Intraoperative tramadol reduces shivering but not pain after remifentanil-isoflurane general anaesthesia. A placebo-controlled, double-blind trial.

BACKGROUND AND OBJECTIVE: Postoperative shivering and pain are frequent problems in patients recovering from anaesthesia with particularly high incidences being observed after remifentanil-isoflurane-based general anaesthesia. The opioid tramadol is generally effective in preventing shivering and treating pain, but its effects are not characterized after remifentanil-based general anaesthesia. This randomized, placebo-controlled, double-blind study evaluated the effects of intraoperative intravenous tramadol on postoperative shivering and pain after remifentanil-based general anaesthesia. METHODS: After Ethics Committee approval, 60 patients scheduled for lumbar disc surgery were included. Surgery was performed under general anaesthesia (remifentanil, isoflurane). Patients were randomly assigned to receive 2 mg kg(-1) tramadol in 30 mL 0.9% saline infused intravenously (n = 30) or 30 mL saline (n = 30) 45-30 min before skin closure. The following parameters were assessed every 10 min for 2 h: shivering, pain, postoperative nausea and vomiting, sedation, heart rate, non-invasive blood pressure and peripheral oxygen saturation. The primary outcome variable was the incidence of shivering during the first 2 postoperative hours. Secondary variables were: shivering intensity, pain, postoperative nausea and vomiting, sedation, heart rate, non-invasive blood pressure and peripheral oxygen saturation. RESULTS: Shivering was less frequent in patients treated with tramadol (20% vs. 70%, P = 0.0009) and was of lower intensity (severe shivering: 10% vs. 46.7%, P = 0.003). Pain scores were similar between the groups and all other secondary outcome variables failed to reveal significant differences. CONCLUSIONS: Compared with placebo, intraoperative intravenous administration of 2 mg kg(-1) tramadol reduces the incidence and extent of postoperative shivering without alterations in pain perception after lumbar disc surgery under remifentanil-isoflurane-based general anaesthesia.

PPADS, a novel functionally selective antagonist of P2 purinoceptor-mediated responses.

We have characterized PPADS (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid) as a novel antagonist which selectively blocks P2 purinoceptor-mediated responses in rabbit vas deferens at pre- and postjunctional sites. PPADS did not interact with alpha 1-adrenoceptors, muscarinic M2 and M3 receptors, histamine H1 and adenosine A1 receptors. Thus, PPADS is a novel and useful pharmacological tool to study co-transmission in tissues where ATP and co-existing neurotransmitters act in concert.

Characterization of the prejunctional muscarinic receptors mediating inhibition of evoked release of endogenous noradrenaline in rabbit isolated vas deferens.

The aim of the present study was to characterize the prejunctional modulation of evoked release of endogenous noradrenaline in rabbit vas deferens by the use of muscarinic receptor agonists and subtype-preferring antagonists. Vasa deferentia of the rabbit were stimulated electrically by trains of 120 pulses delivered at 4 Hz or trains of 30 pulses at 1 Hz. The inhibition by muscarinic agonists of the stimulation-evoked overflow of endogenous noradrenaline in the absence and presence of antagonists was used to determine affinity constants for antagonists. These values were compared with those observed at putative M1 receptors inhibiting neurogenic twitch contractions in the rabbit vas deferens and with affinity data obtained at M1(m1)-M4(m5) receptors in functional studies and binding experiments. The evoked overflow of noradrenaline from sympathetic nerves was enhanced by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), the P2 purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) and indomethacin, indicating a tonic inhibition by endogenous A1 and P2 purinoceptor agonists and prostanoids, respectively. The stimulation-evoked overflow at 4 Hz was not sensitive to inhibition by the muscarinic agonists methacholine or 4-(4-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium iodide (4-Cl-McN-A-343). In contrast, at a stimulation frequency of 1 Hz the evoked noradrenaline release was decreased by muscarinic agonists (EC50): arecaidine propargyl ester (0.062 microM), 4-Cl-McN-A-343 (0.32 microM), 4-(4-fluorophenylcarbamoyloxy)-2-butynyl-N-methyl-pyrrolidinium tosylate (4-F-PyMcN+; 0.48 microM) and methacholine (0.86 microM). The affinity constants of most of the muscarinic antagonists [atropine: pKB = 9.47; (R)-trihexyphenidyl: pKB = 9.18; pirenzepine: pA2 = 7.68; methoctramine: pKB = 6.90] are consistent with estimates of these antagonists at M1(m1) receptors determined in various functional and binding studies. The high antagonistic potency of pirenzepine and (R)-trihexyphenidyl and the agonistic activity of 4-F-PyMcN+ argue for the involvement of M1, and against that of M2 and M3 receptors in the inhibition of evoked noradrenaline overflow. However, the high apparent pKB of 8.30 for himbacine is not in accordance with an M1 receptor; by contrast, it would be compatible with the presence of M2 or M4 receptors. The potencies of the tested muscarinic agonists and antagonists largely agree with those obtained for the inhibition of neurogenic twitch responses (0.05 Hz) in the rabbit vas deferens.(ABSTRACT TRUNCATED AT 400 WORDS)

