Propofol inhibits lidocaine metabolism in human and rat liver microsomes

Purpose.When two drugs are metabolized by similar P450 isoforms, one drug inhibits the metabolism of the other when both the present. The metabolism of lidocaine and propofol can be mediated by similar P450 isoforms. Therefore, we investigated the relationship in the metabolism between lidocaine and propofol in both rat and human liver microsomal P450 (CYP) systems in vitro. Methods.(1) Propofol, 4µg·ml^–1, as the substrate and lidocaine (between 0.5 and 8µg·ml^–1) and (2) lidocaine, 4.7µg·ml^–1, as the substrate and propofol (between 0.5 and 40µg·ml^–1) were reacted separately with human and rat microsomes. The concentrations of lidocaine, its major metabolite (monoethylglycinexylidide, MEGX) and propofol were measured using high-pressure liquid chromatography. The metabolism of lidocaine was presented as a reaction activity (MEGX/lidocaine). Results.The dose-dependent inhibitory effects of propofol on lidocaine metabolism were observed in both the human and rat groups. The IC50 (the concentration producing 50% maximal inhibition) of propofol was 5.0µg·ml^–1 and 0.70µg·ml^–1 in the human and the rat groups, respectively. The propofol concentration of 5.0µg·ml^–1 is within the range of clinical doses for humans. On the other hand, lidocaine did not change propofol metabolism. Conclusion.Propofol possesses a dose-dependent inhibitory effect on the metabolism of lidocaine in both human and rat CYP systems in vitro.     

Effect of propofol on ropivacaine metabolism in human liver microsomes

A combination of the general anesthestic propofol and epidural anesthesia with a local anesthetic is widely used. The metabolism of ropivacaine and that of lidocaine are mediated by similar P450 isoforms. Previously, propofol was found to inhibit the metabolism of lidocaine in vitro. Here we investigated whether propofol inhibits the metabolism of ropivacaine using human liver microsomes in vitro. Ropivacaine (6.0 μmol·l⁻¹) as the substrate and propofol (1–100 μmol·l⁻¹) were reacted together using human microsomes. The concentrations of ropivacaine and its major metabolite 2′,6′-pipecoloxylidide (PPX) were measured using high-performance liquid chromatography. The metabolic activity of ropivacaine was reflected in the production of PPX. The inhibitory effects of propofol on ropivacaine metabolism were observed to be dose-dependent. The IC₅₀ of propofol was 34.9 μmol·l⁻¹. Propofol shows a competitive inhibitory effect on the metabolism of ropivacaine (i.e., PPX production mediated by CYP3A4) in human CYP systems in vitro.     

Biochemical Intestinal Parameters in Germ‐free Minipigs and Rats and in Ex‐germ‐free Minipigs and Rats Monoassociated with Escherichia coli

Intestinal contents of newborn and young germ‐free minipigs and germ‐free rats were investigated for the following biochemical parameters – conversion of cholesterol to coprostanol, degradation of β‐aspartylglycine, level of tryptic activity, formation of urobilinogen and the profile of short‐chain fatty acids. Additionally, germ‐free minipigs and germ‐free rats were monoassociated with non‐pathogenic strains of Escherichia coli and were investigated for the same biochemical parameters. The conversion of cholesterol to coprostanol, degradation of β‐aspartylglycine, tryptic activity and the short‐chain fatty acid profile were similar to those found in previous studies in germ‐free animals. Slightly higher amounts of urobilinogen than in the other species investigated so far were found in samples from germ‐free and monoassociated minipigs. Except for the total amount of short‐chain fatty acids in rats, monoassociation with E. coli did not alter any of the parameters either in the minipigs or in the rats.     

