背驮式原位肝移植2例

目的 总结背驮式原位肝移植治疗终末期肝病的临床经验。方法 回顾性分析2例肝炎后肝硬变患行背驮式原位肝移植手术治疗的临床资料。结果 死亡1例，存活1例。术后并发症包括腹腔内出血1例，肝后下腔静脉扭曲狭窄1例，急性排斥反应1例，肺部感染、呼吸功能衰竭1例，均给予相应的治疗。结论 肝移植手术是终末期肝病的有效治疗手段。术后应积极预防各种并发症的发生，了解各种并发症的发生时间和症状有助于早期诊断，并采取各项积极正确的治疗措施。     

改良双套管法大鼠原位肝移植术

目的制作改良双套管法大鼠原位肝移植模型。方法在原二袖套法的基础上,于受体门静脉和肝下下腔静脉吻合前放出部分高凝血液,而肝上下腔静脉的吻合是供肝膈肌环与受者肝上下腔静脉血管之间进行（降落伞式吻合）,胆道处理的改进和受体肝脏切除时排出肝脏内血液保证受体的有效血容量。结果改良双套管法吻合效果确实可靠,手术成功率达95％,动物的周存活率为97％。结论该模型稳定可靠,可用于大鼠肝移植方面的研究。     

Treatment of hepatitis C in solid organ transplantation

Hepatitis C virus (HCV) infection is highly prevalent worldwide, and results in significant morbidity and mortality. HCV frequently infects haemodialysis patients and appears to impact on long-term survival of kidney transplant recipients. Therefore, treatment is recommended for kidney transplant candidates before transplantation and should be avoided following transplantation because of a high risk of allograft rejection. HCV infection does not appear to influence survival in cardiac transplant recipients and cardiac transplant recipients should also not be treated. In general, HCV-infected patients with cirrhosis are not considered as candidates for either kidney or cardiac transplantation given their risk of decompensation. HCV is the most common indication for liver transplantation and re-infection with varying degrees of liver injury is universal. Survival after liver transplantation is reduced among HCV-infected patients when compared with uninfected controls. Therefore, treatment using interferon and ribavirin is advocated; however, such therapy is frequently limited by adverse effects. Thus, improved antiviral treatment modalities are eagerly awaited in the transplant setting.     

改进小体积肝移植供肝大鼠模型建立方法的实验研究

目的探讨改进切肝技术,以建立更可靠的小体积肝移植供肝大鼠模型。方法以Kamada的“二袖套法”为基础,建立30％小体积肝移植中叶供肝大鼠模型。实验分两组：Ⅰ组（28只）,常规方法切肝,以中叶作供肝;Ⅱ组（36只）,改进为左叶和右叶的切肝方法,余方法步骤同Ⅰ组。观察两组手术并发症和7d生存率。结果Ⅱ组肝后下腔静脉狭窄的发生率明显低于Ⅰ组（P〈0．05）,其他并发症发生率两组间无明显差异（P〉0．05）。术后7d生存率Ⅱ组（60％,21／36）高于Ⅰ组（33％,9／28）,但差异未显示有统计学意义（Χ^2=0．272,P〉0．05）。结论采用中叶供肝、改进切肝技术,可以建立更稳定可靠的部分体积肝移植供肝大鼠模型。     

Cell-based therapy for liver diseases

Although liver transplantation has become standard therapy in the treatment of patients with liver failure, several problems should be considered in the management of these patients. Other approaches have been proposed, in particular cellular-based procedures. Isolated hepatocytes may be used instead of whole organ transplantation or integrated within the bioartificial devices, in order to replace the missing synthetic and metabolic liver functions. Moreover patient's own hepatocytes may be ex vivo genetically modified to provide the function of a mutant gene. However, new cell sources alternative to adult hepatocytes are actually under investigation, on the basis of recent advances in the field of liver repopulation. Xenogenic primary cells, human hepatoma cells, immortalized hepatocytes and stem cells have been testing in several experiments, even if up to now none of them represent a "gold-standard" for cell-based treatment of liver diseases. In the next future, it is possible that different clinical situations will require different therapeutic approaches, that will be finally defined from the concomitant advances in the development of artificial devices and liver cell biology.     

