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Aim: The objective of this study was to evaluate the pharmacokinetics of prostaglandin E1 (PGE1) and its metabolites after infusion of alprostadil in patients undergoing haemodialysis.

To investigate micronutrient supply in phenylketonuria (PKU) patients on a relaxed diet. Sixty-seven patients (6–45 years) with a phenylalanine tolerance ⩾600 mg/day were included in the study. From a 3-day diet record, protein supply as well as consumption of essential amino acids and several micronutrients were assessed and compared with the current recommendations and data for the healthy population. Protein supply and consumption of all essential amino acids were sufficient in all patients. Supply of micronutrients depended on dietary regime. Patients with a total protein supply of 120% or more of the recommended amount and at least 0.5 g protein per kg body weight from amino-acid mixture (AAM) were sufficiently supplied with all investigated micronutrients. All patients without AAM supplement showed severe micronutrient deficiencies in their diet records. PKU patients under a relaxed diet are at risk of an insufficient nutrient supply, if they have first no substitution with AAM, second a protein supply less than 0.5 g per kg body weight from AAM or third a total protein supply less than 120% of the recommendations. Therefore, close monitoring, specific dietary counseling and potential supplementation is mandatory to prevent micronutrient deficiencies in PKU patients.

Background EMD 525797 (DI17E6) is a deimmunized, humanized monoclonal immunoglobulin G2 antibody against the αv subunit of human integrins. Blocking αv integrins may be an effective strategy for inhibiting prostate cancer (PCa) metastasis. Objective Evaluate EMD 525797 safety/tolerability and pharmacokinetics (PK) in castration-resistant PCa patients. Secondary objectives included antitumor activity assessments. Design, setting, and participants A phase 1 open-label study in 26 patients (four European centers). Eligible patients (≥18 yr) had histologically proven PCa with bone metastases after prior chemotherapy and evidence of progressive disease (PD) based on prostate-specific antigen (PSA) values. Intervention Patients received three intravenous EMD 525797 infusions (250, 500, 1000, or 1500mg every 2 wk). Outcome measurements and statistical analysis Treatment-emergent adverse events (TEAEs) and dose-limiting toxicities (DLTs) were assessed. PK parameters were calculated according to noncompartmental standard methods. Antitumor activity measures were response after 6 wk, changes in PSA levels, and pain interference total score. Descriptive statistics were used. Results and limitations Patients were treated for a mean of 16.8 ± 16.7 wk. No DLTs were reported in any of the cohorts. All patients experienced TEAEs, which were considered drug-related in 11 patients. Four deaths occurred during the trial and were considered not related to EMD 525797. EMD 525797 showed dose-dependent, nonlinear PK. Eighteen of 26 patients did not show PD for ≥18 wk. Two patients (500-mg cohort), treated for 42.4 and 76.3 wk, had clinically significant PSA reductions and pain relief, including one patient with confirmed partial response. This trial was not specifically designed to assess clinical activity, and further investigations are needed in randomized controlled trials. Conclusions No DLTs were reported in any of the evaluated cohorts. There was evidence of clinical activity. For the currently ongoing phase 2 trial, EMD 525797 doses of 750 and 1500mg every 3 wk were chosen. Trial registration NCT00958477 (EMR 62242-002).

The adequacy of current supplemental dietary selenium allowances for dairy cattle has been reviewed from the literature and by monitoring responses of dairy herds in a veterinary practice specializing in nutritional consultation. Both information sources tend to agree that a reference range of 70 to 100 ng of Se/mL of serum is an acceptable target concentration. This range can be attained most often by providing > 6 mg of supplemental Se.animal-1.d-1, but several factors affect the serum Se responses of different cows to specific Se intakes. These factors may include forage types and sources, ruminal environment, supplemental fat, dietary calcium, trace metals, and genetics. The major benefits, observed experimentally, of maintaining optimal Se intakes include minimizing the incidence of mastitis and preventing calf losses associated with myopathy and(or) respiratory disease.

