[New support services for the care of young patients with rheumatic diseases]. / Neue Unterstützungsangebote für die Betreuung junger Rheumatiker.

The transition process from pediatric to adult rheumatological and internistic care is a challenge for patients and medical personnel. Every second patient with a pediatric rheumatic disease has not achieved stable drug-free remission at early adulthood and therefore requires continuing rheumatological care. Approximately one third of young people with rheumatic diseases in Germany discontinue regular specialist care on their way to the adult healthcare setting. Newly developed support services and tools to improve the healthcare of young people with rheumatic diseases in Germany are presented.

[Transition from pediatric to adult rheumatological care]. / Transition von der Kinder- und Jugendrheumatologie in die internistische Rheumatologie.

Childhood onset rheumatic and musculoskeletal diseases often continue into adulthood. These diseases are associated with a high risk of permanent disability and impairment in the quality of life of people affected. Adolescence and young adulthood represent a particular risk phase for an unfavorable long-term outcome. During this challenging and future health-determining phase at least one in three patients stops seeking regular specialized healthcare and the health status of these people deteriorates after having left pediatric care. The key principles of transitional care have been defined, are generally accepted and are presented in this article. There is emerging evidence of the effectiveness of transitional care programs. The implementation of a structured transition into the routine care of adolescents and young adults with rheumatic diseases is necessary.

[Transitional care in rheumatology in Germany]. / Transition in die Erwachsenenrheumatologie.

Moving from child- to adult-centred services (transition) is a challenge for patients and health care professionals. Every second adolescent with a rheumatic disease will still have active disease that requires treatment when they are adults. A third of these patients do not arrive in adult-centered care, a consequence that is accompanied by negative consequences on the individual course of disease and contributes to socioeconomical costs. The present article describes the current situation: barriers for successful transfer and transition models are discussed. Transitional care and research must be improved in Germany.

IL28B polymorphisms predict reduction of HCV RNA from the first day of therapy in chronic hepatitis C.

BACKGROUND & AIMS: Single nucleotide polymorphisms (SNPs) associated with IL28B influence the outcome of peginterferon-α/ribavirin therapy of chronic hepatitis C virus (HCV) infection. We analyzed the kinetics of HCV RNA during therapy as a function of IL28B SNPs. METHODS: IL28B SNPs rs8099917, rs12979860, and rs12980275 were genotyped in 242 HCV treatment-naïve Caucasian patients (67% genotype 1, 28% genotype 2 or 3) receiving peginterferon-α2a (180 µg weekly) and ribavirin (1000-1200 mg daily) with serial HCV-RNA quantifications. Associations between IL28B polymorphisms and early viral kinetics were assessed, accounting for relevant covariates. RESULTS: In the multivariate analyses for genotype 1 patients, the T allele of rs12979860 (T(rs12979860)) was an independent risk factor for a less pronounced first phase HCV RNA decline (log(10) 0.89IU/ml among T carriers vs. 2.06 among others, adjusted p < 0.001) and lower rapid (15% vs. 38%, adjusted p = 0.007) and sustained viral response rates (48% vs. 66%, adjusted p < 0.001). In univariate analyses, T(rs12979860) was also associated with a reduced second phase decline (p = 0.002), but this association was no longer significant after adjustment for the first phase decline (adjusted p = 0.8). In genotype 2/3 patients, T(rs12979860) was associated with a reduced first phase decline (adjusted p = 0.04), but not with a second phase decline. CONCLUSIONS: Polymorphisms in IL28B are strongly associated with the first phase viral decline during peginterferon-α/ribavirin therapy of chronic HCV infection, irrespective of HCV genotype.

Prediction of nonSVR to therapy with pegylated interferon-alpha2a and ribavirin in chronic hepatitis C genotype 1 patients after 4, 8 and 12 weeks of treatment.

