Disposition and metabolism of dipropyl disulphide in vivo in rat.

The metabolism of dipropyl disulphide (DPDS), a sulphur compound from onion, was investigated in vivo in the rat. A single dose (200 mg kg(-1)) was administered by gastric intubation and the time courses of DPDS and its metabolites were followed over 48 h by gas chromatography coupled with mass spectrometry in the stomach, intestine, liver, and blood. DPDS was detected in the stomach where it was transformed into propyl mercaptan, whereas the liver contained only traces of DPDS and none at all in the other examined organs. The metabolites methylpropyl sulphide, methylpropyl sulphoxide (MPSO), and methylpropyl sulphone (MPSO2) were sequentially formed in the liver. The route of elimination from the liver seemed to be mainly via the blood. The bile also participated in the excretory process, but only for MPSO2. The pharmacokinetic parameters were determined for all of the above compounds. Whereas the bioavailability of DPDS was very low (0.008 h mM), the areas under the curve were higher for the S-oxidized metabolites MPSO and MPSO2, i.e. 9.64 and 24.15 h mM, respectively. The half-lives for DPDS and its metabolites varied between 2.0 and 8.25 h, except for MPSO2, which had a half-life of 29.6 h. MPSO2 was the most abundant and persistent of these metabolites.

[Are there technological advances in minimally invasive surgery and who will pay them?]. / Gibt es technologische Fortschritte in der MIC und wer soll das bezahlen?

The successful development of minimally invasive surgery would have been inconceivable without continuous advances in medical technology. The users, i.e. the surgeons, however, only accepted innovations with a clear-cut positive impact on clinical care. Accordingly, the expected exponential rise in costs could be avoided. The imbalance in cost/benefit aspects between the deliverers of medical care on one hand, and the patients, the insurance companies and the employers on the other is critical. In addition, further innovations are to be expected. This will not be possible without increasing costs, but there are good reasons to assume that expenses will rise only moderately. Each modern society is able (and obliged) to afford a certain amount of medical progress in order to maintain a high level of medical care and economic strength.

Protective effects of garlic sulfur compounds against DNA damage induced by direct- and indirect-acting genotoxic agents in HepG2 cells.

The aim of this study was to assess the antigenotoxic activity of several garlic organosulfur compounds (OSC) in the human hepatoma cell line HepG2, using comet assay. The OSC selected were allicin (DADSO), diallyl sulfide (DAS), diallyl disulfide (DADS), S-allyl cysteine (SAC) and allyl mercaptan (AM). To explore their potential mechanisms of action, two approaches were performed: (i) a pre-treatment protocol which allowed study of the possible modulation of drug metabolism enzymes by OSC before treatment of the cells with the genotoxic agent; (ii) a co-treatment protocol by which the ability of OSC to scavenge direct-acting compounds was assessed. Preliminary studies showed that, over the concentration range tested (5-100 microM), the studied OSC neither affected cell viability nor induced DNA damage by themselves. In the pre-treatment protocol, aflatoxin B1 genotoxicity was significantly reduced by all the OSC tested except AM. DADS was the most efficient OSC in reducing benzo(a)pyrene genotoxicity. SAC and AM significantly decreased DNA breaks in HepG2 cells treated with dimethylnitrosamine. Additionally, all the OSC studied were shown to decrease the genotoxicity of the direct-acting compounds, hydrogen peroxide and methyl methanesulfonate. This study demonstrated that garlic OSC displayed antigenotoxic activity in human metabolically competent cells.

Analytical method for appreciation of garlic therapeutic potential and for validation of a new formulation.

The consumption of garlic reduces the risk of cardiovascular disease and cancer, S-allylcysteine sulfoxide (alliin), allicin (DATi), diallyl disulfide (DADS), S-allylcysteine (SAC) and several storage dipeptides are the organo-sulphur compounds (OSC) involved in the protective mechanism of garlic against cardiovascular disorders and carcinogenesis. Thus it is very interesting to quantify simultaneously all these compounds in different garlic powders obtained in several cultural conditions. The quantification of OSC by a new ion-pair HPLC method allowed showing the general sulphur-dependence positive effect of garlic on cardiovascular disorder and carcinogenesis and the variable specific activity of each implicated OSC. The screening of 11 garlic tablets proposed on the market showed the variability and particularly the differential instability of each OSC. From these results, a new garlic tablet was realised and each step was controlled by this method. This analytical method proved to be a very powerful tool for the understanding of the garlic protective mechanism against cancer and cardiovascular diseases and the development and quality control of garlic tablets.

[Patient safety in view of specialization, minimum quantity and regionalization]. / Patientensicherheit unter dem Gesichtspunkt von Spezialisierung, Mindestmengen und Zentrenbildung.