Dramatic increases in energy requirements during late gestation and early lactation, superimposed on an animal with a profound drop in DMI just before calving, make the dairy cow highly susceptible to the metabolic diseases ketosis and hepatic lipidosis. Increased serum concentrations of NEFA appear to be causally linked to these problems, and feeding strategies to reduce or avoid this dramatic increase are desirable for optimal health and performance. During the last 3 to 4 weeks prepartum, a diet higher in energy and protein concentration than current NRC recommendations should be fed so that adequate nutrient intake occurs within the limits of the reduced DMI. The additional energy should be provided by glucose precursors, such as starchy concentrates or propylene glycol, and not by lipid. Excessive energy and reduced fiber should be avoided both early in the dry period (more than 28 days prepartum) and immediately postpartum. Attention should be paid to the environment of the cow, especially during the last 3 weeks prepartum, to avoid environmental stressors as much as possible.

Objective: This study was designed to investigate whether the in vivo metabolism of tramadol was influenced by CYP2D6 polymorphism. Methods: The extent of tramadol O- and N-demethylation was calculated by determining the amounts of tramadol and O- and N-desmethyltramadol in 24 h urine after ingestion of a test dose of tramadol. The O- and N-demethylation rates were calculated by dividing the 24-h urinary excretion amount of tramadol by that of O-and N-desmethyltramadol. Volunteers were phenotyped for CYP2D6 polymorphism using sparteine as an in vivo probe. Results and conclusion: High correlation was found between tramadol-O-demethylation and sparteine oxidation in 71 extensive metabolizers of sparteine (r s= 0.544). The mean metabolic ratio of tramadol O-demethylation was significantly higher in poor metabolizers of sparteine than in extensive metabolizers (4.4 vs 0.8). These in vivo results confirm that tramadol O-demethylation is carried out to a large extent by the polymorphic CYP2D6.

In a crossover study 12 healthy volunteers received lansoprazole 15 mg or 30 mg orally, or 15 mg intravenously in randomized order as a single dose. Blood samples were taken and plasma levels of lansoprazole were determined using an HPLC method. The volunteers were phenotyped for the debrisoquine/sparteine and mephenytoin polymorphisms.The total clearance was 517 ml.min-1, and the absolute bioavailability was 91% for the 30-mg and 81% for the 15-mg enteric-coated formulation. The elimination half-life was about 1 h. No correlation of the plasma levels to the sparteine metabolic ratio was found, and no correlation to the mephenytoin type could be established, since all volunteers of the mephenytoin type were extensive metabolizers. Although considerable variation, inter- and intraindividually, was observed, the increase in Cmax and AUC did not deviate from dose proportionality. The present galenic formulation ensures a high bioavailability after a single dose.

Background The cell surface receptor tyrosine kinase c-Met and its ligand, the hepatocyte growth factor (HGF), are implicated in tumor cell migration, invasion, survival and proliferation. EMD 1214063 is a novel potent and highly selective reversible, ATP-competitive small molecule c-Met inhibitor. Methods This is a phase I, first in human (FIH) clinical trial with escalating doses of EMD 121406(NCT 01014936). The primary objective is to determine the MTD. Secondary objectives include evaluation of safety, pharmacokinetics, anti-tumor effect and pharmacodynamics (Pd). Eligible patients had advanced solid tumors not amenable to standard therapies. Following a classical 3 + 3 dose escalation scheme, successive cohorts of patients were treated with once daily oral EMD 1214063 according to two 21-day-cycle schedules, either days 1-14 followed by a 7-day rest(regimen 1, R1), or continuous three times weekly administration (regimen 2, R2). Pd markers were evaluated in paired tumor biopsies. Results As of 30 March 2011, a total of 41 patients had been enrolled, 21 in R1 and 20 in R2. The dose was escalated from 30 mg/day to 115 mg/day in R2 and to 230 mg/day in R1. One DLT was reported in R1 at 115 mg/day, an asymptomatic, grade 4 lipase and G3 amylase elevation. No other DLTs or treatment-related SAEs were observed. The remaining treatment-related AEs of grade 2 or higher included nausea (n = 1), vomiting (n = 1), anorexia (n = 1), diarrhea (n = 1), and fatigue (n = 1) in R1, and neutropenia (n = 1) in R2. 37 patients (90%) had no drug-related toxicity greater than grade 1. At the dose levels investigated, median Cmax and AUC values increased with dose. Immunohistochemical analysis of a patient with pre- and on-treatment biopsies showed a decrease in phospho-c-Met staining intensity under treatment. Preliminary anti-tumor activity has been observed, including an unconfirmed PR in one patient and stable disease lasting for at least 4 months in 5 patients. One patient with sarcomatoid bladder carcinoma and multiple MET copies due to polysomy of chromosome 7 achieved SD for 16+ months. Conclusions The MTD has not yet been reached and dose escalation of EMD 1214063 continues. Updated results of this FIH study will be presented.