In patients with chronic hepatitis C genotype 1, the current algorithm for treatment discontinuation is based on no early virological response (<2 log decline in hepatitis C virus (HCV)-RNA) at 12 weeks. It is important to determine whether prediction of nonsustained virological response (NR) before 12 weeks can be robustly obtained by statistical methods. We used longitudinal discriminant analysis (LDA) to build and cross-validate models including baseline patient characteristics and measurements of serum HCV-RNA in the first 4, 8 or 12 weeks of treatment. The performance of each model was evaluated by the partial AUC (PA) index, exploring the accuracy of prediction in the range of high negative predictive values. Models were compared by computing 95% confidence intervals for the difference in PA indices. NR was best predicted before week 12 by a single HCV-RNA measurement at week 8 taken together with gender, BMI and age (W8 model, PA index = 0.857). This model was not inferior to models that included a measurement at week 12 (PA index = 0.831). The best model obtained with LDA within the first 4 weeks, which included measurements at days 4, 8 and at week 4, was found to be inferior to the week 8 model (PA index = 0.796). These results indicate that lack of sustained viral response is best predicted after 8 weeks of treatment and that waiting until 12 weeks does not improve the prediction.

Clinical use of interferon in hepatitis B and C.

The concept of antiviral therapy with interferon for chronic hepatitis B emerged in the middle of the seventies and was supported by the suppressive effect of human interferon on HBV-DNA polymerase levels in 3 patients. This effect of leukocyte interferon was confirmed in a small controlled study of patients with HBeAg-positive chronic hepatitis B; however, no effect was found on other indices of hepatitis B. More than 10 years elapsed before one large RCT demonstrated clinically relevant virological responses in 35% vs. < 10% in placebo and led to registration of interferon for hepatitis B. Responses in HBeAg-negative chronic hepatitis B were very high during treatment but high relapse rates eliminated most of the long-time treatment effect. Interferon has now to compete with highly effective nucleoside analog therapy, but still has a prominent place as a limited duration therapy leading to sustained and sometimes complete responses. In the middle of the eighties, interferon was tested in 10 patients with non-A, non-B chronic hepatitis and ALT normalization was observed in the majority. After the discovery of the hepatitis C virus and the introduction of the HCVRNA PCR test it became clear that interferon therapy can cure hepatitis C infections. Widespread therapy was introduced after a co-drug ribavirin was found to reduce relapse rates and two pivotal trials with recombinant interferon showed sustained virological responses in about 50% of patients, with much higher positive outcomes in genotype 2 and 3. Therapy-induced sustained virological remission has been shown to reduce liver-related death, liver failure and to a lesser extent hepatocellular carcinoma. Interferon has become the key drug for hepatitis C.

Treatment of chronic hepatitis B virus infection - Dutch national guidelines.