New management options for end-stage chronic liver disease and acute liver failure: potential for pediatric patients

The management of children with end-stage chronic liver disease and acute liver failure mandates a multidisciplinary approach and intense monitoring. In recent years, considerable progress has been made in developing specific and supportive medical measures, but studies and publications have mainly concerned adult patients. Therapeutic approaches to complications of end-stage chronic liver disease and acute liver failure (e.g. refractory ascites, hepatorenal syndrome, encephalopathy, and cerebral edema) that may be applied to children are reviewed in this article.Mild-to-moderate ascites should be managed by modest salt restriction and oral diuretic therapy in the first instance. Large volume paracentesis associated with colloid volume expansion and diuretic therapy may be effective for acute relief. Treatment of hepatorenal syndrome type 1 with vasopressin analogs (terlipressin) is recommended prior to liver transplantation in order to improve renal function. Prevention and treatment of chronic hepatic encephalopathy are directed primarily at controlling the events that may precipitate hepatic encephalopathy and at reducing ammonia generation and increasing its detoxification or removal. In addition to reduction of gut ammonia production using non-absorbable disaccharides such as lactulose and/or antibacterials such as neomycin, sodium benzoate may be used on a long-term basis to prevent, stabilize, or improve hepatic encephalopathy. The management of hepatic encephalopathy in acute liver failure is considerably more unsatisfactory; treatment is aimed at preventing brain edema and intracranial hypertension. Extracorporeal liver support devices are now used commonly in critically ill children with acute renal failure, advanced hepatic encephalopathy, cerebral edema, intracranial hypertension, and severe coagulopathy. Continuous renal replacement therapy could potentially help support patients until liver transplantation is performed or liver regeneration occurs. The Molecular Adsorbent Recirculating System (MARS or albumin dialysis) is the liver support system most frequently used worldwide in adults and appears to offer distinct advantages over hepatocyte-based systems.There are no specific medical therapies or devices that can correct all of the functions of the liver. Apart from a few metabolic diseases presenting with severe liver dysfunction for which specific medical therapies may preclude the need for liver transplantation, liver transplantation still remains the only definitive therapy in most instances of end-stage chronic liver disease and acute liver failure. Future research should focus on gaining a better understanding of the mechanisms responsible for liver cell death and liver regeneration, as well as developments in hepatocyte transplantation and liver-directed gene therapy.     

Budd-Chiari综合征中下腔静脉阻塞膜与肝右静脉的位置关系研究

目的分析下腔静脉阻塞膜与肝右静脉的位置关系,探讨Budd-Chiari综合征（BCS）可能的病因学。方法 35例下腔静脉IVC膜性阻塞性病变患者,DSA观察下腔静脉CIVC阻塞膜与肝静脉的位置关系。结果膜位于肝右静脉以上者32例,肝右静脉以下者3例。膜位于肝右静脉与肝左、中静脉之间者3例,位于三支HV以上者4例。结论某些低毒性物质的作用和IVC壁的损伤可能为BCS发病的始动因素。     

Biowaiver Monograph for Immediate-Release Dosage Forms: Levamisole Hydrochloride

This work describes the potential applicability of the BCS-based Biowaiver to oral solid dosage forms containing Levamisole hydrochloride, an anthelmintic drug on the WHO List of Essential Medicines. Solubility and permeability data of levamisole hydrochloride were searched in the literature and/or measured experimentally. Levamisole hydrochloride is a highly soluble drug, but there is no clear evidence of high permeability in humans, indicating that it should provisionally be assigned to BCS class III. The biowaiver procedure would thus be applicable for solid oral dosage forms containing levamisole hydrochloride as the only active ingredient. Due to the lack of data in the literature regarding excipient effects on the bioequivalence of products containing levamisole, it is currently recommended that the products comply with the ICH and WHO guidelines: the test formulation should have the same qualitative composition as the comparator, contain very similar quantities of those excipients, and be very rapidly dissolving at pH 1.2, 4.5, and 6.8. However, for certain well-studied excipients, there appears to be opportunity for additional regulatory relief in future versions of the ICH BCS Guidance M9, such as not requiring that the quantities of these common excipients in the test and comparator be the same.     