[Phenylalanine hydroxylase activity in the liver as a parameter for distinguishing various forms of hyperphenylalaninemias (author's transl)]. / Phenylalaninhydroxylase-Aktivität in der Leber als Parameter zur Unterscheidung der verschiedenen Formen der Hyperphenylalaninämien

The activity of phenylalanine hydroxylase in the liver without the cofactor 2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8-tetrahydropterin is similar in cases of classical PKU (14 cases), mild hyperphenylalaninemias (2 cases), heterozygotes (1 case) and normal controls (18 cases). The addition of cofactor increases the activity 30-40-fold in normal controls and 2-5 fold in mild hyperphenylalaninemias or heterozygotes. In classical PKU the addition of cofactor is without effect or causes even a diminution of activity. Therefore, for classification of the various forms of hyperphenylalaninemias the effect of cofactor on enzyme activity is important. For decisions from this findings to be made as to whether treatment should or should not be used further investigations are needed.

The immunological evidence for a phenylalanine hydroxylase like immunoreactive protein in different human cells and tissues.

Phenylalanine hydroxylase (PAH) was purified 105-fold from human liver. The rel mol mass of the subunits in sodium dodecylsulfate-polyacrylamide gel electrophoresis was 54,000 Da and the isoelectric point was estimated to be between pH 5.0 and 5.2. The activity of purified PAH was inhibited by p-Cl-phenylalanine (p-Cl-Phe), 3-J-tyrosine (3-J-Tyr) and 6-F-tryptophane (6-F-Trp) by 73%, 26% and 10%, respectively. The Km value was 0.36 x 10(-3) mol/l for L-Phe and 5.88 x 10(-5) mol/l for the synthetic cofactor dimethyltetrahydrobiopterin (DMPH4). Polyclonal antibodies raised in rabbits against the active human enzyme showed only a slight cross-reaction with purified rat liver PAH. Using the rabbit antibodies an immunoreactive protein with the same mol mass and isoelectric point as purified human liver PAH and PAH from crude liver extract was detected in extracts from kidney, heart, spleen, brain, pancreas, lung, placenta, leucocytes, cultured skin fibroblasts and chorionic villus cells.

New functionally selective muscarinic agonists.

The muscarinic pharmacology of two novel agonists related to McN-A-343, 4-F-PyMcN and 4-F-PyMcN+, has been studied by the use of pharmacological and radioligand binding techniques. Both compounds were potent agonists at M1 receptors in rabbit vas deferens (pEC50 = 6.24 and 6.96) and rat duodenum (pEC50 = 5.47 and 6.38), but very weak partial agonists or competitive antagonists at guinea-pig cardiac M2 and ileal M3 receptors. There was no receptor reserve for 4-F-PyMcN in rabbit vas deferens, for which the potency (pEC50 = 6.24) and apparent affinity (pKA = 5.99 and 6.21) were similar. 4-F-PyMcN+ showed only limited binding selectivity between four muscarinic receptor binding assays with apparent affinity constants (pKi) of 5.8, 5.2, 5.6 and 5.7 for M1, M2, M3 and M4 muscarinic receptor subtypes. The two novel functionally M1-selective agonists may provide useful tools with which to study muscarinic receptor mechanisms. The non-quaternary compound, 4-F-PyMcN, might become a starting point for the development of drugs that selectively affect M1 receptors involved in central cholinergic function.

[Subacute and subchronic percutaneous tolerance testing (28-day and 90-day test) of epicutaneously applied dis-infectants as demonstrated by the example of peroxyethanoic acid (author's transl)]. / Subakute und subchronische percutane Verträglichkeitsprüfung im 28-und 90-Tag-Test von Desinfektionsmitteln bei epicutaner Applikation, dargestellt am Beispiel von Peroxyethansäure.