The development of this guideline was initiated and coordinated by the Netherlands Association of Gastroenterologists and Hepatologists (Nederlandse Vereniging van Maag-Darm-Leverartsen). The aim is the establishment of national standards in the evaluation and antiviral treatment of patients with chronic hepatitis B virus (HBV) infection. This includes recommendations on the initial evaluation of patients, choice and duration of antiviral therapy, follow-up after antiviral therapy and monitoring of patients not currently requiring antiviral therapy. The initial evaluation of chronic HBV-infected patients should include testing of liver biochemistry, virus serology and abdominal imaging. In patients without cirrhosis, antiviral treatment is recommended for those with a serum HBV DNA of at least 1.0 x 105 c/ml (>or=2.0 x 10(4) IU/ml) in combination with: a) elevation of serum alanine aminotransferase (ALAT) level above twice the upper limit of normal during at least three months, and/or b) histological evidence of porto-portal septa or interface hepatitis on liver histology. In patients with cirrhosis, antiviral treatment is recommended if serum HBV DNA is 1.0 x 10(4)c/ml (>or=2.0 x 10(3) IU/ml) or higher, independent of ALAT levels or histological findings. If the patient has decompensated cirrhosis, antiviral treatment is recommended if serum HBV DNA is 1000 c/ml (>or=200 IU/ml) or higher. Patients who do not have an indication for antiviral treatment should be monitored because there is a risk of (re)activation of disease activity. Monitoring every three to six months is recommended for HBeAg-positive and HBeAg-negative patients with high viraemia (HBV DNA >or=1.0 x 10(5) c/ml or >or=2.0 x 10(4) IU/ml) and normal ALAT levels. For patients with serum HBV DNA below 1.0 x 10(5) c/ml (<2.0 x 10(4) IU/ml) the recommended frequency of monitoring is every three to six months for HBeAg-positive patients and every six to 12 months for HBeAg-negative patients. Peginterferon (PEG-IF N) therapy should be considered as initial therapy in both HBeAg-positive and HBeAg-negative patients without contraindications for treatment with this drug because of the higher chance of achieving sustained response compared with nucleos(t)ide analogue therapy. In patients starting nucleos(t)ide analogue therapy, the use of lamivudine is not preferred if long-term antiviral treatment is expected due to the high risk of antiviral resistance against this drug. Of the currently licensed nucleos(t)ide analogues, entecavir has the lowest risk of antiviral resistance (compared with lamivudine, adefovir and telbivudine), while suppression of viral replication seems most profound with either entecavir or telbivudine. The recommended duration of treatment with PEG-IF N is one year for both HBeAg-positive and HBeAg-negative patients. In HBeAg-positive patents, nucleos(t)ide analogue therapy should at least be continued until HBeAg seroconversion and a decline in HBV DNA to below 400 c/ml (80 IU/ml) has been achieved and maintained for six months during therapy. Whether nucleos(t)ide analogue therapy can be safely discontinued in HBeAg-negative patients is unknown; usually prolonged or indefinite antiviral treatment is necessary. Patients receiving PEG-IF N should be monitored once a month, while three monthly monitoring suffices for those receiving nucleos(t)ide analogues. Genotypic analysis of the HBV polymerase is indicated if an increase in serum HBV DNA of at least 1 log(10) c/ml (IU/ml) compared with the nadir value is observed during nucleos(t)ide analogue therapy. Antiviral therapy should be changed as soon as possible in case of confirmed genotypic resistance. Adding a second antiviral agent seems beneficial over switching to another agent. With the availability of multiple new antiviral drugs for the treatment of chronic hepatitis B, effective treatment is now possible for more patients and for longer periods. However, the complexity of HBV therapy has also increased. Nowadays, virtually all chronic HBV-infected patients can be effectively managed, either by inducing sustained off-treatment response or by maintaining an on-treatment response.

Treatment of chronic hepatitis C virus infection - Dutch national guidelines.

The development of this guideline was initiated and coordinated by the Netherlands Association of Gastroenterologists and Hepatologists (Nederlandse Vereniging van Maag-Darm-Leverartsen). The aim is the establishment of practical guidelines in the evaluation and antiviral treatment of patients with chronic hepatitis C virus (HCV) infection. This includes recommendations for the initial evaluation of patients, the choice and duration of antiviral therapy and the follow-up after antiviral therapy. Hepatitis C is a slowly progressive disease. The initial evaluation of chronically HCV-infected patients should include liver biochemistry testing, virological testing and abdominal ultrasound imaging. Liver biopsy is no longer a routine procedure. Antiviral treatment should be considered for all HCV-infected patients. Current antiviral treatment is a long-term process and is associated with substantial side effects. When deciding whether to start treatment or not, the chance of successful treatment (80% with hepatitis C genotype 2 and 3 and 50% with hepatitis C genotype 1 and 4), the fibrosis stage, the expected side effects and the compliance of the patient should be taken into consideration. In the absence of significant fibrosis and necroinflammation in liver biopsy, postponing treatment is an option. Current antiviral treatment is contraindicated in patients with Child-Pugh-class B or C cirrhosis. The possibility of a liver transplantation should be investigated in these patients. Significant comorbidity with a limited life expectancy is an absolute contraindication for antiviral treatment Treatment of chronic hepatitis C consists of administration of peginterferon and ribavirin for 24 or 48 weeks. Patients with hepatitis C genotype 1 or 4 are treated for 48 weeks. Patients with hepatitis C genotype 2 or 3 are treated for 24 weeks. In patients with undetectable HCV RNA after four weeks (28 days) of treatment, a shorter treatment is equally effective (12 to 16 weeks for hepatitis C genotype 2 or 3; 24 weeks for hepatitis C genotype 1 or 4). Outpatient clinic visits are recommended at the start and after 2, 4, 8, and 12 weeks of treatment, and thereafter every four to six weeks until the end of treatment. It is recommended to stop treatment if the HCV RNA level has not decreased by at least 2 log10 IU/ml (c/ml) after 12 weeks of treatment or when HCV RNA is still detectable after 24 weeks of treatment. The recommended frequency of outpatient clinic visits for patients who are not being treated is once every six months in patients with cirrhosis, otherwise every 12 months. It is expected that new anti-HCV-medication (STAT-C, specifically targeted antiviral therapy for HCV) will become available in the near future. Therefore treatment of chronic HCV infection will probably be more effective in the future.

