Validation of microdialysis sampling for oral availability studies by means of a new ganciclovir prodrug

Microdialysis sampling was validated for oral availability studies using ganciclovir (9-(1, 3-dihydroxy-2-propoxymethyl) guanine) and a ganciclovir prodrug (9-(1-L-valyloxy-3-octadecanoyloxy-prop-2-oxymethyl) guanine). Three different techniques were used in the study; microdialysis, blood and urinesampling. The oral uptake (11+/-2%) and the urinary recovery (106+/-5%) were determined. Animals given ganciclovir subcutaneously were subject either to microdialysis and blood sampling or to microdialysis alone. There was no significant difference between microdialysis and blood sampling in terms of blood concentration data, CL, Vd, half-life or AUC by means of Student's t-test. The oral bioavailability of the prodrug was 40+/-7% estimated from microdialysis sampling data and 48+/-4% estimated from urine sampling data. It is concluded that microdialysis is a valid method to use in pharmacokinetic studies of oral availability as well as for basic pharmacokinetic parameter estimation.     

An outbreak of Serratia marcescens bacteremia after general anesthesia.

OBJECTIVE: To investigate an outbreak of Serratia marcescens bacteremia among patients after general anesthesia. DESIGN: A case-control study. SETTING: A 304-bed, pediatric teaching hospital. PATIENTS: Twenty-three pediatric patients who developed S. marcescens bacteremia within 2 weeks after general anesthesia between June 15 and September 22, 1999, were compared with 46 age-matched control-patients who had undergone procedures on the same clinical services of the hospital during the same period. RESULTS: Cases were distributed over a wide range of surgical services and were not correlated with exposure to any of the surgical, anesthesia, or nursing staff. Case-patients were significantly more likely than control-patients to have received cefazolin (odds ratio [OR], 11.1; 90% confidence interval [CI90], 1.9 to 24.3) or to have had perioperative placement of a central vascular catheter (OR, 4.2; CI90, 1.2 to 18.8). The timing of the procedures of patients who subsequently developed S. marcescens bacteremia was significantly associated with the shifts of one or more of five operating room technicians (OR, 2.9 to 6.8) who were responsible for preparing intravenous fluids used both to reconstitute perioperatively administered antibiotics and to prime central vascular catheter assemblies. CONCLUSIONS: Our findings are consistent with a pattern of intermittent contamination due to periodic breaches in sterile technique, rather than a point-source of contamination. The unique challenges that such a procedural breakdown presents to an epidemiologic investigation are discussed. This outbreak stresses the importance of providing comprehensive training in antisepsis when multifunctional personnel are incorporated into an operating room work environment.     

Uncovering tacit caring knowledge

Abstract The aim of this article is to present re‐enactment interviewing and to propose that it can be used to reveal tacit caring knowledge. This approach generates knowledge not readily attainable by other research methods, which we demonstrate by analysing the epistemological and methodological underpinnings of re‐enactment interviewing. We also give examples from a study where re‐enactment was used. As tacit knowledge is often characteristic of care, re‐enactment interviewing has the potential to engage the informant in a holistic mode and thereby reveal wisdom of the body. When the care provider recalls an event, the details are articulated, which contributes to in‐depth data, which subsequently serves as a basis for trustworthy analysis.     

COMT inhibition with tolcapone does not affect carbidopa pharmacokinetics in parkinsonian patients in levodopa/carbidopa (Sinemet®)

AIMS: Tolcapone is a novel catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to levodopa/carbidopa or levodopa/benserazide therapy to improve treatment of Parkinson's disease. The aim of the current study was to investigate the potential effect of tolcapone on the pharmacokinetics of carbidopa. METHODS: This was an open-label study in 12 parkinsonian patients receiving optimal levodopa/carbidopa therapy and tolcapone 200 mg three times daily for 6 weeks. Blood samples were taken at baseline (i.e. before the first tolcapone intake) and after 1-2 weeks and 6 weeks so that carbidopa pharmacokinetics before and during tolcapone treatment could be assessed. RESULTS: No changes in any pharmacokinetic parameters of carbidopa were observed. The mean AUC(0,tau) and Cmax values at baseline were 0.39 microg ml-1 h and 0. 14 microg ml-1, respectively. During tolcapone treatment these values were on average 0.35 microg ml-1 h (AUC(0,tau), week 1-2), 0. 34 microg ml-1 h (AUC(0,tau), week 6 and 0.13 microg ml-1 (Cmax, weeks 1-2 and 6). tmax remained unchanged (approx. 2 h). CONCLUSIONS: These results indicate that tolcapone does not affect carbidopa elimination and that no interaction of any clinical relevance occurs between tolcapone and carbidopa.     

Is there a link between infant botulism and sudden infant death? Bacteriological results obtained in Central Germany

Despite the fact that botulism was described in Germany for the first time by Kerner in 1820, the disease is almost forgotten in this country. Only about 10-20 cases of classical botulism (intoxication) are recorded every year, including 1-2 cases of clinical infant botulism. As we assumed a high incidence of botulism to be connected with cases of sudden infant death (SID), we undertook the research work presented here. From every case of unexpected infant death up to 12 months of age, standardised specimens (blood, liver and intestine) were taken at autopsy. They were tested for the presence of botulinum neurotoxin (BoNT) and/or bacterial forms of Clostridium botulinum with subsequent BoNT neutralisation tests by the international standard mouse bioassay. Age, sex, pathological findings and season were recorded. Over a 5-year period, 75 samples including 57 SID cases were tested. Free toxin was found in nine and bacterial forms were detected in six samples. Toxin neutralisation revealed the definite presence of BoNT/BoNT producing bacteria (mainly type E), whereas another 11 toxin tests were inconclusive. According to international literature, these 15 cases are to be interpreted as infant botulism. Conclusion: the results show a remarkable incidence of infant botulism without any known previous medical history, partly hidden as sudden infant death. We propose to systematically search for botulism in connection with sudden infant death.     

Substantia nigra regulates action of antiepileptic drugs

The cholinergic agonist pilocarpine triggers sustained limbic seizures in rodents. Pilocarpine seizures were blocked by systemic administration of benzodiazepines, barbiturates, valproate and trimethadione, while diphenylhydantoin did not affect, and ethosuximide increased the susceptibility of rats to such seizures. This pattern of action antiepileptic drugs is characteristic for pilocarpine seizures and different from other rodent models of epilepsy. Although the anatomical substrates in the forebrain involved in the expression of anticonvulsant activity are unknown, the basal ganglia are believed to be essential for the motor expression of pilocarpine seizures. Bilateral microinjections into the substantia nigra, a major output station of the basal ganglia, of midazolam (ED₅₀ 38.5 nmol; range 29–52 nmol), phenobarbital (ED₅₀ 16 nmol; range 7–39 nmol) and trimethadione (ED₅₀ 30 nmol; range 16–56 nmol) protected rats against pilocarpine seizures (380 mg/kg i.p.). Diphenylhydantoin (up to 100 nmol) remained inactive, while ethosuximide (ED₅₀ 38 nmol; range 22–65.5 nmol) reduced the threshold for pilocarpine seizures, converting subconvulsant doses of pilocarpine (200 mg/kg i.p.) into convulsant ones. The profiles of action of antiepileptic drugs on pilocarpine seizures were similar following intranigral and systemic administration. These observations suggest that the substantia nigra may mediate some actions of antiepileptic drugs.