Pharmacodynamics of the long-acting insulin analogues detemir and glargine following single-doses and under steady-state conditions in patients with type 1 diabetes.

AIM: The pharmacodynamic characteristics of the basal insulin analogues insulin detemir (IDet) and insulin glargine (IGlar) have been examined extensively via euglycaemic clamp studies. However, differences in clamp methodology and in the analysis of clamp data between trials have led to confusion over the duration of action of these two insulins. The aim of this study was to address these ambiguities in the literature by assessing the pharmacodynamic properties of IDet and IGlar over 30 h under single-dose and steady-state conditions using the definitions and procedures previously standardized by Heise and Pieber in 2007. METHODS: This was a single-centre, randomized, double-blind, glucose clamp trial involving 36 patients with type 1 diabetes. RESULTS: The mean duration of action of IDet was 25.9 h, compared with 19.8 h for IGlar after a single-dose (NS), and 23.3 h (IDet) versus 27.1 h (IGlar) at steady-state (p < 0.0001). IDet had a significantly higher area under the curve glucose infusion rate (AUCGIR ) than IGlar over 0-12 h after a single-dose (p = 0.0018). The steady-state AUCGIR for IDet was numerically higher than IGlar over 0-12 h (728 vs. 592 mg/kg, respectively; p = NS), but significantly lower than IGlar at 12-30 h (p = 0.0003). CONCLUSIONS: The duration of action of IDet is 23 h (range: 4.0-30.0), while that of IGlar is 27 h (range: 10.5-29.0) (95% CI: -8.1, 0.6). This suggests both insulins can be used for once-daily dosing, but individual needs must be considered.

Efficacy, usability and sequence of operations of a workflow-integrated algorithm for basal-bolus insulin therapy in hospitalized type 2 diabetes patients.

AIMS: To evaluate glycaemic control and usability of a workflow-integrated algorithm for basal-bolus insulin therapy in a proof-of-concept study to develop a decision support system in hospitalized patients with type 2 diabetes. METHODS: In this ward-controlled study, 74 type 2 diabetes patients (24 female, age 68 ± 11 years, HbA1c 8.7 ± 2.4% and body mass index 30 ± 7) were assigned to either algorithm-based treatment with a basal-bolus insulin therapy or to standard glycaemic management. Algorithm performance was assessed by continuous glucose monitoring and staff's adherence to algorithm-calculated insulin dose. RESULTS: Average blood glucose levels (mmol/l) in the algorithm group were significantly reduced from 11.3 ± 3.6 (baseline) to 8.2 ± 1.8 (last 24 h) over a period of 7.5 ± 4.6 days (p < 0.001). The algorithm group had a significantly higher percentage of glucose levels in the ranges from 5.6 to 7.8 mmol/l (target range) and 3.9 to 10.0 mmol/l compared with the standard group (33 vs. 23% and 73 vs. 53%, both p < 0.001). Physicians' adherence to the algorithm-calculated total daily insulin dose was 95% and nurses' adherence to inject the algorithm-calculated basal and bolus insulin doses was high (98 and 93%, respectively). In the algorithm group, significantly more glucose values <3.9 mmol/l were detected in the afternoon relative to other times (p < 0.05), a finding mainly related to pronounced morning glucose excursions and requirements for corrective bolus insulin at lunch. CONCLUSIONS: The workflow-integrated algorithm for basal-bolus therapy was effective in establishing glycaemic control and was well accepted by medical staff. Our findings support the implementation of the algorithm in an electronic decision support system.

S3-guideline "helicobacter pylori and gastroduodenal ulcer disease" of the German society for digestive and metabolic diseases (DGVS) in cooperation with the German society for hygiene and microbiology, society for pediatric gastroenterology and nutrition e. V., German society for rheumatology, AWMF-registration-no. 021 / 001.