[The practice guideline 'Viral hepatitis and other liver diseases' (second revision) from the Dutch College of General Practitioners; a response from the perspective of gastroenterology]. / De standaard 'Virushepatitis en andere leveraandoeningen' (tweede herziening) van het Nederlands Huisartsen Genootschap; reactie vanuit de maag-darm-levergeneeskunde.

The treatment of chronic viral hepatitis B and C is now so effective that the efforts of health care workers should now be concentrated on tracing infected persons and determining antiviral therapies. It is for these reasons in particular that this revision from the Dutch College of General Practitioners' practice guideline 'Viral hepatitis and other liver diseases' is so necessary. It is estimated that there are 46 patients with chronic viral hepatitis in each general practice of 2300 people, and that only 1 in 64 is registered as such. This calls for active case finding. If a risk factor is present, a feasible approach might be to ask about symptoms and complaints and to establish serum transaminase levels.

[Changes in the management of patients with side effects from the treatment of hepatitis C]. / Wijzigingen in het beleid bij patiënten met bijwerkingen van de behandeling van hepatitis C.

Since hepatitis C can be treated more and more successfully, treatment should be considered in every patient. In some of the patients infected by viral genotype I, the duration of treatment can be shortened: 24 weeks instead of 48 weeks. Maintaining the optimal dosage of ribavirin and peginterferon alpha is of great importance for successful treatment. For this purpose, new guidelines are proposed with reference to the haematological side effects, recommending more restraint with the reduction of the dosage and treatment in case of complaints. Treatment with peginterferon alpha frequently causes psychiatric problems, particularly depressive symptoms that are sometimes severe. Adequate treatment and support, including the use of antidepressants, are necessary in such cases and are often effective.

Determinants of quality of life in chronic liver patients.

BACKGROUND AND AIM: Health-related quality of life of patients with chronic liver disease has been shown to be impaired in numerous studies. However, the factors which influence health-related quality of life in treated chronic liver patients are not quite known. This is the first study to assess the impact of physical and psychosocial determinants on a weighted score of health-related quality of life in patients with chronic liver disease. METHODS: The data of 1175 chronic liver patients were used to assess the relationship between items of the disease-specific Liver Disease Symptom Index 2.0 and the Short Form (SF)-6D weighted utility score by means of linear regression analyses. RESULTS: Health-related quality of life was most strongly related to disease severity (B = -0.029) and joint pain (B = -0.023). Depression (B = -0.014), pain in the right upper abdomen (B = -0.014), decreased appetite (B = 0.014) and fatigue (B = -0.013) were also strongly related to health-related quality of life. In hepatitis C virus patients, disease severity (B = -0.037) and depression (B = -0.030) were strong determinants of health-related quality of life. CONCLUSIONS: This study shows that health-related quality of life in chronic liver patients is clearly determined by disease severity, joint pain, depression, decreased appetite and fatigue. These patients may benefit most from interventions aimed at improving adaptation to the symptoms described.

Dynamic decision analysis to determine optimal treatment duration in chronic hepatitis C.