Background EMD 525797 is a humanized monoclonal IgG2 antibody specifically targeting av integrins involved in tumor progression. Methods The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of EMD 525797 were assessed in metastatic castrate-resistant prostate cancer (mCRPC) patients. 24 patients (43-80 years) were treated with IV infusions of 250, 500, 1000, or 1500 mg EMD 525797 given over 1 h and received 3 doses (weeks 1, 3, and 5) before response assessment at the end of week 6. Patients without progressive disease could receive further doses every 2 weeks. Dose-limiting toxic effects (DLTs) were assessed over the first 6 weeks and safety was monitored until 4 weeks after the last administration of EMD 525797. Results Final analysis showed that 13 of 24 patients had a longer exposure time than expected(≥84 days): 7 patients had exposure times ≥126 days, 3 patients ≥280 days and 1 patient received EMD 525797 for 534 days. All patients experienced adverse events (AEs), and in 11 patients AEs were considered related to EMD 525797. 4 patients had generalized pruritus, erythema, or rash and 3 patients experienced fatigue, mucosal inflammation, or peripheral edema, but no patient had administration site reactions. Changes in clinical lab values were consistent with basic disease. No DLTs occurred. EMD 525797 showed a dose-dependent, nonlinear PK profile in line with a target-mediated drug disposition. Two patients of the 500 mg cohort had a marked decrease in prostate specific antigen. One of them also had primary tumor shrinkage and normalization of lymph node size. These patients had long-term anti-integrin treatment (297 and 534 days, respectively). Both patients showed additional pain relief.

231 Background: EMD 525797 is a humanized monoclonal IgG2 antibody specifically targeting αv integrins involved in tumor progression. Methods: The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of EMD 525797 were assessed in metastatic castrate-resistant prostate cancer (mCRPC) patients (pts). 24 pts (43–80 years) were treated with IV infusions of 250, 500, 1000, or 1500 mg EMD 525797 given over 1 h and received 3 doses (weeks 1, 3, and 5) before response assessment at the end of week 6. Pts without progressive disease could receive further doses every 2 weeks. Dose-limiting toxicities (DLTs) were assessed over the first 6 weeks and safety was monitored until 4 weeks after the last administration of EMD 525797. Results: Final analysis showed that 13 of 24 pts had a longer exposure time than expected (≥84 d): 7 pts had exposure times ≥126 d, 3 pts ≥280 d and 1 pt received EMD 525797 for 534 d (Table). All pts experienced adverse events (AEs), and in 11 pts AEs were considered related to EMD 525797. 4 pts had generalized pruritus, erythema, or rash and 3 pts experienced fatigue, mucosal inflammation, or peripheral edema, but no pt had administration site reactions. Changes in clinical lab values were consistent with basic disease. No DLTs occurred. EMD 525797 showed a dose-dependent, nonlinear PK profile in line with a target-mediated drug disposition. Pt 1 and 2 of the 500 mg cohort had a marked decrease in prostate specific antigen. Pt 1 also had primary tumor shrinkage and normalization of lymph node size. These pts had long-term anti-integrin treatment (297 and 534 d, respectively). Both patients showed additional pain relief. Conclusions: EMD 525797 showed clinical activity in mCPRC pts in salvage setting, pain relief, and tumor regression. EMD 525797 is well tolerated without any premedication and did not show clinically relevant dose-related changes in the safety parameters assessed. [Table: see text]