This guideline updates a prior consensus recommendation of the German Society for Digestive and Metabolic Diseases (DGVS) from 1996. It was developed by an interdisciplinary cooperation with representatives of the German Society for Hygiene and Microbiology, the Society for Pediatric Gastroenterology and Nutrition (GPGE), and the German Society for Rheumatology. The guideline is methodologically based on recommendations of the Association of the Scientific Medical Societies in Germany (AWMF) for providing a systematic evidence-based S 3 level consensus guideline and has also implemented grading criteria according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) process. Clinical applicability of study results as well as specifics for Germany in terms of epidemiology, antibiotic resistance status, diagnostics, and therapy were taken into account.

Imatinib for hepatocellular cancer--focus on pharmacokinetic/pharmacodynamic modelling and liver function.

The effects of imatinib are partly mediated by the inhibition of platelet-derived growth factor (PDGF), which is highly expressed in the liver. In this phase-I/II trial pharmacokinetic parameters of imatinib given for hepatocellular cancer were similar to those previously derived from CML patients. The AUC of N-desmethyl-imatinib depended on liver function; the metabolism of imatinib was otherwise comparable to other populations. During short-termed imatinib treatment (4 weeks, 400 mg/d), plasma PDGF significantly decreased. The AUC of N-desmethyl-imatinib could best be attributed to the pharmacodynamic effect of PDGF inhibition (r=-0.679 [95% CI: -0.917 to -0.0868], p=0.031).

Low-dose aspirin reduces the gene expression of gastrokine-1 in the antral mucosa of healthy subjects.

BACKGROUND: Gastrokine 1 (GKN1), one of the most abundant transcripts in normal stomach, is down-regulated by Helicobacter pylori infection. Aspirin (ASA), which is often used for secondary prevention of cardiovascular events, can damage gastric-duodenal mucosa within 1 or 2 h of ingestion. AIM: To study the gastric mucosal expression of GKN1 during acute low-dose ASA consumption. METHODS: Ten H. pylori-negative human volunteers took 100 mg ASA per day for 1 week, and underwent multiple upper GI endoscopies. GKN1 expression was analysed in antral and corpus mucosa by quantitative reverse-transcriptase polymerase chain reaction, western blot and immunohistochemistry (IHC). Gastric mucosal damage was detected endoscopically and histologically. RESULTS: Gastrokine 1 was similarly expressed in both antral and corpus mucosa. The use of low-dose ASA led to a significant decrease (3.07 a.u. vs. 0.23 a.u., P < 0.001) in antrum at day 7, while GKN1 transcript levels in corpus mucosa were slightly elevated (twofold, P < 0.005). Western blot and IHC confirmed these changes at the protein level. Furthermore, IHC revealed a vesicular staining pattern in the cytoplasm for GKN1 that was confirmed by transfected human gastric adenocarcinoma cell line expressing GKN1. CONCLUSION: Our data demonstrated that low-dose ASA downregulates GKN1 expression specifically in antral mucosa.

The effect of single-dose naproxen on eicosanoid formation in human gastroduodenal mucosa.

BACKGROUND: In animal studies, aspirin and non-aspirin non-steroidal anti-inflammatory drugs contribute to gastroduodenal damage via cyclo-oxygenase inhibition and consecutive leucotriene formation (COX-LOX eicosanoid shunt). AIM AND METHODS: Ten Helicobacter pylori-negative healthy volunteers received a single dose of 500 mg naproxen to address two questions: (i) is there a crosstalk between eicosanoids before medication in the human gastroduodenal mucosa and (ii) can we demonstrate a COX-LOX shunt following single-dose naproxen? RESULTS: Significant correlations in the stomach mucosa before medication were obtained between leucotriene B4 (LTB4) and thromboxane B(2) (TxB(2); r = -0.38, P = 0.05), as well as LTB4 and prostaglandin E(2) (PGE(2); r = 0.71, P < 0.0001). In serum, a >90% inhibition of TxB(2) and PGE(2) occurred within 30 min of naproxen administration. In gastric mucosa, a significant decrease of TxB(2) occurred already at 15 min and preferably in the antrum. For LTB4 there was a non-significant trend towards a transient increase. Mucosal PGE(2) was unchanged in all regions; transcript levels of both cyclo-oxygenases/5-lipoxygenase were unaffected (except for a trend of increasing cyclo-oxygenase-2 in the corpus). CONCLUSIONS: Baseline correlations between LTB4-TxB(2) and LTB4-PGE(2) reflect a crosstalk between these eicosanoids. A COX-LOX shunt; however, cannot be demonstrated following single-dose naproxen in a low-risk population.