Drinking behavior and motivation for treatment among alcohol-dependent liver transplant candidates

Alcohol misuse is the second most common indication for liver transplantation in the United States. Our post-transplant alcoholism treatment trial suggested that current interventions might not be transferable to liver transplantees. We sought to identify differences between patients awaiting liver transplantation and alcoholics entering treatment without severe liver disease. Thirty transplant patients were compared to thirty naltrexone study patients on medical status, alcohol and drug use, alcohol craving, motivation for treatment, psychiatric symptoms, and psychosocial problems. Lifetime alcohol consumption was greater for transplant patients compared to naltrexone patients. In contrast to the naltrexone group, transplant patients denied craving for alcohol and showed little motivation for alcoholism treatment. Groups did not differ on other psychosocial measures. Liver transplant patients differ from patients in alcoholism treatment trials on measures of alcohol consumption, alcohol craving and motivation for treatment. Alcoholism interventions should accommodate their medical condition and boost motivation for continued abstinence.     

The Combination of GIS and Biphasic to Better Predict In Vivo Dissolution of BCS Class IIb Drugs,Ketoconazole and Raloxifene

The formulation developments and the in vivo assessment of Biopharmaceutical Classification System (BCS) class II drugs are challenging due to their low solubility and high permeability in the human gastrointestinal (GI) tract. Since the GI environment influences the drug dissolution of BCS class II drugs, the human GI characteristics should be incorporated into the in vitro dissolution system to predict bioperformance of BCS class II drugs. An absorptive compartment may be important in dissolution apparatus for BCS class II drugs, especially for bases (BCS IIb) because of high permeability, precipitation, and supersaturation. Thus, the in vitro dissolution system with an absorptive compartment may help predicting the in vivo phenomena of BCS class II drugs better than compendial dissolution apparatuses. In this study, an absorptive compartment (a biphasic device) was introduced to a gastrointestinal simulator. This addition was evaluated if this in vitro system could improve the prediction of in vivo dissolution for BCS class IIb drugs, ketoconazole and raloxifene, and subsequent absorption. The gastrointestinal simulator is a practical in vivo predictive tool and exhibited an improved in vivo prediction utilizing the biphasic format and thus a better tool for evaluating the bioperformance of BCS class IIb drugs than compendial apparatuses.     

Current concepts in pediatric liver transplantation

Liver transplantation is the definitive treatment for end-stage liver disease in both children and adults. Advances over the last 2 decades have resulted in excellent patient and graft survival rates in what were previously cases of fatal disorders. These developments have been due to innovations in surgical technique, increased surgical experience, refinements in immunosuppressive regimens, quality improvements in intraoperative anesthetic management, better understanding of the pathophysiology of the liver diseases, and better preoperative and postoperative care. Remarkably, the use of split-liver and living-related liver transplantation surgical techniques has helped mitigate the well-recognized national organ shortage. This review will discuss the major aspects of pediatric liver transplantation as it pertains to indication for transplantation, recipient selection and listing for orthotopic liver transplantation, pre-orthotopic liver transplantation care of children, optimal timing of orthotopic liver transplantation, surgical technical considerations, postoperative care and complications, and patient and graft survival outcomes.     