Background:Paroxysmal Supraventricular Tachycardia (PSVT) is a common condition which until recently has been treated with anti-arrhythmic drugs or surgery. Radiofrequency (RF) catheter ablation is a new mode of treatment which provides a cure of this condition. Aims:To present our early experience of RF catheter ablation for PSVT. Methods:One hundred and thirty-five procedures were performed in 117 patients. The diagnostic study and therapeutic catheter ablation were performed as a combined electrophysiological procedure in 74 patients (63%). In 58 patients (50%), PSVT was due to Atrio-ventricular junctional (nodal) re-entrant tachycardia (AVJRT). Twenty-five of the 58 patients underwent a fast pathway ablation while 33 had ablation of their slow pathway. The mean number of radio-frequency pulses delivered was ten for a mean duration of 25 seconds. Radiofrequency ablation of accessory pathways was attempted in 58 patients; pathways were left-sided in 29 patients, postero-septal in 21, midseptal in five, Mahaim connection in two, antero-septal in one and right free wall in one patient. One patient with incessant automatic atrial tachycardia also underwent a successful RF ablation. Results:Using RF ablation cure of PSVT was achieved in 90% of patients. Cure of AVJRT was achieved in 95% (55/58) of patients using either fast or slow pathway ablation. Only one patient required permanent pacemaker implantation for Mobitz type I AV block following fast pathway ablation. The overall success rate for ablation of accessory pathways was 85%. There is an operator learning curve for this procedure suggested by the fact that the success rate for accessory pathway ablation at first attempt was 63% in the first 29 patients and 93% in the remaining 29. There was no significant morbidity or mortality during or after the procedure. In a mean follow-up of nine months in the patients with successful ablation only two patients with AVJRT had a recurrence of documented PSVT. Both these patients had successful repeat RF ablation. Catheter ablation using radiofrequency energy is an effective and safe therapeutic option for patients with symptomatic PSVT. (Aust NZ J Med 1993; 23: 317–324.)

Percutaneous liver biopsies and blood samples were obtained from 80 multiparous dairy cows in nine Michigan herds. Biopsies and samples were obtained serially over the peripartum period. Thirty-nine cows received 17 g of supplemental myoinositol in the diet to test its use as a possible lipotropic substance and 41 received a placebo. Liver biopsies were assayed for triglyceride (TG) and total myoinositol content. Serum was assayed for dextran precipitable cholesterol and non-esterified fatty acids (NEFA). Inositol supplementation had no effect on any of the lipid variables. There was a significant herd effect on liver inositol, serum dextran precipitable cholesterol and NEFA concentrations. Serum NEFA and liver TG concentrations increased in the immediate postpartum period, while dextran precipitable cholesterol decreased. A significant herd X period interaction existed for liver TG and serum dextran precipitable cholesterol concentrations. Liver TG and serum NEFA concentrations were positively correlated. Excessive infiltration of bovine liver with lipid at calving appears to be an exaggerated manifestation of normal metabolic changes.

Fatty liver syndrome or hepatic lipidosis (HL) is a condition thought to contribute to an increased incidence of peripartum disease, reduced response to therapy and decreased fertility in dairy cows. This syndrome is characterized by excess triglyceride (TG) accumulation in the liver and apparent decreased hepatic lipoprotein output. In lactating rats, a similar condition results from feeding an inositol-deficient diet. It is also characterized by excess hepatic TG accumulation and decreased hepatic lipoprotein output. Myo-inositol is a necessary component of the phospholipid phosphatidyl-inositol, which is an important membrane constituent. Myo-inositol occurs in feed mainly as the inositol hexaphosphate phytic acid. Phytic acid is undigestible by the monogastric but rumen phytases are assumed to adequately hydrolyze it. In early lactation dairy cows, lipid mobilization is intense, and the myo-inositol requirement may exceed the dietary supply or availability. Myo-inositol is being tested in a field trial as a potential lipotropic agent for dairy cows. Preliminary results suggest no lipotropic benefit from added myo-inositol.