Effects of low-dose aspirin on gastric erosions, cyclooxygenase expression and mucosal prostaglandin-E2 do not depend on Helicobacter pylori infection.

BACKGROUND: The mechanisms by which Helicobacter pylori and low-dose aspirin induce gastric damage are not completely elucidated. AIM: To evaluate the effects of low-dose aspirin on gastric damage, mucosal prostaglandin-E(2) levels and cyclooxygenase-enzyme expression in relation to the H. pylori status. METHODS: Twenty healthy volunteers (H. pylori positive, n = 10; H. pylori negative, n = 10) received aspirin 100 mg/die for 1 week. At days 0, 1, 3 and 7, gastric mucosal lesions were studied by oesophagogastroduodenoscopy and histology. COX-1 and COX-2 were determined by immunohistochemistry and reverse-transcriptase polymerase chain reaction, and mucosal prostaglandin-E(2) levels by enzyme-linked immunosorbent assay. Nine H. pylori-positive subjects repeated the protocol after H. pylori eradication. RESULTS: All groups developed a similar number of erosions. COX-1 and COX-2 expression, as well as mucosal prostaglandin-E(2) levels were not influenced by H. pylori status and aspirin medication. Helicobacter pylori-negative and H. pylori-eradicated subjects who developed aspirin-induced erosions had significant lower pre-treatment antral prostaglandin-E(2) levels than those without erosions (3.6 ng/microg vs. 6.3 ng/microg protein and 3.6 ng/microg vs. 6.0 ng/microg protein, respectively, P < 0.01 Mann-Whitney U-test). CONCLUSIONS: In healthy subjects, low-dose aspirin for 1 week does neither affect cyclooxygenase expression nor mucosal prostaglandin-E(2) levels. Antral prostaglandin-E(2)-basal levels appear to be critical for development of aspirin-induced gastric damage in subjects without H. pylori infection.

Impact of biomarkers on disease survival and progression in patients treated with octreotide for advanced hepatocellular carcinoma.

BACKGROUND: Current determination of prognosis for advanced hepatocellular carcinoma (HCC) is mainly based on clinical assessment. We aimed to determine the impact of biomarkers as predictive factors for HCC progression and survival during octreotide-based treatments. PATIENTS AND METHODS: We included patients who had been prospectively randomised to receive either octreotide (30 mg) alone monthly (n = 39) or in combination with rofecoxib (up to 50 mg bid daily, n = 32) for a minimum of 6 months, or until death occurred. RESULTS: Overall median survival (154 days) and median time to progression (94 days) were not different for both treatments and the biomarkers investigated (VEGF-A, IGF-1, PGE-2, ET-A) were similarly distributed amongst treatment groups. Combined univariate group analysis revealed that survival was decreased for an uptake ratio of > 2 on initial octreoscan (P = 0.05); baseline serum VEGF-A and IGF-1 were further significantly associated with survival. On multivariate analysis, uncorrected serum VEGF-A appeared to be the most significant predictor for tumor progression and survival. CONCLUSIONS: Biomarkers, in addition to established tumor markers, are independent predictors of tumor progression and survival in patients with advanced HCC treated with octreotide. Furthermore, the involvement of VEGF-A implies the inhibition of angiogenesis as a potential mechanism of action for this drug.

Omeprazole-induced increase in the absorption of bismuth from tripotassium dicitrato bismuthate.