Biowaivers for oral immediate-release products: implications of linear pharmacokinetics

Bioequivalence of drug formulations plays an important role in drug development. Recently, the Biopharmaceutical Classification System (BCS) has been implemented for the purpose of waiving bioequivalence studies on the basis of the solubility and gastrointestinal permeability of drug substance. Using the rationale of the BCS, it can be argued that biowaivers can, however, also be granted on the basis of standard pharmacokinetic data. If a drug exhibits dose-linear pharmacokinetics and a sufficiently fast dissolution profile, it can be concluded that this drug appears to pose no problem with respect to absorption. It should be noted that a change of an immediate-release tablet formulation can only lead to a deviating rate and/or extent of absorption when release of the drug from the formulation is altered. Logically, the dissolution profiles of the different formulations should be equal to guarantee bioequivalency. Thus, both BCS and the alternative linear pharmacokinetics approach require an evaluation of dissolution profiles. The justification of BCS is found in the permeability classification of the compound, while those of the linear pharmacokinetics lie in the apparent lack of a permeability problem. For example, in this context P-glycoprotein-transported drugs form an interesting class of compounds, which may be treated likewise when complying to the aforementioned requirements. Furthermore, poorly soluble compounds may be less troublesome than expected. It is shown that linear kinetics can be explained by the solubilising activity of, for example, bile salts. In this instance, linear pharmacokinetics shows that elevated doses do not appear to exhibit a limiting role on the dissolution. Hence, a change in formulation without any effect on the dissolution profile is not expected to cause a change in availability. It is clear that the formulations to be compared should not contain excipients that display an effect on (presystemic) drug metabolism.     

An evaluation of eptacog alfa in nonhaemophiliac conditions

We have analysed the published literature on eptacog alfa (recombinant factor VIIa; rFVIIa) for nonhaemophiliac conditions with the aim of determining its current place in therapy. Initial surgical and/or medical management is required for any patient with life-threatening bleeding. In those with continued life-threatening bleeding (i.e. despite maximal surgical and/or medical therapy), eptacog alfa may be considered as additional therapy, in exceptional circumstances. There is good evidence from systematic reviews and randomized controlled trials (RCTs) that eptacog alfa stops bleeding in adults with intracerebral haemorrhage (ICH) if it is given within 4 hours of symptom onset. However, a recent phase III RCT suggests that it does not improve clinically relevant long-term outcomes (death and disability). There is also good evidence against prophylactic use of eptacog alfa during orthotopic liver transplantation or liver resection, and in treating variceal and nonvariceal haemorrhage in patients with cirrhosis. The evidence for the use of eptacog alfa for unexpected life-threatening bleeding in liver, cardiac or other surgery, or in blunt trauma, is not robust. In these circumstances, it should only be given as part of a clinical trial or in exceptional cases when other therapies have failed. The evidence for use of eptacog alfa in penetrating trauma is lacking. Conflicting RCT results exist for the prophylactic use of eptacog alfa in elective surgery; therefore, it cannot be recommended in this situation. There is insufficient evidence for a primary role of eptacog alfa in reversal of anticoagulation with heparin-like molecules and novel anticoagulant agents. There are effective therapies that correct all warfarin-induced factor deficiencies; thus, off-label use of eptacog alfa for reversal of warfarin should only be considered in the context of ICH. The evidence for eptacog alfa use in children is limited. The only RCT is in cardiac surgery for congenital heart disease, where eptacog alfa prophylaxis was actually associated with increased time to chest closure. It may be of potential benefit in some children with life-threatening bleeding in the context of trauma, surgery or liver disease (as additional therapy when surgical and/or medical control of bleeding has failed), but the overall benefit-risk ratio may be unfavourable if there is an underlying risk of thromboembolism (e.g. trauma, congenital heart disease, other hyperviscous or hypercoagulable states, presence of arterial or central venous catheters). Thromboembolism may be associated with eptacog alfa use. Although the magnitude of this risk and possible predisposing factors are not clearly delineated, some data suggest increased risk at higher doses. Variable effects of eptacog alfa use on mortality have been shown in a pooled analysis of RCTs. Data from some observational studies and postmarketing surveillance suggest an increased risk of thromboembolism associated with off-label uses. Further well designed studies are required to more definitively assess the risk of thromboembolism with eptacog alfa and to better determine its effects on mortality. Optimum dosages for nonhaemophiliac conditions are not defined and nor is the optimum timing of administration. Moreover, it is not clear which patients will be most likely to benefit in terms of haemostatic efficacy and mortality. In addition to conventional measures to stop bleeding (i.e. surgery and blood transfusion), correction of hypothermia and acidosis, and reversal of anticoagulation are all recommended. The outcomes (effectiveness and safety) of all off-label uses should be systematically evaluated and reported. Adequate data to assess cost effectiveness for eptacog alfa does not exist for most off-label indications.     