Is the metabolism of alfentanil subject to debrisoquine polymorphism? A study using human liver microsomes

The present study was designed to investigate whether the metabolism of the opiate analgesic alfentanil in humans is subject to the debrisoquine 4-hydroxylation polymorphism. The role of a specific cytochrome P-450 form, debrisoquine 4-hydroxylase, in the metabolism of alfentanil was investigated by competitive inhibition experiments over the concentration range 4-100 microM. Alfentanil was incubated with human liver microsomes in the presence of an NADPH-generating system. Alfentanil and its major metabolites were quantified in the incubates by reversed phase high-performance liquid chromatography (HPLC). Alfentanil was rapidly metabolized, yielding noralfentanil as the main metabolite. Kinetically, alfentanil metabolism occurred monophasically and the kinetic parameters were 22.8 microM for Km app and 3.86 nmol alfentanil metabolized min-1.mg protein-1 for Vm app. Debrisoquine was a weak, noncompetitive inhibitor of alfentanil metabolism and of the formation of its major metabolites, with Ki values between 2.00 and 3.21 mM. It can be concluded that alfentanil is not metabolized in vitro by the human cytochrome P-450 form involved in debrisoquine 4-hydroxylation; therefore, the in vivo disposition of the drug is most likely not affected by deficiency of this enzyme.     

Minipigs and Potbellied Pigs as Pets in the Veterinary Practice – A Retrospective Study

Minipigs have become popular pets in recent years. Therefore, an increasing number of veterinarians are being challenged by specific problems of these animals. This retrospective study gives an overview on the diagnoses and therapeutic interventions of the patients submitted to the clinic for swine at the University of Veterinary Medicine Vienna during the last 6 years (n = 48). Most frequently, colic symptoms of the gastro‐intestinal tract (n = 12) and orthopaedic locomotion disorders (n = 10), mainly due to accidents or long claws, could be observed, followed by urogenital tract and skin disorders (n = 4 each). Therapeutic interventions are discussed with regard to medical aspects as well as statutory provisions.     

How to Increase the Motility of Spermatozoa from the Epididymis of Bulls and Alloplastic Spermatoceles in Minipigs

Summary: The motility of spermatozoa from the head and tail of the epididymis in bulls was studied. Qualitatively and quantitatively, the motility of spermatozoa from the cauda was distinctly better than that from the caput. It was possible to achieve a highly significant increase in the motility of epididymal spermatozoa from the caput as well as the cauda area using caffeine or a caffeine-kallikrein mixture. Above all, motility stimulants improved the local motility of the epididymal spermatozoa as compared to twitching and progressive motility. The motility of caudal spermatozoa was increased by 100%, corresponding to local movement of 59% of the total number of sperm cells. It was possible to demonstrate an increase in the almost totally absent motility of the caput spermatozoa to 27% local motility. Application of kallikrein without addition of kininogens led tø no significant change in spermatozoa motility. By the addition of caffeine, it was possible to increase the motility of minipig epididymal spermatozoa taken by puncture from alloplastic spermatoceles significantly. In 23 aspirates, a prompt increase in the percentage of locally motile “spermatocele spermatozoa” from 12% to 23.5% was observed. Zusammenfassung: Motilitätssteigerung der Spermatozoen aus dem Nebenhoden des Bullen und aus der alloplastischen Spermatozele des Minischweines Die Motilität der Spermatozoen aus Nebenhodenkopf und Nebenhodenschwanz des Bullen wurde untersucht. Die Beweglichkeit der Caudaspermatozoen war qualitativ und quantitativ deutlich höher als die der Caputspermatozoen. Durch Coffein sowie durch ein Coffein-Kallikrein-Gemisch konnte die Motilität der Nebenhoden-spermatozoen für den Kopfbereich sowie für den Schwanzbereich hochsignifikant gesteigert werden. Vor allem die Ortsbewegung der Nebenhodenspermatozoen wurden im Vergleich zur Zitter- und Progressivbewegung durch motilitätsstimulierende Substanzen verbessert. Für Caudaspermatozoen konnte eine Motilitätssteigerung von 100% erzielt werden, dies entsprach 59% Ortsbewegung der Gesamtspermatozoenzahl. Eine Steigerung der nahezu fehlenden Motilität von Caputspermatozoen auf 27% Ortsbewegung ließ sich nachweisen. Kallikrein ohne zusätzliche Gabe von Kininogen führte zu keiner signifikanten Veränderung der Spermienmotilität. Nebenhodenkopfspermien des Miniaturebers, die durch Punktion alloplastischer Spermatocelen gewonnen wurden, konnten durch Zugabe von Coffein signifikant verbessert werden. Eine prompte Steigerung des Anteils ortsbeweglicher ?Spermatocele-Spermien” von 12% auf 23,5% ließ sich bei der Untersuchung von 23 Aspiraten nachweisen.     