As compared to control animals, guinea-pigs to the shaved backs of which a dose of 0.16 ml of a 0.12% solution of PES/100g. of body mass had been applied twice daily for periods of 28 and 90 d, respectively (5 d of application being followed by 2 d without treatment), showed erythema, loss of hair, slower increase in mass, increased heart rate, smaller body mass/kidney mass and body mass/spleen mass ratios, increases in leucocytes, ASAT, ALAT, LDH I and LDH III. In the 28-d test, slight inflammatory symptoms of the liver, kidneys and heart were observed in the experimental animals. These symptoms were more marked in the 90-d test, granulomata in the livers being particularly striking. A pneumonia of moderate to very marked degree is suggestive of the activation of a clinically latent PES infect whereby the inflammatory alterations in the kidneys might be explained by the formation of metastases.

[Death by burning in open spaces. Death caused by suicide or homicide?]. / Verbrennen im Freien. Tod durch eigene oder fremde Hand?

The authors report on four cases of suicidal fire deaths in the open air. In three cases the proper cause of death was severe burning and in one case deep cuts of the neck. In all these events the concentrations of CO-Hb were < 30%. Kerosene was indicated in lipophile tissue or lung in two cases. There was no evidence of incapacitation preceding the exposition to fire. The autopsy findings and the scene allowed a reconstruction of the course of events. All victims had motives of suicide. The authors conclude that close cooperation between police, fire experts and forensic medicine is necessary to permit a correct classification of the mode of death in such cases.

[Lodged bullet or bullet penetration? Re-entry of a projectile and pseudo-shot]. / Steckschuss oder Durchschuss? Reentry eines Projektils bzw. Pseudoausschuss.

In an extended suicide an 11-year-old boy was killed by two shots into the back. In spite of corresponding entry and exit points one of the projectiles was found inside the body. By laying open the respective bullet track, examination of the deformations of the bullet, on which a total of three ricochet points were identified, and a second visit to the scene both the order in which the shots were fired and the reason why one of the projectiles was lodged inside the body, although there was an exit point, could be clarified: On firing the second shot the victim had been lying on the wooden threshold of a door, from which the projectile ricochetted. The terms "reentry" and "pseudo exit point" are discussed. The retention of the bullet in the depth of an alleged exit wound emphasizes the importance of post-mortal X-ray examinations.

[Methods of suicide in an autopsy sample of the Institute of Forensic Medicine of the Hannover Medical School]. / Suizidmethoden im Sektionsgut des Instituts für Rechtsmedizin der Medizinischen Hochschule Hannover.

Between 1978 and 1987 513 cases of suicide were examined at the Institute of Legal Medicine of the Medical School of Hannover (337 males (65.7%) and 176 females (34.3%). The greatest share of the suicides was found in the age group 18 to 30. 42.1% of the cases showed positive alcohol concentrations with men accounting for a relatively higher share. The most frequently used methods for committing suicide were intoxications (28.1%), hanging (25.3%), firearms (17.2%), falling from great height (9.7%) and drowning (7.6%). The incidence in terms of sex showed marked differences in distribution, however. Women mostly used the following methods for committing suicide: Intoxication (37.4%), falling (17.6%) and hanging (17%). With men we found the following order: Hanging (29.7%), firearms (24.3%) and intoxications (23.1%). Compared with other institutes of legal medicine the five most frequent suicide methods showed similar distributions, but with a higher rate of intoxications. On the other hand there were distinct differences as to the relative frequency of the individual suicide methods in the total population and the respective number of autopsies performed. Especially in cases of gunshot wounds the number of autopsies performed to rule out homicide was higher. Of 2390 case of suicide registered in Greater Hannover an autopsy was ordered by the court in only 6.7%. According to our experience the autopsy rate seems too low, because homicide in the form of pretended suicide is not too rare.

Coordination processes in a human motoneuronal pool.

Using two leads of a multielectrode the EMG from biceps brachii muscle in man was recorded. The test-persons were ordered to produce a sustained isometric flexion force in the elbow joint which they could control optically. In the range of about 3-5% of maximum force it was possible to identify 2-5 active motor units under this condition. Cross interval histograms were calculated showing two types of coordination between two simultaneously active motor units: 1st, periods of relative phase-coordination in different extent. This means that cross-intervals are fluctuating in a small range for short time periods. An arbitrary subdivision of the fluctuation ranges and the time periods into different classes shows that about 20-35% of the total of the cross-intervals are coordinated by relative phase dependence. In these cases the ratio of the mean discharge rates is 1:1 approximately. 2nd, another type of relationship -f the motor units active at the same time we have called "frequency coordination". This means that the fluctuations of cross-intervals around the mean discharge rate ratio are smaller than the fluctuations of the discharges of both single units around their own mean value. In these cases, which are more frequent than phase-coordination (up to 50%), the ratios of the mean discharge rates are 1:1,2 and more.

