Results of a double blind study of 89-strontium therapy of skeletal metastases of prostatic carcinoma

Forty-nine patients were treated with either 3×75 MBq ⁸⁹Sr or saline as placebo. Analysis of results 1 to 3 years after therapy revealed the ineffectiveness of ⁸⁹Sr to relieve pain from metastases. Unexpectedly, a higher survival rate was found after Sr application (46% vs 4% after 2 years). Covariate analysis underlines the effect of ⁸⁹Sr therapy on life expectation.     

Max Brödel (1870–1941): his life and his role in the development of surgery

Summary. Max Br?del (1870–1941), from Leipzig, Germany, is often referred to in the USA as the father of modern medical illustration and mentioned in the same breath as Leonardo da Vinci or Andreas Vesal. After a classical formal art education in Leipzig he worked in Carl Ludwig's laboratory of physiology and anatomy, where he came in contact with American physicians. In 1894, the anatomist F. P. Mall convinced him to work for the recently inaugurated Johns Hopkins School of Medicine in Baltimore, where he collaborated with world-famous surgeons such as H. A. Kelly, W. S. Halsted, and H. Cushing. His illustrations were characterized by meticulous observation, both realistic and explanatory intention, technical superiority, and artistic merit. In 1911 he established the first “Department of Art as applied to Medicine”. Here, he proved to be an innovative artist, a creative scientist, and an inspiring and skillful instructor. By the time of Br?del's retirement in 1939, 160 students had graduated as medical illustrators. His pupils spread his principles and style throughout the USA and Canada, and several similar academic programs for medical illustration have been founded in these countries.      

Radioreceptor Assay of Metoprolol in Human Plasma: Comparison with an Enantiospecific High-Performance Liquid Chromatographic (HPLC) Procedure

Plasma concentrations of metoprolol after acute and repetitive administration of R/S-metoprolol to healthy volunteers were measured by a -adrenoceptor subtype-specific radioreceptor assay (RRA) and by an enantiospecific high-performance liquid chromatographic (HPLC) method. In the RRA, R/S-metoprolol showed a 20-fold ₁-subtype selectivity: the S-( – )-enantiomer was 35-fold more potent than the R-( + )-enantiomer. A comparison between S-( – )-metoprolol concentrations detected in the plasma samples by HPLC and those detected by RRA yielded a 1/1 relationship, indicating that active metabolites are not present to a significant extent. These results were independent of the widely scattering metabolic clearance of metoprolol (with the potential of differences in the rate and extent of formation of active metabolites) in the volunteers. In general, HPLC methods can be validated by comparison with RRA in order to clarify whether active metabolites are present and—on the basis of the K_i value from RRA—whether the detection limit of the physicochemical procedure is sufficient to cover the therapeutically relevant range.     

Procedures to Characterize In Vivo and In Vitro Enantioselective Glucuronidation Properly: Studies with Benoxaprofen Glucuronides

The diastereoisomeric glucuronic acid conjugates of R/S-benoxaprofen are the major benoxaprofen metabolites and are found in urine at high concentrations. The conjugates of R- and S-benoxaprofen can be separated directly on a C₁₈ reversed-phase column using a mixture of acetonitrile and tetrabutylammonium hydroxide buffer, pH 2.5 (28:72, v/v), as the mobile phase. The k values of S- and R-benoxaprofen glucuronides are 57.5 and 63.0, respectively. Diluted urine or deproteinized plasma samples were injected without further treatment. With fluorescence detection at 313/365 nm, quantifiable limits of 50 ng equiv./ml were found for the conjugates. The intra- and interday variability was below 12%. Utilizing this analytical procedure it is possible to characterize enantioselective glucuronidation both in vivo and in vitro. For in vitro procedures, apparent rates of formation and the R/S ratio may be substrate (benoxaprofen) and cosubstrate (UDPGA) dependent. Moreover, enantioselective cleavage of the formed benoxaprofen glucuronides by alkaline hydrolysis, hydrolytic enzymes, and acyl migration must be controlled for both in vitro and in vivo studies since R-benoxaprofen glucuronide is degraded faster than the S-diastereomer under certain conditions.     

Inhibition of interleukin-6 synthesis in an animal model of septic shock by anti-C5a monoclonal antibodies

The complement activation fragment C5a was recently shown to induce interleukin (IL)-6 synthesis by peripheral blood mononuclear cells. To understand better the role of C5a in cytokine regulation in vivo, we investigated the effects of complement depletion by cobra venom factor (CVF) or of anti-C5a monoclonal antibodies (mAb) on IL-6 generation in an animal model of septic shock. Complement-depleted pigs which were subsequently challenged with Escherichia coli generated significantly (p < 0.05) less IL-6 during the 6-h observation period than complement-sufficient controls. To address specifically the role of C5a in IL-6 regulation, we produced a C5a(57–74) peptide-specific mAb (T13/9) which neutralizes the bioactivity of porcine C5a. The mAb T13/9 does not crossreact with the precursor protein C5. The pretreatment of pigs with anti-C5a mAb T13/9 prior to the induction of sepsis resulted in a decrease of over 75 % in serum IL-6 bioactivity compared to control animals (p < 0.0001). These results indicate a role for C5a in the modulation of IL-6 synthesis in Gram-negative bacteremia.     

