Monday, 27.03.2017

Barry Blackwell: Ervin Varga: Family, Culture, Persona and Career

Joseph Knoll’s comment

 Ervin Varga’s life, like mine, a survivor of Auschwitz and Dachau, illustrate that a system promoted by hatred makes the society insane and anything and everything can happen. There was a resurgence of political anti-Semitism in our country, Hungary, when the Horthy era began in 1920. Horthy’s Hungary was the first country in Europe to codify the infamous Numerus Clausus Laws, which set quotas for the number of Jewish students in Universities. This was the first step in mid-Europe in that long chain of deprivation of civil and human rights which culminated finally in the Holocaust. Ervin Varga was my schoolmate. We were born in 1925 in Hungary. Both of us wanted to be physicians, however, in 1943 we were refused entry to the university, thus, we lost two years and got our MD degree in 1951. We both worked in the University of Medicine in Budapest (now Semmelweis University) when my deprenyl-story, which made my collaboration with Ervin imperative, started. I worked in the Department of Pharmacology, Ervin in the Department of Psychiatry.

In 1963, a calamitous number of clinical reports (Womack, Foster, Maan, Davies) appeared in The Lancet concerning patients treated with MAO inhibitors (tranylcypromine, nialamide, pargyline) who developed temporary clinical symptoms (hypertension, palpitation, neck stiffness, headache, nausea, vomiting), similar to a paroxysm produced by pheochromocytoma. Blackwell realized that these hypertensive crises are associated with the ingestion of high amounts of tyramine in cheese, and MAO inhibitors impede metabolism (a.k.a. the “cheese effect”) (Blackwell 1963).

 In the early 1950s, I started my behavioral studies which initiated my structure-activity-relationship study to develop an amphetamine derivative free from its catecholamine-releasing property (recently summarized in Knoll 2016). The selected compound for further development was E-250 (later named deprenyl). We worked first with the racemic form and since 1966 with (-)-E-250, known now as selegiline/ (-)-deprenyl (DEP), registered at present in more than 60 countries and marketed under more than 100 trade names. Our detailed pharmacological studies convinced me, already in 1965, that DEP is the first MAO inhibitor free of the cheese effect and the prima-facie experimental evidence was published three years later (Knoll et al. 1968).

Johnston, developer of clorgyline, proposed the existence of two forms of MAO, “type A” and “type B”. The former is selectively inhibited by clorgyline, and the latter is relatively insensitive to it. Johnston’s nomenclature has become widely accepted and is still in use. Clorgyline remained the classic selective inhibitor of A-type MAO (Johnston 1968).

For further studies, a selective inhibitor of MAO-B was greatly needed. I was astute enough to realize that DEP was the missing, highly selective inhibitor of MAO-B and presented this finding in my lecture at the First International MAO Meeting in Cagliari (Sardinia) in 1971. DEP was used, thereafter, as the specific experimental tool to analyze B-type MAO. The first paper which described this novel property (Knoll and Magyar 1972) has become a citation classic within ten years (Knoll J, This Week’s Citation Classic, January 15, 1982). DEP’s selective MAO-B inhibitory effect was at the center of our interest for many years. However, it delayed the discovery of the drug’s enhancer effect. The MAO inhibitory effect of the compound led to the first clinical application of DEP.

Because of the serious side effects of levodopa in Parkinson’s disease, Birkmayer and Hornykiewicz attempted to achieve a levodopa-sparing effect with the concurrent administration of levodopa with an MAO inhibitor. As such combinations frequently elicited hypertensive attacks; they soon terminated this line of clinical research (Birkmayer and Hornykiewicz 1962).

Unfortunately, because 1960s Hungary was isolated from the western world’s mainstream science, our results remained largely unnoticed. I asked Ervin in 1964, who worked as psychiatrist in our University Clinic, to test the antidepressant effect of racemic E-250. He published a preliminary note (in German) on the promising results of the running clinical trial with racemic E-250 on depressed patients (Varga 1965). Ervin wrote with his coworker the first paper, in English, describing that racemic E-250 is an efficient, prompt acting antidepressant (Varga and Tringer 1967). In 1971 they wrote the first paper demonstrating that DEP is a potent antidepressant (Tringer et al. 1971). In retrospect, it is incredible that selegiline (DEP) with the indication to treat major depressive disorder was only first registered in 2006 in the United States and marketed as the first transdermal antidepressant (Emsam) despite the fact that our first paper on racemic E-250 proposing its use as an antidepressant appeared in Hungarian literature in 1964 and in English in 1965 (Knoll et al. 1964, 1965).

Varga also found that DEP is free of the “cheese effect” in humans. As stated in personal communication, he said, “Even provocative cheese consumption failed to produce headache or hypertensive crisis” (Knoll et al. 1968; p.111). Varga moved to the USA, where he still lives, and he discontinued his clinical studies with DEP. His convincing preliminary study which confirmed that DEP is devoid of the “cheese effect” was never completed and has 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 DEP was devoid of the “cheese effect” (Kardos and Füredi 1966; Juhász personal communication). None of them were completed, but later performed studies with DEP confirmed these observations (Knoll 2016).

Sandler and his co-workers in London demonstrated that after pretreatment with DEP parkinsonian volunteers who had received levodopa or levodopa/carbidopa suffered no adverse pressor reaction after challenged with oral tyramine in considerably greater amounts than likely to be encountered in a normal diet (Elsworth et al. 1978; Sandler et al. 1978). Thus, they acceptably confirmed finally that DEP is an MAO inhibitor free of the cheese effect, which aligned with our findings in animal experiments and with preliminary studies of Hungarian clinicians.