OBJECTIVE: Omeprazole is an effective drug for treating active peptic ulcer, whereas tripotassium dicitrato bismuthate can prevent ulcer relapse if Helicobacter pylori is eradicated. Because both drugs will be given concomitantly, drug interactions have to be considered, especially since absorption of bismuth may be dependent on intragastric pH, which will be elevated by omeprazole. METHODS: In a placebo-controlled crossover study, six healthy volunteers received daily oral doses of 40 mg omeprazole for 1 week and a single oral dose of 240 mg tripotassium dicitrato bismuthate. Plasma concentration-time profiles (AUC) and urinary excretion (Ae) of bismuth were measured by atomic absorption spectrophotometry and plasma levels of omeprazole by HPLC. In addition, intragastric pH values were monitored for 8 hours. RESULTS: As expected, control mean pH values (2.1) were evaluated to 4.7 by omeprazole (p = 0.001), which was eliminated with a half-life of 1.3 +/- 0.7 hours (mean +/- SD) and an oral clearance of 387 +/- 221 ml/min. The increase of intragastric pH was related to the AUC of omeprazole (r = 0.89; p = 0.017). Omeprazole increased absorption of bismuth because AUC and Ae were higher (p < or = 0.05) during omeprazole treatment (172 +/- 158 micrograms/L.hr and 1.9 +/- 2.0 mg/8 hr, respectively) compared with placebo (46 +/- 33 micrograms/L.hr and 0.27 +/- 0.28 mg/8 hr, respectively). A significant correlation (r = 0.85; p = 0.038) could be observed between intragastric pH differences and Ae values. CONCLUSIONS: Omeprazole caused an increase of the systemic availability of bismuth from tripotassium dicitrato bismuthate. Whether this pharmacokinetic interaction between both drugs results in alterations of H. pylori eradication or the toxic potential of bismuth remains to be elucidated by further clinical studies.

Disposition of ibuprofen in patients with liver cirrhosis. Stereochemical considerations.

Following a single oral dose of racemic ibuprofen 600mg the stereoselective disposition of its enantiomers was studied in 8 patients with moderate to severe cirrhosis. Compared with the elimination half-life (t1/2) of (-)-R- and (+)-S-ibuprofen in 8 healthy age-matched controls (1.7 +/- 0.3h and 1.8 +/- 0.5h, respectively), t1/2 was prolonged significantly (p < 0.045 and < 0.001, respectively) in patients with cirrhosis (t1/2 = 3.1 +/- 1.7h and 3.4 +/- 1.0h, respectively). Whereas the low amounts excreted unchanged into urine differed slightly in both groups studied, much less (p < 0.01) conjugated ibuprofen was recovered either as the R-enantiomer (0.9 +/- 0.4% vs 4.1 +/- 2.8% of the dose) or the S-enantiomer (6.4 +/- 2.5% vs 26.5 +/- 12.9% of the dose) in patients with cirrhosis. Metabolic inversion of the inactive (-)-R-ibuprofen to the active (+)-S-ibuprofen may be impaired in hepatic dysfunction since the normal ratio of areas under the curve (AUC) for R- and S-enantiomers (0.79 +/- 0.18) was significantly (p < 0.02) higher in patients with cirrhosis (1.10 +/- 0.28). In a second study, a single oral dose of 400mg (+)-S-ibuprofen was administered to 8 healthy volunteers and 8 patients with cirrhosis. Elimination of this enantiomer was slightly impaired as could be seen from the prolonged t1/2 (1.6 +/- 0.1h vs 2.6 +/- 0.5h; p < 0.001) and the increase in AUC (101 +/- 35 vs 144 +/- 41 mg/L.h; p = 0.041). In conclusion, in patients with liver disease, hepatic elimination of ibuprofen is impaired. This should be taken into consideration especially if the racemic drug is used. Direct administration of the active (+)-S-enantiomer seems to offer less vulnerable treatment.

Effects of cyclosporin A upon humoral and cellular immune parameters in insulin-dependent diabetes mellitus type I: a long-term follow-up study.