The pharmacokinetics of tranylcypromine enantiomers in healthy subjects after oral administration of racemic drug and the single enantiomers

The pharmacokinetics of the two enantiomers of tranylcypromine were evaluated in six healthy subjects after oral dosage of the racemate (20 mg of the sulphate) and the single enantiomers (10 mg of the sulphate) using an enantiospecific assay. Significant differences in AUC, Cmax, lambda(z), and CLR of the two enantiomers were observed both on administration of the racemate and of the individual enantiomers. The plasma concentrations and urinary excretion rates of (-)-tranylcypromine exceeded those of (+)-tranylcypromine. AUCs of the (-)-enantiomer [arithmetical means 197 ng ml(-1) h after the racemate, 130 ng ml(-1) h after the enantiomer] were greater than those of the (+)-enantiomer [26 ng ml(-1) h after the racemate, 28 ng ml(-1) h after the enantiomer] (P = 0.0001). No in vivo racemisation was detected. The power of the study was insufficient to establish any enantiomer-enantiomer interaction except for a possible interaction at the level of renal clearance (P = 0.013 for both enantiomers).     

Eisen-Resorption an isolierten Dünndarmpräparaten von normalen und anämischen Ratten

Zusammenfassung 1. Am isoliert durchströmten Darmpräparat der Ratte wurde die Eisen-Resorption mit Hilfe von radioaktiv markiertem Eisen (⁵⁹Fe) untersucht. Hierzu wurden von jeder Ratte, an der Flexura duodenojejunalis beginnend, 4 Jejunumstücke präpariert, die im Mittel 8 cm lang waren. Die Fe-Konzentration in der Durchströmungsflüssigkeit war 10^–5 m.2. Die Fe-Konzentration im Resorbat der beiden proximalen Darmabschnitte betrug etwa 3%, die der beiden distalen Darmabschnitte etwa 1% der Fe-Konzentration in der angebotenen Flüssigkeit, wenn das Fe zu Versuchsbeginn als Fe²⁺ zugesetzt wurde. 16–20 cm unterhalb der Flexura duodenojejunalis nahm die Fähigkeit der Darmpräparate, Eisen zu resorbieren, steil ab.3. Wurde der Durchströmungsflüssigkeit zu Versuchsbeginn Fe³⁺ zugegeben, so war die Fe-Konzentration im Resorbat der beiden proximalen Darmsegmente nur 0,7% der Fe-Konzentration der angebotenen Flüssigkeit, die Fe-Aufnahme in die Mucosa der Darmabschnitte nur ein Viertel derjenigen, die man nach Zugabe von Fe²⁺ zur Durchströmungsflüssigkeit messen konnte.4. Der zeitliche Verlauf der Eisen-Resorption zeigte, daß der Penetration des Fe durch die Darmwand offenbar die Bindung des Eisens in der Mucosa vorangeht.5. Bei Angebot einer niedrigen Fe-Konzentration (2,5 · 10^–7) wird prozentual mehr Eisen resorbiert als bei Angebot einer höheren Fe-Konzentration (10^–4 m).6. Durch eine vorhergehende Fe-Beladung der Darmsegmente in vivo kann der Anteil des angebotenen Eisens, der in vitro resorbiert wird, vermindert werden. Umgekehrt ist die Eisen-Resorption bei Darmpräparaten von Tieren mit Eisenmangel-Anämie gegenüber derjenigen von gesunden Tieren mehr als doppelt so hoch. Beim anämischen Tier kann die gesteigerte Eisen-Resorption in vitro durch eine vorhergehende Fe-Beladung des Darmes in vivo wieder gesenkt werden. Die Befunde sprechen dafür, daß die Mucosa des Darmes ein System mit begrenzter Kapazität besitzt, das für die Eisen-Resorption und deren Regulation verantwortlich ist.

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Summary 1. The absorption of iron was studied in the isolated gut preparation of the rat using ⁵⁹Fe as a tracer. Gut segments of a mean length of 8 cm were prepared starting from the duodenojejunal flexur. The iron concentration of the perfusing medium was 10^–5 molar.2. When iron was presented in the ferrous state the iron concentration of the fluid absorbed by the two proximal gut segments was 3% and of two more distal segments was 1% of the inital concentration of the perfusing medium. At a distance of 16–20 cm distal to the duodenojejunal flexure the ability of gut to absorb iron decline steeply.3. When iron was presented in the ferric state the iron concentration on fluid absorbed by the proximal segments of the gut was only 0.7% of the concentration of the perfusing medium. The uptake of iron into the wall of the gut reached only 1/4 the value obtained with iron in the ferrous state.4. The time course of absorption suggests that the penetration of iron through the wall of the gut is preceded by the binding of iron to the mucosa cells.5. The percentage of iron absorbed from a perfusing medium of low iron concentration (2,5 × 10^–7 molar) was greater than that absorbed from a higher one (10^–4 molar).6. A single administration of iron in vivo 2 hours prior to the preparation diminished the percentage of iron in vitro. The iron absorption was, however, increased, if gut segments were taken from animals made anemic by bleeding and by feeding a diet low in iron content. This enhancement of iron absorption could be abolished if the anemic animals were treated in vivo with a single iron dose 2 hours before the gut segments were isolated.These findings are in favour with the assumption that the mucosa cells are provided with an iron binding system of limited capacity, which seems to adjust iron utilization to iron demand.

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Mit 4 Textabbildungen

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Herrn Professor Georg von Hevesy zum 80. Geburtstag in Verehrung gewidmet.

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Über einen Teil der Ergebnisse wurde bereits auf dem 1. Internationalen Symposion über Radioisotope in der Hämatologie (1.—3. 3. 1962) in Freiburg berichtet.     

Umwelteinflüsse medizinisch bewerten

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