BACKGROUND: The introduction of a set of volume standards in Germany 2003 has lead to a discussion whether statutory volume thresholds as well as the enhancement of further regionalization would do more harm than good. The objective of this study is to evaluate the influence of specialization, volume standards and regionalization on patient safety. METHODOLOGY: According to study objectives patient safety was defined as "hospital mortality", "hospital morbidity", "long-term outcome" and "readmission rate". A MEDLINE analysis was performed using the following terms: "hospital", "volume", "outcome", "specialization", "regionalization", "readmission", "patient safety" and "review". In order to lower the high number of studies only journals published between 1999 and 2004 with high impact factors were used for evaluation. RESULTS: A vast majority of studies have been published in recent years finding significant higher probabilities for good outcome in high volume hospitals compared with low volume hospitals. However, the magnitude of the volume - outcome relation varies greatly among procedures and conditions, showing a strong and persistent relation for severe ill patients and high-risk procedures. Patient safety can also be influenced by surgeon volume and specialization. CONCLUSIONS: Specialization, volume standards and regionalization have shown to be effective in improving patient safety. Further studies are needed to estimate the potential benefits of this strategy to foster patient safety in German hospitals.

Post-initiation modulating effects of allyl sulfides in rat hepatocarcinogenesis.

Effects of administration of diallyl sulfide (DAS) and diallyl disulfide (DADS) on the promotion stage of hepatocarcinogenesis were investigated in rats using the Ito model. They were compared with those of phenobarbital (PB), a well-known liver promoter in rats. Initiation was induced by a single dose of N-nitrosodiethylamine (NDEA) and 3 weeks later, a partial hepatectomy was conducted. Two weeks after the NDEA injection, rats received either 0.05% allyl sulfides, PB or both in their diet for 8 weeks. Feeding with DAS increased the number of liver preneoplastic foci by 63% with respect to the untreated group. However, rats fed DAS showed a lower foci development than rats fed PB. The DADS group did not differ from control group for any of the measured morphometric parameters. Simultaneous administration of DADS with PB partially reduced the promotional activity of PB whereas DAS co-treatment did not modify PB properties. These findings confirm that DAS can act as a promoter in rat liver but exerts no co-promoting effect. Conversely, DADS was found to have promotion-inhibiting ability, suggesting that DADS has greater value than DAS as a chemopreventive agent.

Hepatic metabolism of diallyl disulphide in rat and man.

1. The metabolism of diallyl disulphide was investigated in vitro with rat and human liver cell subfractions and ex vivo with an isolated perfused rat liver. 2. Diallyl disulphide was oxidized to diallylthiosulphinate by rat liver microsomes with an apparent K(m) = 0.86 +/- 0.1 mM and an apparent V(max) = 0.47 +/- 0.12 nmol min(-1) mg(-1) protein (mean +/- SE). Both cytochrome P450 (CYP) and flavin-containing monooxygenases were involved, with CYP2B1/2 and CYP2E1 being the most active CYP enzymes. 3. In rat and man, microsomal oxidation of allylmethyl sulphide to allylmethyl sulphoxide and allylmethyl sulphone also occurred, although at a low rate. Diallyl disulphide was also metabolized to allylglutathione sulphide and allylmercaptan. In addition, diallylthiosulphinate reacted non-enzymatically with glutathione to form allylglutathione sulphide. 4. When an isolated rat liver was perfused with diallyl disulphide, the metabolites allyl mercaptan, allylmethyl sulphide, allylmethyl sulphoxide, allylmethyl sulphone and allylglutathione sulphide were detected primarily within the liver tissue, with only small amounts of metabolites found in the bile and perfusion medium. The pharmacokinetic parameters for diallyl disulphide were t(1/2) = 6.09 min; AUC(0- infinity ) = 4.77 min mmol l(-1); clearance = 34.22 ml min(-1). 5. A scheme for the metabolism of diallyl disulphide in rat and man is proposed.

[What is outcome quality?]. / Was ist Ergebnisqualität?

Modern scientific surgery is outcome-oriented, i.e., the success of surgical therapy is quantified and assessed, generally in clinical studies, according to certain criteria such as survival time or complication rates. The public and health policy makers have recently started demanding not only greater transparency in outcome quality assessment, but also that the results obtained be made available for comparisons about medical performance as a whole. Outcome quality would thus cease to be concerned with a limited range of therapy options and to interest merely doctors and surgeons and a small number of selected patients; it would then affect a number of very different hospitals with heterogeneous patient populations and attract the attention of various lobbies in the health sector. What is problematical, however, is that there is no single interpretation of what outcome quality in medicine is supposed to be. Consequently, assessments and comparisons of quality and performance are difficult and often erroneous. Comparisons of performance in surgery should only be done with selected and evaluated parameters of outcome quality and with a critical examination of how they can be implemented and published.

[Quality management and experiences with the "cancer center"]. / Qualitätsmanagement und Erfahrungen mit dem "Cancer Center".