Patients who had been included in a randomized double-blind placebo-controlled trial on the efficacy of cyclosporin A (CyA) in producing remissions in insulin-dependent diabetes mellitus (IDDM) type I were investigated for humoral and cellular immunologic parameters. Whereas metabolic derangement before the initiation of insulin treatment led to small but significant decreases in the percentage of CD4-positive lymphocytes as well as of the activity of natural killer (NK) cells and antibody-dependent cellular cytotoxicity (ADCC), the administration of CyA did not influence any of the immunologic parameters tested, which included proliferative lymphocyte responses to mitogens and alloantigens and serum concentrations of immunoglobulins G, A and M. Thus NK cell activity, ADCC as well as the percentage of CD4-positive lymphocytes returned to normal levels in parallel with the normalization of glycosylated haemoglobin (HbAlc), but were not further influenced in their course by the administration of CyA, as compared with patients receiving placebo. Interferon-induced augmentation of NK cell activity did not differ between patients with IDDM on placebo and those under CyA therapy. All other investigated parameters also remained unchanged during the time of CyA therapy. We conclude that metabolic derangement leads to a reversible disturbance of certain cellular immune functions, but their normalization achieved by insulin treatment and their further course remains uninfluenced by the administration of CyA.

Age-dependent eradication of Helicobacter pylori with dual therapy.

BACKGROUND: Combined treatment using an acid-inhibiting drug with antibiotics can cure Helicobacter pylori infection. However, eradication rates are highly variable, especially if a proton pump inhibitor is used with amoxycillin. Therefore it is important to define factors/predictors of the clinical outcome. METHODS: In a single-blind study, 60 H. pylori-positive patients prospectively matched for diagnosis (erosive gastritis, duodenal and gastric ulcer), age (above and below 50 years) and smoking habits were randomly treated (each group n = 20) for 2 weeks with amoxycillin (1 mg b.d.) and either omeprazole (20 mg b.d.), lansoprazole (30 mg b.d.) or ranitidine (300 mg b.d.). Intragastric pH and plasma levels of the administered drugs were monitored over a dosing interval of 12 h. RESULTS: The overall eradication rates were 45% (intention-to-treat, ITT, 27/60) or 47% (per protocol 27/58); they did not differ (ITT) between omeprazole (50%), lansoprazole (40%) and ranitidine (45%). Median pH and time at which intragastric pH was above 4 was slightly lower for ranitidine (4.0 +/- 1.7; 51 +/- 25%) than for omeprazole (5.4 +/- 1.1: 77 +/- 25%; P < 0.05) or lansoprazole (4.4 +/- 1.6: 68 +/- 32%). Plasma concentrations of amoxycillin were comparable in all three treatment groups. Post-treatment H. pylori status was not dependent on those levels, or the drug-induced extent or duration of increased intragastric pH. However, H. pylori-eradicated patients were significantly (P < 0.05) older (56 +/- 13 years) than patients still H. pylori-positive (47 +/- 14 years). In addition, in patients older than 50 years (n = 33), eradication was higher (P < 0.01) than in patients (n = 25) below 50 years (65 vs. 24%). Eradication rate was highest (75-83%) in subgroups of patients (> 50 years and history of peptic ulcer or smokers). Neither activity/grade of peptic ulcer or erosive gastritis nor initial diagnosis were predictors for clinical outcome. CONCLUSION: The age of patients must be regarded as a major determinant of H. pylori eradication rate and may represent an important factor contributing to the highly variable clinical results.

Influence of age on the steady state disposition of drugs commonly used for the eradication of Helicobacter pylori.

BACKGROUND: The success of eradication therapy for Helicobacter pylori might be affected by the age of patients. AIM: To investigate whether disposition of drugs commonly used for H. pylori eradication is age-dependent. METHODS: Trough steady state serum levels of lansoprazole or ranitidine, amoxycillin, clarithromycin and metronidazole were monitored in 232 patients during the last dosing interval of a 5-day quadruple H. pylori eradication regimen. Detailed pharmacokinetic analysis was performed in 28 patients. RESULTS: Linear correlations between age and trough serum levels were observed with lansoprazole (r=0.25; P=0.002), ranitidine (r=0. 38; P=0.001) and clarithromycin (r=0.36; P < 0.0001). These associations were also inversely dependent of creatinine clearance for ranitidine (r=0.36; P=0.001) and clarithromycin (r=0.30; P < 0. 0001). Multiple linear regression revealed age as an important factor influencing trough serum levels of lansoprazole, clarithromycin and ranitidine. There were significant inverse relationships between creatinine clearance and area under curve of ranitidine (r=0.88; P < 0.0001) and amoxycillin (r=0.56; P=0.002). Multiple linear regression revealed serum creatinine as the most important factor influencing the area under curve of ranitidine, clarithromycin and amoxycillin. CONCLUSIONS: Age per se has little influence on pharmacokinetics of amoxycillin and ranitidine, which depend more on age-dependent decline in renal function. The influence of age, but not renal function was established for lansoprazole. Age and renal function have independent impacts on clarithromycin disposition.

