[Promoting research from the viewpoint of industry]. / Forschungsförderung aus Sicht der Industrie.

Industry sponsors medical research in the fields of pharmaceutical products, diagnostics, medical technology, medical equipment, clinical nutrition and information systems. In pharmaceutical research, the companies of VFA invested a total of DM 4.3 billion in 1995, that means 18% of the turnover. DM 1.4 billion were spent mainly on clinical research studies. Beyond this, industry shares the costs of academic research institutes and gives support through its foundations. The decreasing number of domestic clinical studies, that German clinics complain about, is caused by organisational and administrative deficiencies, leading to major economic disadvantages. Recommendations of how to improve the situation exist and must be implemented.

Determination of islet cell antibodies using an ELISA system with a preparation of rat insulinoma (RIN A2) cells.

An enzyme-linked immunosorbent assay (ELISA) was established for the detection of islet cell antibodies in human sera. The antigen was prepared from rat insulinoma (RIN A2) cells. Cells were dissociated in lysis buffer and the lysate was centrifuged at 100,000 x g. The supernatant was used to coat microtiter ELISA plates (10 micrograms protein/ml in PBS pH 7.2). Non-specific binding sites on the plates were blocked with 2% PBS-BSA. Human test sera were preabsorbed on separate plates using 2% PBS-BSA and incubated on precoated plates at an optimal dilution of 1/10 in 60 mM PBS for 60 min at 37 degrees C. Phosphatase-labeled anti-human IgG serum and phosphatase substrate were applied and the reaction was stopped by adding 3 M NaOH. Out of 90 sera from type I diabetic patients, 47 (52.2%) reacted in the new ELISA whereas none of 15 type II diabetics, 50 sera containing non-islet specific antibodies or 100 normal controls were positive. In the same group of patients, ICA were positive in 63.3%. When both, the ELISA and conventional ICA testing were applied, the number of positives was increased to 83%. The ICA-ELISA with the above described antigen preparation provides a well standardized and reproducible test method which is highly specific for type I diabetes. It may therefore be useful for large screening procedures.

Comparison of the effects of betamethasone and L-carnitine on dipalmitoylphosphatidylcholine content and phosphatidylcholine species composition in fetal rat lungs.

Antepartum administration of L-carnitine to pregnant rats results in an increase of both total phospholipid (80 +/- 11 mg/g dry weight (dw); mean +/- SD) and dipalmitoylphosphatidylcholine (DPPC) content (7.7 +/- 2.1 mg/g dw) in fetal lungs as compared to controls (72 +/- 10 and 7.0 +/- 2.5 mg/g dw, respectively). On the other hand, no effect of L-carnitine could be demonstrated on the DPPC portion in the total phosphatidylcholine (PC) or on the portion of palmitic acid in the PC fatty acids. Betamethasone elevated the DPPC content in fetal lungs (8.1 +/- 2.0 versus 7.0 +/- 2.5 mg/g dw in the controls), while total phospholipid content remained unaffected (71 +/- 19 versus 72 +/- 10 mg/g dw). The portion of DPPC in the PC species increased significantly (p less than 0.01) from 27.6 +/- 4.5 in the fetal lungs of the control group to 34.2 +/- 3.3 in the lungs of the betamethasone-treated group, while the palmitic acid portion in the PC fatty acids was nearly unchanged (45.9 +/- 3.2 versus 43.9 +/- 2.6 in the controls). Further, after betamethasone treatment, a significant diminution (p less than 0.01) of the monoenic PC 32 species (palmitoyl-palmitoleyl PC and palmitoleyl-palmitoyl-PC) and the PC 34 species (consisting primarily of palmitoyl-oleoyl-PC) could be demonstrated both in absolute and relative terms. This is in agreement with a significant reduction of the portions of palmitoleic (p less than 0.01) and oleic (p less than 0.05) acids in the total PC fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)

[Chemistry of phenoxyacetic acid esters of oxyalkyltheophyllines and 1-(theophyllin-7-yl)-ethyl-2-[2-(p-chlorophenoxy)-2-methyl-propionate] (etofylline clofibrate), a novel antilipaemic agent (author's transl)]. / Zur Chemie der Phenoxyessigsäureester von Oxyalkyltheophyllinen und 1-(Theophyllin-7-yl)-äthyl-2-[2-(p-chlorphenoxy)-2-methylpropionat] (Etofyllinclofibrat), einem neuen Antilipämikum.

Esters of phenoxyacetic acids and oxyalkyltheophyllines were prepared as potential antihyperlipaemics. The basic idea was to ameliorate the known antilipaemic potency of phenoxyacetic acids and that of clofibric acid as the best known representative, respectively, by using alcoholic ester components with therapeutical efficacy of their own and to expand their therapeutical spectrum. Syntheses and preparative routes of these esters are presented. 1-(Theophyllin-7-yl)-ethyl-2-[2-(p-chlorophenoxy)-2-methyl-propionate] (ML 1024; etofylline clofibrate; Duolip) was selected for further investigations. Characteristics and spectroscopic data of ML 1024 are described.