SummaryAn improved platelet aggregometer is described which permits the simultaneous recording of two aggregation curves obtained under technically strictly identical conditions which can be recorded with any single pen recorder. The curves are superimposed thus facilitating the visual or mathematical assessment of differences in the aggregation pattern. The instrument is particularly suitable for serial testing of aggregation inhibiting agents. It is equally suitable in the conventional way as any single channel aggregometer for routine testing of platelet aggregation.

Ein 15jahriger Patient mit idiopathisch-thrombozytopenischer Purpura, die sich gegen Corticosteroid-Behandlung, Splenektomie und immunsuppressiver Therapie mit Vincristin als resistent erwies, wurde mit Thrombozyten-Vinblastin-Komplex behandelt. 5 Tage nach der Applikation dieses Komplexes zeigte sich ein Anstieg der Thrombozyten, der nach Wiederholung der Therapie mit autologem Thrombozyten-Vinblastin-Komplex andauerte und bis zu 600 × 109 Thrombozyten/Liter ging. Die Remission dauert auch 15 Wochen nach Therapiebeginn noch an. Auser einer passageren Granulozytopenie zeigten sich keine Nebenwirkungen.

8 healthy volunteers (age 25±4 years) received in randomized sequence 50, 100, 200, 400, and 600 mg Atenolol orally and 50 mg Atenolol intravenously during 5 minutes under continuous ECG monitoring. On 3 consecutive days prior to the first application of Atenolol the volunteers were exercised on the treadmill under continuous measurement of the blood-pressure until a heart rate of 150 min was achieved. This individually determined load was used on the treadmill 3 h after oral and 1 hour after i.v.-application of Atenolol. Systolic and diastolic blood pressure and heart rate was measured at rest and after 1.5 min and 3 min of exercise. The results are expressed as difference between rest (=0) and exercise in blood pressure (Δs=systolic2 1Δd=diastolic RR in mm Hg) and heart rate (HR in min).

Serum nifedipine concentrations and hemodynamic changes were evaluated in ten healthy volunteers after a single 40-mg oral dose of nifedipine. Peak serum concentrations averaged 45 micrograms/l, attained 2.7 h after dosage. The mean elimination half-life was 5.9 h (range: 3-12 h). Blood pressure, ventricular rate, and echocardiographically-determined rate of circumferential fiber shortening did not differ between placebo and nifedipine trials. Five additional subjects ingested nifedipine once in the control state and on a second occasion with a standard breakfast. Coingestion of food delayed the peak serum nifedipine concentration but did not alter the area under the serum concentration curve. Thus the pharmacokinetic profile of nifedipine indicates that a three- or four-times-daily dose is, in general, appropriate in clinical practice. Completeness of absorption is not altered by coadministration with food. Adverse hemodynamic effects of single oral doses in healthy persons are not evident.

Percutaneous liver biopsies and blood samples were obtained from 80 dairy cows in nine Michigan herds over the peripartum period. Thirty-nine cows were fed 17 g of supplemental inositol and 41 were fed a placebo. Liver biopsies were assayed for total myoinositol and triglyceride (TG) concentrations. Blood samples were assayed for serum dextran precipitable cholesterol, nonesterified fatty acids (NEFA), insulin, thyroxine (T4), free (FT4), triiodothyronine (T3) and free T3 (FT3) concentrations. Serum concentrations of insulin and the thyroid hormones decreased near parturition, with lowest concentrations occurring in the immediate postpartum period. Concentrations of T3 correlated well with T4, and the concentrations of free thyroid hormones reflected concentrations of total thyroid hormones. The percentage of hormone in the free fraction remained constant over time. Serum insulin, T3 and T4 were negatively correlated with serum NEFA and liver TG concentrations. Thyroid hormone concentrations were positively correlated with serum dextran precipitable cholesterol concentrations. Inositol supplementation was associated with reduced circulating T3 and FT3 concentrations, but not T4 and FT4 concentrations. Changes in hormone concentrations at parturition and their relationship to liver TG and serum NEFA concentrations were consistent with a metabolic adaptation by the dairy cow to the negative energy balance of early lactation.

