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Summary.: The spectrum of action of flupirtine includes analgesia, muscle relaxation and neuroprotection. N-methyl-D-aspartate (NMDA) receptor antagonism has been discussed as a possible mechanism of action of this compound with little direct evidence. The objective of the present study was to develop a plausible model to explain flupirtine's spectrum of action. A four-stage strategy was selected for this purpose: Firstly, the serum concentration of flupirtine under therapeutic conditions was determined on the basis of the current literature. The second stage involved assessing the known in-vitro effects in light of the therapeutic active concentration. Using whole cell patch clamp recordings from cultured rat superior colliculus neurones interactions between flupirtine and NMDA receptors were assessed. Only very high concentrations of flupirtine antagonized inward currents to NMDA (200 μM) at −70 mV with an lC50 against steady-state responses of 182.1 ± 12.1 μM. The effects of flupirtine were voltage-independent and not associated with receptor desensitization making actions within the NMDA receptor channel or at the glycine modulatory site unlikely. NMDA receptor antagonism probably has little relevance for the clinical efficacy of flupirtine as the concentrations needed were far higher than those achieved in clinical practice. However, the activation of a G-protein-regulated inwardly rectifying K+ channel was identified as an interesting molecular target site of flupirtine. In the next stage, the central nervous spectrum of action of experimental K+ channel openers (PCO) was considered. As far as they have been studied, experimental K+ channel openers display a spectrum of action comparable to that of flupirtine. In the final stage, a global model was developed in which flupirtine stabilizes the resting membrane potential by activating inwardly rectifying K+ channels, thus indirectly inhibiting the activation of NMDA receptors. The model presented here reconciles the known functional NMDA receptor antagonism of flupirtine with the activation of K+ channels that occurs at therapeutic concentrations, thus providing an understanding of flupirtine's spectrum of action. This makes flupirtine the prototype of a clinically applicable substance group with analgesic, muscle-relaxant and neuroprotective properties.

The continuation of the primary and secondary antibody response to human serum albumin (HSA), induced in vivo, was followed in explanted chicken spleen fragments. The effect of actinomycin D (AMD) on the in vitro response was studied in spleens from chickens injected with various doses of HSA and removed at differing intervals after injection. The antibody response of "early spleen" cultures was AMD-sensitive, while cultures of spleens removed later were AMD-resistant. It was suggested that this shift represented the development of cells with in vivo preformed RNA involved in specific immunoglobulin synthesis. With increasing doses of HSA, the AMD-sensitive phase was prolonged, suggesting the delay of mRNA formation or some other AMD-inhibitable process in vivo. With large doses of HSA, the immune response in vitro was decreased, starting after a 1–2 day delay and not occurring in the presence of AMD. Massive doses of HSA completely inhibited the continuation of the response in vitro by spleen fragments removed between the 2nd and 5th day after injection. The results point to the controlling role of antigen dose in determining the onset of macromolecular synthesis during immunocyte maturation.

The present report concerns investigation of bladder disturbances in 31 juvenile diabetics. It was shown that: 1. The predominant lesion is one of neuropathy. — 2. Vesical involvement such as increased capacity and atony was demonstrated by cystometry in 27 out of the 31 cases (87%). — 3. 4 cases had neck hypertrophy. — 4. The most striking symptom was a large volume of first morning urine. This information was elicited from the patients. They had no urological complaints. — 5. A high incidence of impotence was seen in diabetics with neurogenic bladder. — 6. The possible causes of such lesions and the value of certain therapeutic measures was discussed. Le présent travail concerne une investigation sur les troubles de la vessie chez 31 diabétiques jeunes. Il a été démontré que: 1. La lésion prédominante est une lésion de neuropathie. — 2. Des signes vésicaux tels que la capacité accrue et l'atonie mesurées par cystométrie, ont été démontrés dans 27 cas sur les 31 (87%). — 3. 4 cas avaient une hypertrophie du col. — 4. Le symptome le plus frappant était l'important volume de la première urine du matin. Ceci a été indiqué par les patients. Ils ne se plaignaient d'aucun trouble urologique. — 5. On trouve une haute fréquence d'impuissance chez les diabétiques ayant une vessie neurogène. — 6. Les causes possibles de telles lésions et la valeur de certaines mesures thérapeutiques sont discutées. Es wird über Blasenstörungen bei 31 jugendlichen Diabetikern berichtet. Es konnte gezeigt werden, daß: 1. die Neuropathie die vorherrschende Störung darstellt; 2. bei 27 von 31 Fällen (87%) eine Blasenbeteiligung (gesteigerte Kapazität und zytometrisch nachweisbare Atonie) vorlag; — 3. bei 4 Fällen eine Blasenhalshypertrophie bestand; — 4. hervorstechendes Symptom war die große Harnmenge bei der ersten morgendlichen Blasenentleerung, über das die Patienten auf Anfrage berichteten. Sie äußerten keine urologischen Beschwerden; — 5. Bei vielen Diabetikern mit einer neurogenen Blasenstörung ist eine Impotenz festzustellen; — 6. Die für diese Läsionen in Frage kommenden Ursachen und der Wert einiger therapeutischer Maßnahmen werden diskutiert.