[Clinical effects and tolerance of etofylline clofibrate]. / Klinische Wirkungen und Verträglichkeit von Etofyllinclofibrat.

The efficacy of 1-(theophyllin-7-yl)-ethyl-2-[2-(p-chlorophenoxy)-2-methylpropionate] (etofylline clofibrate, Duolip) was investigated in 47 hyperlipidaemic patients of type II--V in an open within-patient study. All patients were dietary adapted before the preliminary wash-out period of 4 weeks and received etofylline clofibrate in a dosage of 500 mg/day (2x1 capsule) over 4 weeks, and 750 mg/day (3 x 1 capsule) over further 4 months. Depending on type reductions of cholesterol between 15 and 23% and of triglycerides between 24 and 52% were achieved. The total lipids were reduced, too, between 14 and 31%. Except for type IIb, all reductions were statistically significant. The rate of responders was between 47 and 80%. The higher dose (750 mg) only affected the cases of type III and IV, in which a higher rate of responders was found coinciding with more pronounced lipid level reductions. However, the influence of the treatment duration on this increased activity may play an important role. Etofylline clofibrate did not show any side effects and was well tolerated. This clinical finding coinciding with the results of the preceding pilot study on the human tolerability in 10 volunteers. From all parameters tested only GPT and cholesterol showed significant alterations (reduction).

[Comparative study of relative biovailability of several spironolactone formulations in a steady-state test (author's transl)]. / Vergleichende Untersuchung der relativen Bioverfügbarkeit mehrerer Spironolacton-Zubereitungen im Steady-state-Versuch.

By the US Food and Drug Administration spironolactone is regarded as a drug with problems related to bioavailability. A steady-state study was performed comparing the 50- and 100-mg formulations of two manufacturers with each other. Applying a fluorimetric method to both canrenone and canrenoate--the major biologically active metabolites of spironolactone--the two brands were compared in 11 volunteers for the 50 mg, and in 10 volunteers for the 100 mg dosage form.

[Relative bioavailability of a vincamine retard formulation. Pharmacokinetic study in normal subjects (author's transl)]. / Relative Bioverfürgbarkeit einer Vincamin-Retard-Zubereitung. Pharmakokinetische Untersuchungen an gesunden Versuchspersonen.

The study was carried out in 6 healthy volunteers in cross-over design. The pharmacokinetic parameters were calculated after application of 60 mg vincamine base in comparison to a sustained release formulation (vincamine ratio-pharm 30 mg) on the basis of a GC method. Summarizing it can be stated that the sustained release formulation has a flatter profile and is therefore more adapted to clinical application. The extent of absorption expressed as AUC of the serum concentration-time curve, has three times the extent of the curve with the pure substance.

Hypolipemic activity of clofibrate-related compounds. 2nd Communication.

Clofibrate-related compounds were synthesized from substituted phenoxyacetic acids by esterification with salicylic acid derivatives, by amidation of thiazolidines or by reaction with cinnarizine. Lipid lowering effect was investigated in normolipemic and hyperlipemic rats. The long-term hyperlipemic model used permits differentiation of hypolipemic efficacy, i.e., from clofibrate or compounds of similar activity.

1-(Theophyllin-7-yl)-ethyl-2-[2-(p-chlorophenoxy)-2-methylpropionate] (ML 1024), a new hypolipemic agent.

1-(Theophyllin-7-yl)-ethyl-2-[2-(p-chlorophenoxy)-2-methylpropionate] (ML 1024) was tested on acute and chronic toxicity, on teratogenesis and fetotoxicity, on blood pressure and blood flow behaviour, on hypolipemic activity and general pharmacological behaviour in a screening test using 54 parameters. Results warrant further investigation of the potential therapeutic application of ML 1024 in humans based on its superiority to the well-known antilipemic clofibrate (CPIB).

Hypolipemic activity of clofibrate-related compounds.

Ethyl-2(p-chlorophenoxy)-2-methylpropionate (clofibrate) related compounds were synthesized from substituted aryloxy acetic acids (III) either by esterification with selected alcohols (3,3,5-trimethylcyclohexanol and oxyalkyltheophyllines), by introduction into heterocyclic ring system (triazine type) or by amidation (aminotriazines and p-aminobenzoates). Lipid lowering effect was tested in normolipemic and hyperlipemic rats against clofibrate as reference. Some of these derivatives show high activity at low dosage, even under hyperlipemic conditions, whereas clofibrate is only slightly effective. From pharmacological results it can be suggested that the nature of acid group substituent is the main factor for efficacy, while the role of alpha-substituent is important for differentiation of activity against cholesterol and/or triglyceride.