Uterus transplantation

Until recently, only life and death situations warranted organ transplantation. Nonvital transplantation, to further a patient s wishes and goals, was not considered justified. It can be argued, however, that this distinction is not morally significant. Patients with kidney failure, for example, can be kept alive by dialysis. But their quality of life would be greatly enhanced by kidney transplant, which is thus considered a justified procedure. So a spectrum of rationales may justify transplantation. Transplantation of the uterus would relieve the anguish of women who greatly desire to conceive a child. Some women do not have a uterus. In some cases this is due to a congenital absence (Rokitansky s syndrome). In other cases, surgical removal of the uterus was required to repair an obstetrical rupture. With a transplanted uterus, many of these women could have the opportunity to become pregnant as a result of nonvital organ transplant. While other organ transplant donations most often come from cadavers and less often from living donors (kidney or partial liver), the donor source for a uterus may be an otherwise healthy living patient who requires uterus removal as a standard care procedure. Furthermore, it should be possible to remove the transplanted uterus from the recipient after successful pregnancies, so the patient would not be subjected to lifelong antirejection medications. Since animal uterus transplantation has been done successfully, human uterus transplantation might be considered for select cases. One such case has been reported.     

Clopidogrel use with stenting

Previous clinical trials have established that clopidogrel is beneficial when used with coronary artery stenting. However, questions remain as to when the clopidogrel treatment should be started and how long treatment should be continued for. In a Clopidogrel Registry, it was shown that when subjects received a loading dose of clopidogrel 300 mg, 6-24 h before the intervention and clopidogrel maintenance for 1 month, the primary end point at 30 days (acute myocardial infarction, all cause death and revascularisation) was lower than in subjects who were just given clopidogrel maintenance. An observational study has shown that there are no additional benefits from continuing to use clopidogrel after 6 months from bare-metal stenting. In contrast, long-term treatment with clopidogrel is beneficial in subjects given drug-eluting stents, when long-term stent thrombosis can be a rare complication. Thus, in subjects given drug-eluting stents, there was an incidence of death and non-fatal myocardial infarction (6-24 months after stenting) of 8.4% without clopidogrel and 2.1% with clopidogrel. These results suggest that clopidogrel pretreatment should be used with stenting, and that with drug-eluting stents, clopidogrel treatment should be continued for at least 24 months.     

From concept(ion) to life after death/the grave: The ‘natural’ history and life cycle(s) of novel psychoactive substances (NPS)

A range of information needs should be met in order to better understand and predict the longevity/existence of novel psychoactive substances (NPS). This conceptual paper argues that one way of assessing how long a molecule may be around is to document how the life cycles or natural histories of ‘traditional’ drugs and NPS evolve. The earliest indication of the possible appearance of a new substance might be evidenced on the DeepWeb. However, this means they are less visible, in line with the clandestine nature of drug use and supply. Therefore, monitoring discussion groups/fora needs the development of new methods compared to those used in the Surface Net. Issues needing consideration in establishing NPS life cycles are outlined here, together with the probable outcomes that could result. The approach advocated means that it should be easier to identify which NPS are likely to come up or are emerging in real time, and, therefore, pre‐empt/prevent their supply.     