Fatty acids,calcium and bone metabolism

Epidemiological, clinical and experimental evidence suggests that fatty acids may have an effect (due to their chemical structure) on calcium metabolism in animals and man. Fatty acid deficiency in animals can lead to a loss of bone calcium and matrix, resulting in marked bone demineralization, and treatment with a mixture of omega-3 and omega-6 polyunsaturated fatty acids can induce significant reduction in some biochemical markers of bone reabsorption. A relationship, between phospholipid fatty acid content, calcium-regulating hormones and intestinal, renal, and bone calcium metabolism alterations, has been reported in patients with renal stones and hypercalciuria. Recent studies have shown specific effects of fatty acids on the gene expression of some bone cytokines. Fatty acids might be involved in calcium metabolism influencing cellular calcium ion transport directly, as second messengers, or generating, through the cyclooxygenase pathway, potential biological mediators which have complex effects on bone remodeling. Experimental and clinical documentation of the specific and indirect effects of fatty acids on calcium and bone metabolism could open up new and interesting clinical prospects.     

Monitoring intracranial pressure, perfusion and metabolism

Cerebral monitoring is important for management of severe headinjury. It is also used in subarachnoid haemorrhage, stroke,intracerebral haematoma, meningitis, encephalopathies, hepaticfailure, after neurosurgery and in patients undergoing carotidartery surgery. This article provides an overview of cerebralmonitoring techniques available in clinical practice.     

Use of the continuous glucose monitoring system in Goettingen Minipigs, with a special focus on the evaluation of insulin-dependent diabetes

OBJECTIVES: Adult pig islet isolation has greatly improved in the past few years. Islet grafts may now be tested in large animals. Continuous Glucose Monitoring System (CGMS) was applied to diabetic Goettingen Minipigs (GMP) to improve the management of hyperglycemia and hypoglycemia and their welfare before transplantation. METHODS: GMP (25-35 kg) received a minipig diet once daily. Diabetes was induced by streptozotocin (STZ; 150 mg/kg intravenous [IV]; n = 5) or by surgical pancreatectomy (PGMP; n = 3). Interstitial glucose concentration (IGC) was monitored continuously with an implanted sensor; CGMS was calibrated using conventional blood glucose tests 3-4 times per day; CGMS data were fed into the monitor memory and analyzed using CGMS software. RESULTS: Glucose sensors were handled accurately. Diabetes occurred 2-3 days after STZ or immediately after pancreatectomy with basal C-peptide secretion of <0.4 ng/mL (measured using intravenous glucose tolerance test) and prompt loss of body weight. Insulin substitution was necessary to keep the GMP in good condition for up to 5-6 months, with stable body weight and normal behavior. Some GMP became hypoglycemic, which was only documented by CGMS, but not by conventional glucose assays. Tight glucose control and substitution of exocrine enzymes (Creon 25,000 E/d) reduced morbidity of the PGMP, which was then comparable with that of STZ-GMP. CONCLUSIONS: The CGMS, developed for humans, is equally suitable for the 2 GMP diabetes models. Close-meshed glucose monitoring and insulin treatment improved the general condition of the diabetic GMP, ie, the islet graft recipients, and will thus greatly add to posttransplantation success.