BACKGROUND: Current guidelines for stopping treatment of chronic hepatitis C are based on hepatitis C ribonucleic acid measurements at 12 and 24 weeks. AIM: To explore an alternative approach for making individualized recommendations about treatment duration, based on simple alanine aminotransferase tests and on cost-per-cure. METHODS: We analysed individual patient data from 13 randomized, controlled trials with interferon alone or combined with ribavirin. Using multiple logistic regression, we built a model that estimated the probability of sustained virological response for treatment durations of 24 and 48 weeks. Decisions to prolong treatment were based on an increase in probability of sustained virological response. If the increase was 10%, the cost-per-cure became decisive with a limit of 50,000. RESULTS: Noncirrhotics with genotype 2 or 3 did not benefit when treatment was continued beyond 24 weeks. Sustained virological response rates in cirrhotic patients increased by 14-47% if treatment was continued up to 48 weeks. In noncirrhotic genotype 1 or 4 patients who had elevated alanine aminotransferase levels at week 4, the probability of sustained virological response increased by <10% if treatment was continued up to 48 weeks; the cost-per-cure for these patients would exceed 50,000. CONCLUSION: The dynamics of alanine aminotransferase levels and cost-per-cure provides a useful alternative to determine the duration of therapy in chronic hepatitis C.

The safety of pegylated interferon alpha-2b in the treatment of chronic hepatitis B: predictive factors for dose reduction and treatment discontinuation.

BACKGROUND: Treatment with interferon-alpha has been shown to be effective in one-third of hepatitis B e antigen-positive chronic hepatitis B patients, but is clinically associated with relevant adverse events. AIM: To investigate the safety of pegylated interferon alpha-2b in 300 hepatitis B e antigen-positive patients with compensated liver disease. METHODS: Patients were treated with pegylated interferon alpha-2b for 52 weeks combined with either lamivudine 100 mg/day or placebo. Pegylated interferon alpha-2b was administered for 100 microg once a week for 32 weeks; thereafter, the dose was reduced to 50 microg once a week. Adverse events and their effect on study medication were reported at monthly visits in a standardized way. RESULTS: The most frequently reported side-effects were flu-like syndrome (68%), headache (40%), fatigue (39%), myalgia (29%) and local reaction at the injection site (29%). These symptoms typically occurred within the first month of therapy and subsided during the course of therapy. Neutropenia and thrombocytopenia induced by pegylated interferon alpha-2b increased the risk of infections and bleeding complications, but these complications were rare and mild. The frequency of all side-effects was not different between patients treated with pegylated interferon alpha-2b combined with lamivudine or placebo. In 69 (22%) patients the dose of pegylated interferon alpha-2b was reduced prematurely. Of these dose reductions, 36 (52%) were because of neutropenia. Therapy was discontinued in 28 (8%) patients. The most frequent reasons for early discontinuation were psychiatric side-effects (depression, psychosis) and flu-like symptoms. Multivariate Cox regression analysis showed that low neutrophil count at baseline and cirrhosis were independent predictors of dose reduction or therapy discontinuation. CONCLUSION: We conclude that in patients with chronic hepatitis B and compensated liver disease prolonged pegylated interferon alpha-2b therapy is safe, and that pre-existent cirrhosis and neutropenia are the most important predictors of dose reduction or early treatment discontinuation.

The optimal treatment strategy for chronic hepatitis C.

The treatment of chronic hepatitis C forms a considerable burden for society. The present standard treatment with PEG-Interferon and Ribavirin is costly, has side effects and is not always effective. The current trend is to prolong treatment from 24 to 48 or even 72 weeks in patients infected with genotypes 1 and 4 virus, in order to prevent relapses after cessation of therapy. There are, however, suggestions that treatment of relapses gives a response rate similar to that of first-time treatment. We, therefore, compared the sustained response rates and the mean treatment durations of one-time treatment and cyclic treatment in a model that incorporates the rates of non-response to antiviral therapy, of breakthrough during and of relapse after cessation of treatment. Our calculations show that, even under the most unfavourable assumptions, repeated 6-month treatment lowers the mean treatment duration from 9.6 to 7.5 months when compared to a single 12-month treatment, without jeopardising the overall effectiveness. If the results of our model calculations can be confirmed, current guidelines for the treatment of infections with genotype 1 hepatitis C virus ought to be reconsidered.