Dyspeptic symptoms associated with Helicobacter pylori infection are influenced by strain and host specific factors.

BACKGROUND: Dyspepsia can be associated with H. pylori infection. AIM: To assess dyspeptic symptoms and potentially influencing factors before and up to 6 months following successful H. pylori eradication therapy. METHODS: Prospective cohort study involving H. pylori positive subjects from ambulatory or hospitalized care. Main outcome measures were symptoms during baseline and follow-up, the proportion of symptom-free patients, and symptom scores. RESULTS: After successful eradication, the summary score of all dyspeptic symptoms decreased and during follow-up, the proportion of symptom-free patients was higher in the group with peptic ulcers (69.4% vs. 40.9%, P < 0.0001) than with functional dyspepsia (FD). Regardless of diagnosis, virulent strains of H. pylori were associated with a higher prevalence of epigastric pain before treatment: absolute risk-difference (ARD) with Oip-A: 18.2%, Odds Ratio (OR) 2.35 [1.3-4.2, 95%-CI], P = 0.01; with Cag-A: 24.6%, OR 2.81 [1.6-5], P = 0.01. Low-dose aspirin in part was a major risk factor in FD for previous weight loss bdfore study entry. Post-treatment, non-ulcer patients were more likely to suffer from distention/bloating. Likewise, alcohol induced persistence of nausea and vomiting in this population. CONCLUSIONS: Dyspeptic symptoms in H. pylori infected patients are more common with virulent strains. Symptoms are more likely to persist despite successful eradication if patients initially harboured virulent strains or concomitant aspirin or alcohol intake are present. In one-third of peptic ulcer patients, symptoms will not be cured 3 months after therapy.

Tripotassium dicitrato bismuthate: absorption and urinary excretion of bismuth in patients with normal and impaired renal function.

We have investigated the absorption and urinary excretion of tripotassium dicitrato bismuthate during a treatment course of 4 weeks in 7 patients with normal renal function (creatinine clearance 115 +/- 29 ml/min; mean +/- S.D.), in 7 patients with impaired renal function (creatinine clearance = 34 +/- 19 ml/min) and in 4 dialysed patients. Following the first dose of tripotassium dicitrato bismuthate (216 mg bismuth b.d.), and after 2 and 4 weeks of treatment (dialysed patients received only 108 mg/b.d.), plasma and urine concentrations of bismuth were monitored for 2 and 24 h, respectively. After stopping therapy plasma and urine concentrations of bismuth were followed for 4 and 6 weeks, respectively. In all three groups of patients small amounts of bismuth (mean values 0.26 to 0.28% of dose) were rapidly (transient mean peak concentrations between 40 and 134 micrograms/L) reached within about 30 to 40 min, absorbed and plasma levels demonstrated a wide intra- and inter-individual variability. Absorption profiles were not altered during the treatment course; however, the trough plasma concentration of bismuth demonstrated an about 3- to 5-fold accumulation (correlated to creatinine clearance) from about 5 micrograms/L to 15 micrograms/L (normal renal function) or to 20-25 micrograms/L (impaired renal function). Pre-study bismuth levels could be detected within 2 to 4 weeks after stopping therapy in all subjects whereas urinary concentrations were still elevated 6 weeks after the course of treatment. Our results indicate that tripotassium dicitrato bismuthate is absorbed in very low amounts during standard therapy. However, dependent on renal function, accumulation to non-toxic levels does occur during a course of treatment. It appears prudent to halve tripotassium dicitrato bismuthate dosage in patients with severe renal insufficiency (creatinine clearance less than or equal to 20 ml/min) to avoid any possible toxic risks. In such patients monitoring of the plasma bismuth concentration might be helpful, especially if longer or repeated treatment is anticipated.