Considering the peculiar pharmacological profile of DEP, Birkmayer in Vienna was the first clinician who dared to combine DEP with levodopa in Parkinson’s disease. The trial, the first clinical study with DEP in the West, was successful. The levodopa-sparing effect was achieved in patients without signs of significant hypertensive reactions (Birkmayer et al. 1977). This study initiated and a following Lancet Editorial (September 25, 1982) enhanced the world-wide use of DEP in Parkinson’s disease.

DEP achieved its place in research and therapy as the first selective inhibitor of MAO-B. Prior to the discovery of the catecholaminergic activity enhancer (CAE) effect of DEP (Knoll 1998), it was my firm belief that the selective inhibition of B-type MAO is responsible for the drug’s beneficial therapeutic effects. In my lecture at the ‘Strategy of Drug Research’ IUPAC/IUPHAR Symposium in Noordwijkerhout (The Netherlands) in 1982, I presented experimental evidence that preventive daily administration of DEP during the post-developmental phase of life is an unexpected chance to improve the quality and prolong the duration of mammalian life (Knoll 1982).

Since further behavioral studies indicated that important central stimulatory effects of DEP are unrelated to MAO inhibition, it stands to reason to develop (-)-1-phenyl-2-propylaminopentane, (-)-PPAP, the DEP-analog containing a propyl-group which is unable to make a covalent binding with the flavin in MAO-B rather than the propargyl-group in DEP. Thus, (-)-PPAP leaves MAO-B activity unchanged, however, as a central stimulant (-)-PPAP proved to be as potent as DEP (Knoll et al. 1992).

The high pressure liquid chromatography (HPLC) method with electrochemical detection allows exact measurement of the continuously released catecholamines from freshly excised brain tissue. This method ensured us to obtain unequivocal experimental evidence regarding the operation of the enhancer regulation in the life-important catecholaminergic and serotonergic systems of the brain stem. In 1993, we began to use this technique to measure the amount of dopamine released from the striatum, substantia nigra, and tuberculum olfactorium, as well as norepinephrine from the locus coeruleus and serotonin from the raphe.

In 1994 we presented the results from the first series of experiments performed with the HPLC method which demonstrated that multiple, small dose administration of DEP keeps the catecholaminergic and serotonergic neurons on a significantly higher activity level, and how DEP’s peculiar enhancer effect  is unrelated to MAO-B inhibition (Knoll and Miklya 1994).

The discovery of the enhancer regulation in the mammalian brain and the development of the synthetic enhancer substances were recently summarized (Knoll 2016). This study presents final evidence that the enhancer effect of DEP and BPAP, the presently known most potent synthetic enhancer substance, is responsible for the prolongation of life in mammals. Rats treated three times a week with 0.0001 mg/kg BPAP, which is the peak dose exerting its specific enhancer effect (Knoll 2016, Fig. 24), significantly prolonged the life of rats (Knoll 2016, Fig. 28). This study also shows that the 0.25 mg/kg dose of DEP, used from the beginning (Knoll 1988), in the longevity studies, has two effects: it is the peak dose which blocks completely MAO-B in the brain, and is also the peak dose which exerts the non-specific enhancer effect of DEP (Knoll 2016, Fig. 12). Since  the presently used 10 mg daily dose of DEP in therapy, was originally selected as the one equivalent with the dose used in animals, it remains for the future to clarify the role of the non-specific enhancer effect of DEP in the therapeutic benefits observed in the last decades.

All in all, the complicated pharmacological profile of DEP was recognized in phases.

The first phase was the structure-activity-relationship study performed in the early 1960s with the aim to develop for my behavioral studies a methamphetamine derivative devoid of the catecholamine-releasing effect of its parent compound. I selected the compound, later named deprenyl, as the most suitable one for further research. Being devoid of the catecholamine-releasing property, DEP was the first MAO inhibitor free of the cheese-effect.

The second phase in DEP-research which attracted international attention started in the 1970s. This was the discovery that DEP is a selective inhibitor of MAO-B.

The third phase in DEP-research, the discovery of the enhancer regulation in the rat brain, started in the 1990s. We realized that β-phenylethylamine (PEA) and tryptamine are endogenous enhancer substances, DEP is a PEA-derived synthetic enhancer substance and we developed BPAP, the tryptamine-derived synthetic enhancer substance (as the first summary, see Knoll 2005).

It is not to be questioned that since the early 1960s the DEP story had always a surprise in store. DEP-research forwarded us to the discovery of the enhancer regulation in the mammalian brain, to the realization that the catecholaminergic and serotonergic neurons are enhancer-sensitive units, and to the development of BPAP. Whatever happened since the 1960s, Ervin Varga was the first clinician who tested, under the miserable circumstances in Hungary, racemic E-250, and later DEP in humans. He was compelled to leave Hungary, left his work unfinished, but his findings were later corroborated in the West. I am still thankful for his excellent cooperation which was for me so helpful in the mid-1960s.

It was a pleasure to read Barry Blackwell's Biography of Ervin Varga, full of sympathetic and loving understanding of the life of a talented Jewish young man with a sense of vocation to be a physician, who was, unfortunately, born in 1925 in Hungary, survived the Holocaust, but nevertheless, lived a full and happy life in the USA as a dedicated psychiatrist and is fortunately still active.



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Joseph Knoll

June 9, 2016