Long-term follow-up of antiviral combination therapy in chronic hepatitis B.

For patients with chronic hepatitis B e (HBe)-positive hepatitis, long-term results of pilot studies with lymphoblastoid interferon-alpha, acyclovir, or a combination, and of a randomized controlled trial of interferon/desciclovir combination therapy are presented. HBe seroconversion was observed in more than 40 percent of patients treated with combination therapy, 30 percent with interferon therapy, 18 percent with acyclovir, and 0 percent with no treatment. HBe reactivation occurred in two patients with cirrhosis. Hepatitis B surface seroconversion followed HBe seroconversion in 11 to 30 percent of treated patients. HBe seroconversion was significantly related to initial low levels of viral replication and to transient aminotransferase elevation during the second half of the interferon treatment of 16 weeks. Clinical improvement and persistent normalization of aspartate aminotransferase was observed in all patients with HBe seroconversion. Conversion to a state of virus latency (HBe negative) mostly occurred after therapy, suggesting that the specific immunologic host response had been brought about by the suppression of virus replication through antiviral agents. Recommendations for selection of patients for antiviral combination therapy are made on the basis of these long-term results.

The appearance of donor heparin in the recipient after reperfusion of a liver graft.

The release of heparin has been mentioned as one of the causes of hypocoagulability after reperfusion of the liver graft. It has been ascribed to endogenous heparin released from the donor liver or to exogenous heparin in the preservation fluid that is released into the recipient after sequestration into the graft during preservation. The aim of this study was to investigate whether systemic administration of heparin to the donor before the hepatectomy contributes to the appearance of heparin in the recipient after reperfusion. We studied 20 patients undergoing an auxiliary heterotopic liver transplantation; 15 donors had received heparin immediately before circulation arrest (median 300 IU/kg body weight), but 5 had not. The thrombin time (TT), activated partial thromboplastin time (aPTT), and heparin neutralization test were determined at several intervals during the transplantation.

Prevention of hepatitis B infection in newborns through mass screening and delayed vaccination of all infants of mothers with hepatitis B surface antigen.

Beginning in 1982 all pregnant women undergoing prenatal routine blood analysis in three large city hospitals and one large rural area were tested for hepatitis B surface antigen (HBsAg). Infants of all HBsAg-positive mothers received hepatitis B immunoglobulin (HBIg), 0.5 mL/kg of body weight within two hours of birth and, after randomization, 10 micrograms of hepatitis B vaccine either at 0, 1, 2, and 11 months of age (schedule A) or at 3, 4, 5, and 11 months of age (schedule B). A second injection of HBIg (1 mL) was given to infants on schedule B at 3 months of age. Blood samples were obtained at 3, 6, 11, 12, 24, and 36 months. In a two-year period, 28,412 pregnant women were tested for HBsAg; screening efficiency varied between 85% and 98%. The overall prevalence of HBsAg was 0.8%, with a marked variation between urban centers (2.2%) and the rural area (0.3%). Vaccinations were received by 180 of 193 infants of HBsAg-positive mothers (90 on schedule A and 90 on schedule B). Concentrations of hepatitis B surface antibody less than 10 IU/L were observed in nine instances in five children from group A and in seven instances in six children from group B. Four hepatitis B viral infections (two HBsAg carriers, two who underwent antihepatitis B core seroconversions) were recorded in group A v one infection (antihepatitis B core seroconversion) in group B. The protective efficacy of the program (screening plus passive immunization and delayed vaccination) was 94%. The estimated cost of preventing one cae of hepatitis B infection in neonates was $3,000 (US currency).(ABSTRACT TRUNCATED AT 250 WORDS)

Intravascular coagulation in liver transplantation--is it present or not? A comparison between orthotopic and heterotopic liver transplantation.