Clinical characteristics of fulminant-type autoimmune hepatitis: an analysis of eleven cases

BACKGROUND: Although a few adult cases of fulminant-type autoimmune hepatitis have been reported, their clinical features and prognosis have remained uncertain. AIM: To assess the clinical features and prognosis of patients with fulminant-type autoimmune hepatitis. METHODS: Eleven patients (10%) diagnosed with fulminant-type autoimmune hepatitis in accordance with the 1999 criteria of the International Autoimmune Hepatitis Group were analysed. RESULTS: All 11 patients were female, with a median age of 53 years. Five patients survived without liver transplantation, one received a liver transplantation, and five died without liver transplantation. Nine patients (82%) survived for 2 weeks or more following diagnosis, without liver transplantation. Except for the patient receiving a liver transplantation, serum total bilirubin levels measured during the clinical course were significantly higher in non-survivors than in survivors, although the accompanying serum alanine aminotransferase levels measured for the two groups were similar. Most significantly, serum total bilirubin levels in non-survivors worsened during days 8-15, while levels in survivors improved during the same period. CONCLUSIONS: The short-term prognosis for patients with fulminant-type autoimmune hepatitis may be good. However, patients whose serum total bilirubin levels worsen during days 8-15 should be considered for liver transplantation.     

Natural history, risk factors and management of hepatitis C after liver transplantation

Recurrent HCV is universal after liver transplantation in patients viremic at the time of transplantation and leads to cirrhosis in up to 30% of patients by five years. This has led to recurrent HCV emerging as an important yet controversial indication for liver retransplantation. Despite encouraging results with pegylated interferon and ribavirin therapy in the non-transplant HCV population, these findings have not translated to transplant recipients where viral eradication is frequently unsuccessful largely due to drug intolerance. The lack of effective therapies, severe side effects and reports of hepatic decompensation despite HCV eradication raises the question of whether recurrent HCV genotype 1 should be treated with interferon-based therapies. Although protease inhibitors were recently approved for the treatment of genotype 1 HCV patients in combination with pegylated interferon and ribavirin, these new agents are contraindicated in liver transplant patients due to severe drug toxicity.     

Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride

Literature data on the properties of chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride related to the Biopharmaceutics Classification System (BCS) are reviewed. The available information indicates that these chloroquine salts can be classified as highly soluble and highly permeable, i.e., BCS class I. The qualitative composition of immediate release (IR) tablets containing these Active Pharmaceutical Ingredients (APIs) with a Marketing Authorization (MA) in Belgium (BE), Germany (DE), Finland (FI), and The Netherlands (NL) is provided. In view of these MA's and the critical therapeutic indication of chloroquine, it is assumed that the registration authorities had evidence that these formulations are bioequivalent to the innovator. It is concluded that IR tablets formulated with these excipients are candidates for a biowaiver.     

Review article: hepatitis B and liver transplantation

Liver transplantation is an excellent treatment for hepatitis B virus infected patients who have acute or chronic liver failure and/or primary liver cancer. Advances in antiviral prophylaxis prevent clinically significant graft re-infection for the majority of patients. Graft and patient survival has improved significantly during the past decade, and results of transplantation for hepatitis B virus are now superior to those achieved for most other indications. In particular, the availability of lamivudine and adefovir have transformed outcome. The addition of lamivudine to passive immunoprophylaxis with hepatitis B virus immunoglobulin prevents re-infection in most cases. Adefovir should be added to this combination when the patient develops lamivudine resistance before transplantation. The significance of serum hepatitis B virus DNA positivity in the absence of circulating hepatitis B surface antigen is uncertain. Hepatitis B virus infection of the graft can be observed when prophylaxis is inadequate, when the donor liver contains latent hepatitis B virus infection (so-called de novo infection from the hepatitis B virus core antibody positive donor), and when the donor is exposed to third party infection (sexual or nosocomial transmission). Established hepatitis B virus graft infection is a good indication for combination nucleoside analogue therapy. Combination therapy can achieve sustained suppression of viral replication, and hepatitis B e antigen and hepatitis B surface antigen clearance can also be observed.