy-N-cyclopropylmethylmorphinan in dog and man.

The major metabolic pathway of the (-) enantiomer and the (+) enantiomer of 2-hydroxy-N-cyclopropylmethylmorphinan in dogs was shown to be conjugation with glucuronic acid and/or sulfate. Gas chromatography mass spectrometry, nuclear magnetic resonance spectroscopy and X-ray crystallography were used to identify additional metabolites of the two enantiomers in dog urine after hydrolysis with Glusulase. Metabolites of the (-) enantiomer were identified as 2-hydroxymorphinan and 2,7beta-dihydroxy-N-cyclopropropylmethylmorphinan. The major metabolites of the (+) enantiomer in hydrolyzed dog urine were identified as 2-hydroxymorphinan,2,3-dihydroxy-N-cyclopropylmethylmorphinan and 2-methoxy-3-hydroxy-N-cyclopropylmethylmorphinan. In addition, tentative or partial structures were postulated for three minor metabolites of the (+) enantiomer: 2-methoxy-3-hydroxymorphinan, a metabolite containing a hydroxyl group on either carbon 4, 5, 6 or 7 and a methylated catechol metabolite containing a hydroxyl group on carbon 4, 5, 6 or 7. Thus, the major oxidative pathways of the (-) enantiomer were N-dealkylation and aliphatic hydroxylation, while the (+) enantiomer mainly underwent N-dealkylation and aromatic hydroxylation, followed by phenolic methylation. Analysis of urine from a human subject administered the (-) enantiomer suggested that the metabolism of this isomer by man was similar to its metabolism by dog.

Radioimmunoassay for the simultaneous determination of morphine and codeine.

Antiserum against morphine was produced in rabbits immunized with morphine hapten conjugated to bovine serum albumin. The carrier protein was conjugated to the nitrogen atom of the opiate alkaloid in order to make the phenolic hydroxy group on C3 and the alcoholic group on C6 as determinant groups. The antibody does not recognize codeine or the major metabolite of morphine, 3-O-monoglucuronide. This antibody was used in conjunction with an antibody prepared against 3-O-carboxymethylmorphine to develop a radioimmunoassay which can measure codeine in the presence of morphine. The assay was used to follow both the plasma and brain levels of codeine and its biotransformation to morphine. Codeine when administered at a dose of 5 mg/kg i.v. showed a biphasic plasma decay curve the first phase of which had a +1/2 of 26 min. Peak concentrations of morphine were detected in the plasma following that dose of codeine at 0.5 h. 30 min after the injection of 20 mg/kg i.p. codeine, the brain levels of morphine were only 2% that of codeine. Thereafter, the brain levels of morphine slowly declined.