TNF Lectin-Like Domain Restores Epithelial Sodium Channel Function in Frameshift Mutants Associated with Pseudohypoaldosteronism Type 1B.

Previous studies have indicated that tumor necrosis factor (TNF) activates amiloride-sensitive epithelial sodium channel (ENaC) current through its lectin-like (TIP) domain, since cyclic peptides mimicking the TIP domain (e.g., solnatide), showed ENaC-activating properties.

Restoration of Epithelial Sodium Channel Function by Synthetic Peptides in Pseudohypoaldosteronism Type 1B Mutants.

The synthetically produced cyclic peptides solnatide (a.k.a.

Glycosylation-dependent activation of epithelial sodium channel by solnatide.

Dysfunction of the epithelial sodium channel (ENaC), which regulates salt and water homeostasis in epithelia, causes several human pathological conditions, including pulmonary oedema. This is a potentially lethal complication of acute lung injury at least partially caused by dysfunctional alveolar liquid clearance, which in turn impairs alveolar gas exchange. Solnatide (named TIP-peptide, AP301), a 17 residue peptide mimicking the lectin-like domain of TNF has been shown to activate ENaC in several experimental animal models of acute lung injury and is being evaluated as a potential therapy for pulmonary oedema.

A FIM study to assess safety and exposure of inhaled single doses of AP301-A specific ENaC channel activator for the treatment of acute lung injury.

AP301 is an activator of ENaC-mediated Na(+) uptake for the treatment of pulmonary permeability edema in acute respiratory distress syndrome (ARDS). The purpose of this "first-in-man" study was to examine local and systemic safety and systemic exposure of ascending single doses of AP301, when inhaled by healthy male subjects. In a double-blind, placebo-controlled study, 48 healthy male subjects were randomized to 6 ascending dose groups (single doses up to 120 mg) of 8 subjects each (3:1 randomization of AP301: placebo).

Mechanism of action of novel lung edema therapeutic AP301 by activation of the epithelial sodium channel.

AP301 [Cyclo(CGQRETPEGAEAKPWYC)], a cyclic peptide comprising the human tumor necrosis factor lectin-like domain (TIP domain) sequence, is currently being developed as a treatment for lung edema and has been shown to reduce extravascular lung water and improve lung function in mouse, rat, and pig models. The current paradigm for liquid homeostasis in the adult mammalian lung is that passive apical uptake of sodium via the amiloride-sensitive epithelial Na⁺ channel (ENaC) and nonselective cyclic-nucleotide-gated cation channels creates the major driving force for reabsorption of water through the alveolar epithelium in addition to other ion channels such as potassium and chloride channels. AP301 can increase amiloride-sensitive current in A549 cells as well as in freshly isolated type II alveolar epithelial cells from different species.

AP301, a synthetic peptide mimicking the lectin-like domain of TNF, enhances amiloride-sensitive Na(+) current in primary dog, pig and rat alveolar type II cells.

Pulmonary permeability oedema is a frequent complication in a number of life-threatening lung conditions, such as ALI and ARDS. Apart from ventilation strategies, no specific therapy yet exists for treatment of these potentially fatal illnesses. The oedema-reducing capacity of the lectin-like domain of TNF (TIP) and of synthetic peptides, mTIP and hTIP, which mimic the TIP domain of mouse and human TNF, have been demonstrated in various studies in rodents.

Essential structural features of TNF-α lectin-like domain derived peptides for activation of amiloride-sensitive sodium current in A549 cells.

The amiloride-sensitive epithelial sodium channel (ENaC) plays a prominent role in sodium uptake from alveolar fluid and is the major component in alveolar fluid clearance in normal and diseased lungs. The lectin-like domain of TNF-α has been shown to activate amiloride-sensitive sodium uptake in type II alveolar epithelial cells. Therefore, several synthetic peptides that mimic the lectin-like domain of TNF-α (TIP) were synthesized and their ability to enhance sodium current through ENaC was studied in A549 cells with the patch clamp technique.

[Scientific conflicts. Conflict over water].

Scientific progress results from conflicts about the existence of new phenomena. Two theorems are formulated: Whatever is predicted by a sufficiently famous theorist will be discovered independently of whether it exists or not. Thus the criterion for existence of a phenomenon is not its discovery but rather its reproducibility! Whatever is "discovered" by a sufficiently famous experimentalist will be explained independently of its existence.

Increased serum osteocalcin levels in elderly females with vitamin D deficiency.