UNLABELLED: It is still not clear whether disseminated intravascular coagulation (DIC) contributes to the hemostatic disturbances in orthotopic liver transplantation (OLT). Theoretically the lack of hepatic clearance of procoagulant factors during the anhepatic period and the release of thromboplastic material from the graft might trigger DIC. During heterotopic liver transplantation (HLT) the host liver is left in situ and procoagulant factors may still be cleared; DIC, if present, may not occur until after reperfusion. The aim of the present study was to gain more insight into the underlying mechanism of the coagulation changes during liver transplantation by comparison of OLT and HLT. Thrombin-antithrombin-III complexes (TAT), and indicator of thrombin generation, fibrin degradation products (FbDP) and routine clotting times were assayed in 12 OLTs, 18 HLTs and in a control group of 10 partial hepatic resections (PHR). TAT increased dramatically after reperfusion to 136 micrograms/l in OLT and to 94 micrograms/l in HLT (p n.s.). In contrast, FbDP levels increased only in OLT, to a maximum of 13.8 micrograms/ml. Routine clotting times changed mildly and similarly in both OLT and HLT. CONCLUSIONS: Graft reperfusion triggers excessive thrombin formation, but there are no other signs of subsequent DIC. Any thrombin formed is probably rapidly inhibited by antithrombin-III. The rise in FbDP during OLT is the result of increased fibrinolysis, which occurred only in OLT and not in HLT.

Development of radioimmunoassays for prednisone and prednisolone. Application to studies of hepatic metabolism of prednisone.

Radioimmunoassays for measuring prednisone and prednisolone (delta1 corticosteroids) in serum have been developed. By using 6,7-3H-delta1 corticosteroids as tracer, rabbit antibodies against delta1 corticosteroid-21-hemisuccinate in bovine serum albumin, and ammonium sulfate precipitation, the assays detected less than 0.8 ng/ml of delta1 corticosteroid and interassay coefficients of variation were less than 8.5 %. The specificity of antibodies, tested against all drug metabolites and major endogenous steroids, showed that only 21-glucuronic acid esters of delta1 corticosteroids had cross-reactivity of possible clinical importance. Assays were validated by measuring levels in samples of fastingstate sera with or without adding known amounts of prednisolone. Measurements of serum concentrations of both prednisone and prednisolone in normal dogs and in those with hepatic vascular exclusion were made after intravenous administration of prednisone. Although high levels of prednisolone appeared rapidly in normal dogs, only slight amounts were measured in dogs with hepatic vascular exclusion, which emphasized the importance of the liver in the conversion of prednisone to prednisolone, its active metabolite.

Oral pharmacokinetics of cyclosporin in patients with primary biliary cirrhosis and patients with skin diseases.

The pharmacokinetics of cyclosporin after oral administration were studied in seven patients with non-end stage primary biliary cirrhosis (PBC) without previous cyclosporin treatment (Group I), a control group of nine patients with skin diseases (mainly psoriasis; Group II) and six patients with PBC after prolonged cyclosporin treatment (Group III). Whole blood concentrations of cyclosporin were measured using a non-specific (N) radioimmunoassay (RIA) and--in a majority of the cases--also by a RIA specific (S) for the parent drug. No difference in cyclosporin absorption was observed between patients with PBC and those with a skin disease. The mean values for the area under the blood concentration-time curve for the first 6 h after the test dose (AUC0-6) and the maximal blood concentrations (Cmax) were significantly higher for Group I compared with Group II patients (P = 0.007 and 0.03, respectively), but the time to maximal blood concentrations (tc,max) did not differ. There was a trend toward higher mean AUC0-6 (P = 0.08) and Cmax (P = 0.08) values for Group III compared with Group I patients. Tc,max values were not influenced by prolonged cyclosporin treatment. The ratio of cyclosporin whole blood concentrations measured by the non-specific and specific RIA's (N/S ratio) increased with time without obvious differences between the three groups. These data suggest that cyclosporin absorption and its biotransformation in the liver are not impaired in patients with non-end stage PBC and that neither is affected by prolonged treatment.