Thomas A. Ban
Neuropsychopharmacology in Historical Perspective.
Education in the field in the Post-Psychopharmacology Era
Collated 24
Neuropsychopharmacology in Historical Perspective.
Ildiko Miklya: The History of Selegiline (-) Deprenyl the First Selective Inhibitor of B-Type Monoamine Oxidase and the First Synthetic Catecholaminergic Enhancer Substance
This document includes Ildiko Miklya’s essay and the exchange that followed it’s posting.
Ildiko Miklya March 13, 2014 Essay
Ervin Varga August 7, 2014 Comment
Ildiko Miklya November 27, 2014 Reply to Varga
Samuel Gershon December 11, 2014 Comment on Miklya’s reply to Varga
Ildiko Miklya January 22, 2015 Reply to Gershon’s comment
on Miklya’s reply
Ervin Varga January 29, 2015 Comment on Miklya’s reply to
Gershon’s comment
Samuel Gershon February 19, 2015 Reply to Varga’s comment on his
comment on Miklya’s reply to
Varga’s comment
Ildiko Miklya: The History of Selegiline (-) Deprenyl the First Selective Inhibitor of B-Type Monoamine Oxidase and the First Synthetic Catecholaminergic Enhancer Substance
(-)-Deprenyl (D) was developed in the early 1960s by Joseph Knoll, professor and head of the Pharmacological Department of the Semmelweis University in Budapest. Knoll, a survivor of Auschwitz and the Dachau death train (Dunn 1988), started in the early 1950s his behavioral studies on rats: (i) aiming to understand the mechanism of the manipulability of the behavior of the most developed, domesticable mammals; (ii) to find a reasonable explanation why humans possess the most manipulable brain among all living beings on earth; and (iii) to throw light upon the role of the manipulability of human behavior in the birth and development of the human society. He summarized his findings and conclusions in three monographs (Knoll 1969, 2005, 2012).
The early resounding success of his work was the discovery that manipulability of behavior appeared with the development of species capable to fix acquired drives. The rat for example possesses this ability; the mouse is devoid of it.
He realized from the very beginning the extraordinary importance of the catecholaminergic brain machinery (he called it: the engine of the brain) in the fixation of acquired drives. To stimulate the brain engine he used amphetamines as experimental tools. His problem with the amphetamines was that as soon as the dose surpassed the 1-2 mg/kg level they blocked purposeful behavior because the drug-induced continuous, irresistible release of catecholamines from the intra-neuronal stores in the brain stem neurons resulted in aimless hypermotility. He decided to start a structure-activity-relationship (SAR) study in an attempt to develop an amphetamine derivative devoid of this unwanted effect. Amphetamine and methamphetamine are long-acting synthetic analogues of b-phenylethylamine (PEA). In order to change substantially their pharmacological profile, Knoll decided to combine in the same molecule the structural features of methamphetamine and pargyline, the newly developed monoamine oxidase inhibitor (MAOI). It was the propargyl group in pargyline which, by making a covalent binding with the flavin in the enzyme, inhibited monoamine oxidase (MAO) activity irreversibly. He designed a series of new structures and asked Mészáros, his close friend, the research director of Chinoin, the Hungarian pharmaceutical company, to contact him with a chemist experienced in the synthesis of phenylethylamines and pargyline. Zoltán Ecsery synthesized about 30 of the compounds designed by Knoll who selected for the detailed studies E-250 as the one fitting best with his expectations; E-250 was later named deprenyl, to emphasize that the compound was planned for treating depression. The first publication on E-250 appeared in 1964 in Hungarian, followed by a paper in English in 1965. For further pharmaceutical development Knoll chose the (-)-enantiomer (R)-N-methyl-N-(1-phenylpropan-2-yl)prop-1-yn-3-amine (Selegiline, (-)-Deprenyl, Eldepryl, Jumex, Zelepar, Emsam, Anipryl and about 100 further trade names). Selegiline is the presently world-wide available drug, registered in 63 countries to treat Parkinson’s disease (PD), Alzheimer’s disease (AD), major depressive disorder (MDD) and also used as a prophylactic anti-aging compound to slow the age-related-decline of the catecholaminergic brain engine (Knoll 2012).