[Studies of tryptophan metabolism in cancer of the urinary bladder]. / Tryptophanstoffwechseluntersuchungen beim Harnblasenkarzinom.

In 100 patients suffering from urinary bladder cancer (pTA-4, Nx, M0-1, G0-3) we created an oral tryptophan load administering 5 g of L-type tryptophan. Thereafter the amount of both xanthurenic acid and kynurenin was determined quantitatively in the 24-hour urine. 16 patients revealed pathological test results and excretion pattern of tryptophan metabolites via kynurenin were similar to vitamin B6-dependent xanthurenic aciduria both in its homocygotic and heterocygotic pattern. It has not been possible to prove a direct correlation between xanthurenic aciduria and urinary bladder cancer. However, xanthurenic aciduria may be of significance as a risk factor in the etiopathogenesis of urinary bladder cancer.

[Occurrence of phenylalanine hydroxylase in the human kidney]. / Zum Vorkommen der Phenylalaninhydroxylase in menschlicher Niere.

Phenylalanine hydroxylase activity, determined by fluorimetric procedure in human kidney (cortex) of 17 patients, who had a kidney operation, was on the average 4.7 nkat tyr/g protein (25 degrees C), which is 28% in comparison to the enzyme activity in human liver. This is in good accordance with the results of AYLING et al. who investigated 15 human kidneys. They found by the spectrophotometric method 22% of the liver enzyme activity. A nonspecific hydroxylation could be excluded by tests with the inhibitors p-Cl-phenylalanine, 3-I-tyrosine and 6-F-tryptophan.

On the brain barrier system function and changes of cerebrospinal fluid concentrations of phenylalanine and tyrosine in human phenylketonuria.

In 6 patients with classic phenylketonuria (PKU) the plasma and cerebrospinal fluid (CSF) concentrations of phenylalanine and tyrosine were measured fluorimetrically. The results of the PKU group were compared with data obtained from 17 children without abnormal CSF parameters and free of metabolic or central nervous disorders, in whom a diagnostic lumbal puncture has been performed. The PKU patients showed statistically significant differences in comparison with the controls: plasma and CSF phenylalanine contents were markedly higher (on the average 6.4 and 4.6 times, respectively) in PKU patients. Plasma tyrosine was 1.8 times lower, but CSF tyrosine was about 2.2 times higher in comparison to the controls. In general, the plasma CSF-ratio ( PLR ) of phenylalanine did not change in PKU and could be found in the same range as in the normal controls. In contrast to this, the PLR of tyrosine was found to be significantly lower in PKU patients. The results are discussed with respect to an altered function of the brain barrier systems for the amino acid transport in PKU, and that increased CSF tyrosine contents in PKU may rather reflect disturbances of the intracellular metabolism of the brain cells than changes of the amino acid transport through the brain barrier produced by hyperphenylalaninemia.

[Distribution of cystinuria subtypes in the Democratic Republic of Germany]. / Zur Verteilung der Subtypen der Zystinurie in der DDR.

The classic cystinuria is a hereditary disorder characterized by a defective transport of cystine and the dibasic amino acids arginine, lysine and ornithine in the epithelial cells of the renale tubule and the gastrointestinal tract. The excretion patterns of cystine and the dibasic amino acids in 24-hour urine samples from heterozygotes can be used to the differentiation between the genetic subtypes. 120 probands in the age range from 3 to 70 years from 22 families with cystinuria were investigated by thin-layer chromatography and by ion exchange chromatography. In patients with cystinuria the genotype I-I has a frequency of 50%. These results and the distribution of the other subtypes are in accordance with published data. From 98 persons investigated in 22 families with cystinuria 14 run the risk to form cystine stones. Therefore, the knowledge of the subtypes is relevant for practice.

Increased concentrations of tyrosine and phenylalanine in the cerebrospinal fluid as a possible reflection of related changes of the brain tissue in newborns with intra-uterine growth retardation.

Plasma and cerebrospinal fluid concentrations of tyrosine and phenylalanine were measured fluorometrically in human term neonates appropriate for gestational age and in neonates small for gestational age with severe intra-uterine growth retardation of Type II. The intra-uterine retarded newborns showed significant differences of both plasma and cerebrospinal fluid tyrosine levels as compared with the non-retarded newborns: the mean plasma and cerebrospinal fluid tyrosine were determined to be 2.0 and 2.5 times, respectively, higher in the retarded group. The mean cerebrospinal fluid phenylalanine content was also increased in these newborns. The findings may reflect cellular disturbances of the tyrosine metabolization in the developing brain as it can also be found in experimental intra-uterine growth retarded animals.