Sunday, 24.09.2017

Reply to Ervin Varga’s Comment by Ildiko Miklya

ILDIKO MIKLYA’S REPLY TO ERVIN VARGA’S COMMENT ON HER HISTORY OF DEPRENYL

Thank you very much Dr. Varga for your comment. The relatively slow international acceptance of deprenyl (selegiline) in the treatment of depression is difficult to understand considering the world wide use of selegiline in increasing amounts supported by thousands of publications. Professor Knoll is working now on his new book (“The enhancer regulation in the mammalian brain”) from which two paragraphs presented with his permission below should provide a better understanding of the story of selegiline in psychiatry.  

“Unfortunately, Hungary was in 1960s cut from the western world, we worked isolated from the mainstream of science and our results remained almost unnoticed. Since our studies confirmed that E-250, now known as selegiline, is antagonizing the effect of tyramine, I asked my good friend and classmate, Ervin Varga, who worked as a psychiatrist in our University Clinic, to test in a preliminary trial the antidepressive effect of E-250 and also the lack of the 'cheese effect'. Varga published in 1965 a preliminary note (in German) on the promising results of a clinical trial with racemic E-250 in depressed patients (Varga 1965). He wrote with his coworker the first paper, in English, showing that racemic E-250 is an efficient, prompt acting antidepressant (Varga and Tringer 1967). They wrote in 1971 the first paper demonstrating that E-250, is a potent antidepressant (Tringer and Varga 1971). In retrospect it is almost incredible that selegiline was first registered as an antidepressant only in 2006 (luckily in the USA: Emsam), though our first paper which proposed this indication appeared in the Hungarian version in 1964 and in the English version in 1965 (Knoll et al.1964, 1965).

Varga also found that in harmony with our findings in animal experiments, E-250 was free of the cheese effect in humans. This finding was cited in the discussion of our paper published in 1968 as follows: ‘Even provocative cheese consumption failed to produce headache or hypertensive crisis’ (Knoll et al. 1968; p.111). Since Varga left Hungary for the USA, where he still lives, he never continued his clinical studies with selegiline. His convincing preliminary study which confirmed that E-250 is devoid of the 'cheese effect' was never completed and remained unpublished. It marks the era in Hungary in the 1960s that in the discussion of the Knoll et al.1968 paper also two other Hungarian studies are mentioned which confirmed that E-250 was devoid of the 'cheese effect' (Kardos and Füredi 1966; Juhász personal communication). None of them were completed, but later performed studies confirmed the correctness of their observation. The validity of my proposal that deprenyl must be free of the 'cheese effect' was tested with perfection in volunteers by Sandler and his co-workers and published in 1978. They confirmed that in harmony with our findings in animal experiments, (-)-deprenyl is in humans an MAO inhibitor free of the cheese effect. After pretreatment with deprenyl, parkinsonian volunteers who received levodopa or levodopa+carbidopa suffered no adverse pressor reaction after challenged with oral tyramine in considerably greater amounts than the dose likely to be encountered in a normal diet (Elsworth et al., 1978; Sandler et al., 1978).”

Let me again thank you for sharing with us the story of the first experiences with deprenyl in humans.

Elsworth JD, Glover V, Reynolds GP, Sandler M, Lees AJ, Phuapradit P, Shaw KM, Stern GM, Kumar P. Deprenyl administration in man; a selective monoamine oxidase B inhibitor without the "cheese effect". Psychopharmacology 1978; 57: 33-8.

Juhász P. Personal Communication 1966; (Quoted in Knoll et al., 1968).

Kardos G, Füredi J. On the clinical application of a new psychoanaleptic drug (E-250) in psychoses. In: Dumbovich B, Fekete G, Raáb K, editors. IV. Conferentia Hungarica Pro Therapia et Investigatione In Pharmacologia. Budapest; Akadémiai Kiadó (Publishing House of the Hungarian Academy of Sciences); 1968, pp. 63-5.

Knoll J, Ecsery Z, Kelemen K, Nievel J, Knoll B. Phenylisopropylmethyl-propinylamine HCL (E-250) egy új hatásspektrumú pszichoenergetikum. MTA V. Oszt. Közl. 1964; 15: 231-8 (in Hungarian).

Knoll J, Ecseri Z, Kelemen K, Nievel J, Knoll B. Phenylisopropylmethyl¬propinylamine (E-250) a new psychic energizer. Archives internationales de Pharmacodynamie et de Thérapie 1965; 155:154-64.

Knoll J, Vizi ES, Somogyi G. Phenylisopropylmethylpropinylamine (E-250), a monoamine oxidase inhibitor antagonizing the effects of tyramine. Arzneimittelforschung 1968; 18: 109-1.

Sandler M, Glover V, Ashford A, Stern GM.  Absence of „cheese effect” during deprenyl therapy: some recent studies’, Journal Neural Transmission, 1978; 43: 209-15.

Tringer L, Haits G, Varga E. The effect of (-)E-250, (-)L-phenyl-isopropylmethyl- propinyl-amine HCl, in depression. In: Leszkovszky G, editor. V. Conferentia Hungarica pro Therapia et Investigatione in Pharmacologia. Budapest: Akadémiai Kiadó (Publishing House of the Hungarian Academy of Sciences); 1971, pp. 111-4.

Varga E. Vorläufiger Bericht über die Wirkung des Präparats E-250 (phenyl-isopropyl-methyl-propinylamine-chlorhydrat). In: Dumbovich B, editor. III. Conferentia Hungarica pro Therapia et Investigatione in Pharmacologia. Budapest: Akadémiai Kiadó (Publishing House of the Hungarian Academy of Sciences); 1965, pp. 197-201.

Varga E, Tringer L. Clinical trial of a new type of promptly acting psychoenergetic agent (phenyl-isopropylmethyl-propinylamine HCl, E-250). Acta Medica Hungarica 1967; 23: 289-95.

 

Ildiko Miklya

November 27, 2014