What constitutes failure for Helicobacter pylori eradication therapy?

Apart from patients with peptic ulcer disease, the use of eradication therapy for Helicobacter pylori infection has been extended to patients with H pylori-positive dyspepsia and conditions at risk for gastric cancer. Standard treatments comprise a proton pump inhibitor plus two antibiotics for at least one week. The main factors leading to treatment failure are noncompliance and antibiotic resistance. Provided the patient is sufficiently informed about possible side effects, discontinuation of the newer triple therapies has become rare. The prevalence of antibiotic resistance varies considerably among different geographic regions, reflecting the habits of prescription of these antibiotics for other indications. Largely, it ranges from 1% to 15% for macrolides, and from 7% to 60% for nitroimidazoles. With nitroimidazole resistance, treatment failure occurs in only less than 50%; with macrolide resistance, by contrast, in more than 50% of the cases. Furthermore, bacterial and host-related factors (Cag A virulence factor, grade of inflammation) contribute to eradication success. In case of treatment failure, post-therapeutic resistance is frequent. Important principles for the choice of second-line treatment are: not to repeat an antibiotic with potential post-therapeutic resistance, and to ensure sufficient acid suppression.

Addition of misoprostol to ranitidine in non-responders to H2-blockers and pirenzepine.

In the present study, which comprised 14 patients in whom 300 mg and 900 mg of ranitidine as well as in combination with pirenzepine had failed to suppress acid secretion, we tested the effect of adding misoprostol. Night-time intragastric pH was continuously monitored, a rise in the intragastric pH above 4.0 h more than 6 h following the oral dose at 18.00 h being considered a response. In only 1 of the 7 patients with cirrhosis, and in 1 of the 7 control patients, did the combination of 300 mg ranitidine and 400 micrograms of misoprostol result in sufficient acid suppression. Mean pH profiles during the four study periods were not significantly different and the effect of misoprostol was similar in cirrhotics and controls. The inefficacy of the addition of misoprostol in this selected group of patients who did not respond even high doses of ranitidine (+/- pirenzepine) does not favour the hypothesis that gastric mucosal prostaglandin efficiency may be an important factor in the non-response to H2-receptor antagonists. It appears unlikely that the cause is localized solely at the site of H2-receptors.

[Results of cyclosporin A therapy in the early phase of type I diabetes mellitus]. / Ergebnisse der Cyclosporin-A-Therapie in der Frühphase des Typ-I-Diabetes mellitus*.

A number of findings concerning the pathogenesis of insulin-dependent diabetes mellitus have shown that an autoimmune process is responsible for the destruction of the beta-cell mass, and that a major part of this process has already occurred during the prediabetic phase of the disease. Various immunosuppressive intervention trials have, thus, recently been performed. Remission rates of between 30% and 50% in the Canadian cyclosporin A (CyA) pilot study prompted two placebo-controlled double-blind studies applying this medication. In the French CyA trial 122 patients were followed up for 9 months. 37% of those on high-dose CyA (whole blood levels greater than 300 ng/ml) achieved total remission, compared with 16.7% of those on low-dose CyA (blood level less than 300 ng/ml) and 5% of the placebo group. The Canadian-European trial included 188 patients, of whom 42 were treated in the Viennese centre. Diabetes had been diagnosed in these 42 patients not more than 6 weeks previously, and the duration of their symptoms did not exceed 14 weeks. Whole blood CyA levels ranged from 400 to 800 ng/ml. In relation to short duration of symptoms and early commencement of treatment up to 10 times higher total remission rates were found in the CyA group as compared with the placebo group. In both studies similar side effects were seen. Apart from the cosmetic side effects (hypertrichosis, gingival hyperplasia) a decrease of 20% in creatinine clearance and an increase of 20% in plasma creatinine level seemed to be of clinical importance.(ABSTRACT TRUNCATED AT 250 WORDS)

[The function of lytic effector cells in schizophrenic patients]. / Funktion lytischer Effektorzellen bei schizophrenen Patienten.