A total of 188 patients with uncomplicated acute myocardial infarction (long-term Norris prognostic index 3.2) were rapidly mobilised, underwent a symptom-limited exercise test around the day of discharge from hospital (day 10), and returned to work at a median of six weeks after the acute event. The incidence of cardiac death six months, one year, and three years after infarction was 2.7%, 4.5%, and 7.3% respectively, and the corresponding figures for recurrent heart attacks were 3.4%, 8.2%, and 18.5% respectively. The risk of recurrence of heart attack was predicted by three variables assessed at discharge--namely, a history of classical effort angina (p less than 0.01), radiological heart failure (p less than 0.05), and angina induced by the exercise test (p less than 0.05). The presence of any of these risk factors defined a group of patients with a sevenfold risk of recurrent heart attacks within six months of the initial acute infarct. It is concluded that these risk factors identify a group of patients with a high risk of recurrence early after infarction, in whom vigorous secondary prophylaxis is desirable.

The nonlactating period should be regarded as a preparatory phase for the next lactation, rather than a rest phase from the preceding one. During the early dry period, a diet should be provided that meets nutrient requirements for energy, protein, calcium, phosphorus, selenium, vitamins, and other minerals. This can usually be accomplished by feeding a blend of roughages with little or no grain and providing a vitamin and mineral supplement. The diet during the late dry period, or transitional stage, should provide increased energy (an additional 3 to 4 Mcal), and a PP preventive regimen can be instituted at this time. Five to six pounds of concentrate containing 200 gm of an ammonium sulfate and chloride mixture and 6 gm of niacin can be added to the diet to aid in the transition to lactation. Feeding of high-calcium, lactating-cow grain mix should be avoided until after parturition. Stress should be minimized at and after parturition, and a quiet maternity area should be available. The normal depression in dry matter intake at parturition should be minimized; feeding high-quality roughages at this time is beneficial. Concentrate consumption should be increased gradually following parturition, and careful attention to the soluble and undegradable protein fractions of the diet is warranted. In group feeding situations, introduction to the energy-dense, high-lactation ration should probably be avoided for the first 10 to 14 days postpartum, until the cow is acclimated to the forage mix. Body overconditioning should be avoided. However, attempts to manipulate body condition during the dry period tend to be unrewarding and counterproductive. Following these guidelines should reduce the incidence of metabolic diseases in high-producing dairy cattle.

SummaryDog serum-induced aggregation of pig platelets in plasma has been considered to be an in vitro model for xenograft rejection. In this paper it is shown that this aggregation can be reduced or totally prevented by pretreatment of the dog serum with certain synthetic fibrinolytic agents or pentosane polysulfo esters or by adding the latter to pig plasma. The common denominator of these compounds is their complement suppressing activity.

Liver biopsies obtained from cattle over the penpartum period were assayed for triglyceride. Subsequent reproductive performance was measured as days open. Preliminary analysis suggests a relationship between liver triglyceride and days open. Factors increasing hepatic fat postpartum may be related to reproductive performance. Key words: Hepatic lipidosis, days open, cattle

Salt-resistant postheparin plasma lipase in recently parturient cows increased with increasing serum lipids and faster recovery from surgery. This lipase activity was decreased by fasting and excess liver fat. It seemed predominantly extrahepatic although a lipase with characteristics similar to hepatic triglyceride lipase was detected. Key words: Postheparin lipase, lipoprotein lipase, fatty liver, serum lipids