Serum levels of osteocalcin (OC), a 49 amino acid bone matrix protein, have been found to be a biochemical parameter of bone formation. In order to study bone metabolism in aging subjects we measured serum levels of OC, parathyroid hormone (PTH) and 25 hydroxy-vitamin D (25 OH Vit D) in 36 institutionalized elderly females (age range: 80-93 years) and in 21 premenopausal control subjects. Serum levels of 25 OH Vit D were significantly decreased in the elderly subjects (p less than 0.

Double-blind, placebo-controlled, clinical, psychometric and neurophysiological investigations with oxiracetam in the organic brain syndrome of late life.

The therapeutic efficacy and safety of oxiracetam (ISF 2522), a new nootropic cyclic GABA derivative, were investigated in a double-blind, placebo-controlled study in 40 patients with organic brain syndrome in late life. The psychopathology was characterized by memory deficits, intellectual dysfunction, lack of drive, and disturbance of affectivity. Patients were randomly assigned to a 4-week treatment with either 2 X 400 mg oxiracetam capsules t.

[Long-term treatment with Des-Phe-Insulin].

At a geriatric department 61 insulin-dependent diabetics have been treated with des-phe-insulin (DPI) for periods of up to 6 years since 1976. The use of either pure DPI, amorphous DPI or DPI mixed with varying amounts of crystalline non-modified insulin of the same species allowed flexible longterm therapy, as well as management of metabolic emergencies. Comparison of the doses needed before and after change to and from other insulin preparations showed no difference in efficacy.

[Monoclonal gammopathy and platelet function (author's transl)].

This study of 20 patients with monoclonal gammopathy (17 patients with multiple myeloma and 3 patients with Waldenström's syndrome) showed a decreased platlet aggregation induced by ADP and collagen, a reduced platlet retention and a prolonged bleeding time in 25% of the cases in comparison with 30 age- and sex-matched healthy controls. Using Wu and Hoak's technique as increased number of reversible platelet aggregates was observed. There was no relationship between the parameters of primary haemostasis and protein analysis.

Enzymes of the purine interconversion system in chronic lymphatic leukemia: decreased purine nucleoside phosphorylase and adenosine deaminase activity.

Activities of adenosine deaminase (ADA), adenosine kinase (AK), adenine phosphoribosyltransferase (APRT), hypoxanthine guanine phosphoribosyltransferase (HGPRT), and purine nucleoside phosphorylase (PNP), all enzymes of the purine interconversion system, were determined in lymphocytes of 25 patients with chronic lymphatic leukemia (CLL) and in 23 controls. A statistically significant decrease of PNP activities and a reduction of ADA activities at borderline levels were found in the patients, whereas for the other enzymes assayed no deviation from normal values was observed.

[New aspects in the clinical course determination and therapy in multiple myeloma].

Multiple myeloma can be regarded as model disease for quantification of tumor mass, investigation of tumor cell kinetics and of tumor response to therapy. The quantification of the tumor cell number allows evaluation of prognosis and monitoring of disease as well as of therapy induced responses. Treatment of multiple myeloma is primarily based on the alkylating drugs cyclophosphamide and melphalan.

[Monocyte cytotoxicity in Hodgkin's disease].

Monocyte mediated antibody dependent cellular cytotoxicity (ADCC) was determined in 23 patients with Hodgkin's disease and 29 normal healthy controls. ADCC activity of monocytes was found to be significantly increased (p less than 0.01) in patients when compared to the controls.

[The problems of informing oncological patients].

The "phase-model" of Kübler-Ross represents useful auxiliary means, which however prove correct only in a portion of the cases. The information of the diagnosis of a malign disease constitutes one of the most difficult medical problems and requires certain basic conditions. As a rule it cannot be delegated but must be solved within the realm of oncology.

[Ferrokinetic studies in haemoglobin Wien haemolytic anaemia (author's transl)].

Ferrokinetic studies in two patients with haemolytic anaemia due to haemoglobin Wien revealed increased haemoglobin synthesis and an increase in effective erythropoiesis. Haemolysis is due to an instability of the haemoglobin itself. The spleen does not appear to play any appreciable role in the aetiology of this condition.

[Determination of the tumor cell mass and its significance as a parameter for prognosis and therapy in patients with multiple myeloma].

In 19 patients with multiple myeloma tumor cell mass was determined. In addition the influence of tumor cell number on certain clinical parameters as well as on survival time has been analysed. In some patients the behaviour of tumor cell number in the course of different therapeutic regimen was studied.

[The question of the diagnostic value of increased erythrocyte enzymes in leukemia].

The investigated erythrocyte enzymes (LDH, pyruvatkinase, Glukose-6-phosphat-dehydrogenase) are moderately to extremely elevated in most cases of leucemia. There exists no significant correlation to the number of reticulocytes and the erythrocyte half life time.