The present study aimed at elucidating lytic effector cell function in 32 schizophrenic patients and comparing the results with data obtained in 27 normal probands. Natural killer cell (NK) activity and antibody dependent cellular cytotoxicity (ADCC) were tested. Schizophrenics did not differ from normal controls in either test system. Within the schizophrenic group, higher NK activity was detected in patients with neuroleptic monotherapy (p less than 0.05). Patients given a combination of neuroleptics, antidepressants and/or lithium did not differ from drug-free patients in either test system. There was no influence of psychopathological variables on lytic effector cell function.

Ultra-long pharmacokinetic properties of insulin degludec are comparable in elderly subjects and younger adults with type 1 diabetes mellitus.

BACKGROUND: Management of diabetes in elderly subjects is complex and careful management of glucose levels is of particular importance in this population because of an increased risk of diabetes-related complications and hypoglycaemia. OBJECTIVE: The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg), a basal insulin with an ultra-long duration of action, in elderly subjects with type 1 diabetes compared with younger adults. METHODS: This trial was a randomised, double-blind, two-period, crossover trial conducted in a single centre and included both inpatient and outpatient periods. Subjects were men and women aged 18-35 years inclusive (younger adult group) or ≥65 years (elderly group) with type 1 diabetes who received IDeg (0.4 U/kg) via subcutaneous injection in the thigh once-daily for six days. Following 6-day dosing, a 26-hour euglycaemic glucose clamp procedure was conducted to evaluate the steady-state pharmacodynamic effects of IDeg. Blood samples were taken for pharmacokinetic analysis up to 120 h post-dose. Pharmacokinetic endpoints included the total exposure of IDeg, ie the area under the IDeg serum concentration curve during one dosing interval at steady state (AUC(IDeg,τ,SS)) (τ = 0-24 h, equal to one dosing interval) and the maximum IDeg serum concentration at steady state (C(max,IDeg,SS)). Pharmacodynamic endpoints included the total glucose-lowering effect of IDeg, ie the area under the glucose infusion rate (GIR) curve at steady state (AUC(GIR,τ,SS)), and the maximum GIR at steady state (GIR(max,IDeg,SS)). RESULTS: Total exposure (AUC(IDeg,τ,SS)) and maximum concentration (C(max,IDeg,SS)) of IDeg were comparable between elderly subjects and younger adults. Estimated mean age group ratios (elderly/younger adult) for AUC(IDeg,τ,SS) and C(max,IDeg,SS) and corresponding two-sided 95 % confidence intervals (CIs) were 1.04 (95 % CI 0.73-1.47) and 1.02 (95 % CI 0.74-1.39), respectively. Mean AUC(IDeg,0-12h,SS)/AUC(IDeg,τ,SS) was 53 % in both younger adult and elderly subjects, showing that in both age groups IDeg exposure was evenly distributed across the first and second 12 h of the 24-hour dosing interval. No statistically significant differences were observed between younger adult and elderly subjects with regard to AUC(GIR,τ,SS) (the primary endpoint of this study) and GIR(max,IDeg,SS). Estimated mean age group ratios (elderly/younger adult) for AUC(GIR,τ,SS) and GIR(max,IDeg,SS) and corresponding two-sided 95 % CIs were 0.78 (95 % CI 0.47-1.31) and 0.80 (95 % CI 0.54-1.17), respectively. Duration of action was beyond the clamp duration of 26 h in all subjects. CONCLUSIONS: The exposure of IDeg at steady state during once-daily dosing was similar in younger adult and elderly subjects. The glucose-lowering effect of IDeg was numerically lower in elderly subjects compared with younger adults, but no significant differences were observed between age groups. The ultra-long pharmacokinetic and pharmacodynamic properties of IDeg observed in younger adults were preserved in elderly subjects with type 1 diabetes. Clinical trials.gov number: NCT00964418.