BACKGROUND: The goal of quality management in oncology is to achieve the best possible therapeutic outcome. Improved diagnostic methods, more sophisticated therapies in various fields of specialisation and the increased implementation of multimodal therapies have led to considerable advances in the treatment of certain tumors in recent years. However, these advances depend on an interdisciplinary approach necessitating an increased division of labour. These in turn, because of the more complex organizational requirements within hospitals, make greater demands on quality management. METHODS: In October 1999 first steps were taken in the Klinikum rechts der Isar der TU München to organisationally integrate the various institutions involved in the treatment of patients with gastro-intestinal tumors. All the oncologic competence available was bundled in a Cancer Center thus creating the structural prerequisites for interdisciplinary quality management. A daily multidisciplinary Tumor Board, a computer-supported interdisciplinary information and communications system, an interdisciplinary Disease Management Team, an outpatients department and a study centre were all called into life. RESULTS: By the time the outpatients department went into service in November 2001 all the other structural innovations underlying interdisciplinary quality management had already been implemented. Since October 1999 2438 patients had been presented to the Tumor Board, 74% of them with primarily curative intent. CONCLUSIONS: The disease-oriented structure of the Cancer Center has proved worthwhile. The impact of the structure on the quality of processes and results, however, has yet to be evaluated.

[Necessary prerequisites for the function of an oncological competence center. Information technology, documentation of findings and telecommunication]. / Notwendige Voraussetzungen für die Funktion eines onkologischen Kompetenzzentrums. Infomationstechnologie, Befunddokumentation und Telekommunikation.

INTRODUCTION: The organisation of an interdisciplinary cancer center, especially the establishment of a daily tumorboard requires adequate hardware and intelligent software, which is not available in most hospitals and described here with concepts, realisation and first clinical results. MATERIALS AND METHODS: Based on a TCP/IP network and several inhomogeneous department subsystems we developed an intranet-based oncological documentation- and conference software (oncofile), which can be easily operated and administered in a web browser. Common digital media can be imported and the concept allows for paperless organisation of the daily tumor board. The expert decisions are documented online during tumor board runtime together with selected clinical images and the consensus of the decisionmakers. Local therapeutic guidelines as well as trial information can be accessed over the intranet, and interfaces for internet- and telecommunication are used for second opinion and integration of external expertise. RESULTS: Between 10/99 and 2/2002 3298 presentations of 2438 cases were made in the daily tumor board. 74% of the patients had a curative oncological treatment concept, and 24% of the patients received neoadjuvant treatment. 49% of the patients were scheduled for primary resection. Six patients can be effectively handled in a 30 minute tumorboard. CONCLUSION: The establishment of a daily tumorboard is possible by help of intranet-technology, a central database with web clients and moderate hardware investments. The composition of the patient cohort as well as all decisions ever made to a particular patient are transparent at all times. Prospective quality control studies are under way.

[Clinic communication and disease-oriented centers]. / Klinikkommunikation und krankheitsorientierte Zentren.

German hospitals and surgical clinics/departments are facing far-reaching changes. One triggering factor is the imminent reorganization of hospital financing to a system of compensation, which is universally based on diagnosis-related groups (DRGs) and entails a market-economy orientation in the hospital sector. Digital technologies, which facilitate making the necessary adjustments to clinic structures to meet forthcoming challenges, represent another element. The "digital transformation" of the hospital of the future takes place on three levels. The restructuring of the surgical realm runs rather a traditional course by increasing use of information technology, mostly to optimize documentation and existing procedures or to reduce costs. The second sphere reaches substantially further, encompassing reorganization of disease-oriented cooperation between the different medical specialties and enabling the establishment of suitably structured disease-oriented medical centers. This is followed by the third phase, which involves networking clinics or medical centers with private practitioners, aftercare and rehabilitation services, and other disease-oriented care providers.

In vivo metabolism of diallyl disulphide in the rat: identification of two new metabolites.

1. Diallyl disulphide (DADS), a compound formed from the organosulphur compounds present in garlic, is known for its anticarcinogenic effects in animal models. 2. The aim was to identify and analyse the metabolites produced in vivo after a single oral administration of 200 mg kg(-1) DADS to rats. The organic sulphur metabolites present in the stomach, liver, plasma and urine were measured by gas chromatography coupled with mass spectrometry over 15 days. 3. Data indicate that DADS is absorbed and transformed into allyl mercaptan, allyl methyl sulphide, allyl methyl sulphoxide (AMSO) and allyl methyl sulphone (AMSO(2)), which are detected throughout the excretion period. Overall, the highest amounts of metabolites were measured 48-72h after the DADS administration. AMSO(2) is the most abundant and persistent of these compounds. The levels of all the sulphur compounds rapidly decline within the first week after administration and disappear during the second week. Only AMSO and AMSO(2) are significantly excreted in urine. 4. These potential metabolites are thought to be active in the target tissues. Our data warrant further studies to check this hypothesis.