Knoll planned originally to use Deprenyl as a new antidepressant and asked his close friend, the psychiatrist Ervin Varga, who worked that time in the Semmelweis University, later in the USA, to perform a clinical study with E-250. Already in 1965 a preliminary note on the promising clinical trial with racemic E-250 in depressed patients was published in German (Varga 1965). The first paper showing that racemic E-250 is an efficient prompt acting antidepressant was published in English in 1967 (Varga and Tringer 1967). The first clinical trial with (-)-E-250 (later named Selegiline) in depressed patients showing its significant antidepressant effect was published in 1971 (Tringer, Haits and Varga 1971). The finding was later confirmed in a couple of papers; nevertheless, Selegiline was first registered as an antidepressant only in 2006 in the USA. Emsam is the first transdermally applied antidepressant (Bodkin and Amsterdam 2002).
Knoll discovered in 1967 that Deprenyl is a unique MAO inhibitor which, in contrast to the known ones, does not potentiate the catecholamine releasing effect of tyramine. Thus he realized that his compound must be free of the “cheese effect.” The hypertensive crisis associated with the ingestion of high amounts of tyramine in cheese, the metabolism of which is inhibited by MAO inhibition, restricted in the early 1960s the clinical use of the MAO inhibitors. An exact analysis of this nature of E-250 was published in 1968 (Knoll, Vizi and Somogyi 1968). Knoll asked Varga to perform a rapid test investigating the safeness of E-250. Varga found that, as expected, even provocative cheese consumption failed to produce headache or hypertensive crisis. This finding was cited as a personal communication in the Knoll, Vizi and Somogyi paper (1968), but since Varga left Hungary, the work was not brought to completion and was never published. The first two publications which exactly proved that Deprenyl is free of the cheese effect in humans were published in 1978 in England (Elsworth, Glover, Reynolds et. al. 1978; Sandler, Glover, Ashford et. al. 1978).
Knoll realized in 1970 that Deprenyl is a highly selective inhibitor of B-type MAO and presented his finding at the First International MAO Symposium, held in Cagliari (Sardinia, Italy) in 1971. The first paper which described this novel property (Knoll and Magyar 1972) has become, 10 years later, a citation classic. Deprenyl became first famous as a key important experimental tool in MAO research.
The finding that Deprenyl protects the nigrostriatal dopaminergic neurons from the toxic effect of 6-hydroxy-dopamine (6-OHDA) (Knoll 1978) was the first proof of the neuroprotective effect of the drug. The finding that Deprenyl protects the striatum from the toxic effect of 6-OHDA via the blockade of B-type MAO, the inhibition of the uptake of 6-OHDA into the neuron, the facilitation of scavenger function and the improvement of the removal of the neurotoxic free radicals (Knoll 1987) catalyzed the discovery that Deprenyl is significantly enhancing scavenger function in the striatum. Knoll’s discovery that Deprenyl treatment significantly enhances in the striatum of both male and female rats the activity of superoxide dismutase (SOD) (Knoll 1988) was soon confirmed (Carillo, Kanai, Nokubo and Kitani 1991) and Deprenyl-induced enhancing of scavenger function was analyzed later in detail in series of papers. It was later described in dozens of papers that Deprenyl protects neurons against a variety of neurotoxic agents:1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), DSP-4, 5,6-dihyroxyserotonine, AF-64A (Ebadi, Sharma, Shavali and El Refaey 2002) and enhances the production of neurotrophins which are natural protective agents of neurons (Shimazu, Tanigawa, Sato et. al. 2003).
The first clinical trial with D, published in Lancet, proved that, in contrast to the known MAO inhibitors, Deprenyl can be safely combined with levodopa and with this combination the levodopa sparing effect was achieved in patients without signs of significant hypertensive reactions (Birkmayer, Riederer, Ambrozi and Youdim 1977). This paper and the following Lancet Editorial (1982) initiated the world-wide use of Deprenyl in PD.
Knoll first presented in his lecture at the Second Strategy in Drug Research IUPAC-IUPHAR Symposium held in Noordwijkerthout (The Netherlands) in 1981 his concept that preventive Deprenyl medication which facilitates dopaminergic and trace-aminergic activity in the brain is a reasonable strategy to improve the quality of life in the latter decades (Knoll 1982). He first presented in his lecture at the 7th European Symposium on Basic Research in Gerontology held in Budapest in 1983 experimental evidence proving that this effect of Deprenyl is unrelated to the inhibition of MAO-B (Knoll 1985). To support his concept, Knoll proposed Birkmayer, that time the only clinician who treated long-lastingly hundreds of patients with Deprenyl, to analyze in retrospect the survival of his patients treated with Deprenyl. In an open, uncontrolled study the long term (9 years) effect of treatment with Madopar alone (n=377) or in combination with Deprenyl (n=564) was compared in parkinsonian patients. The survival analysis revealed a significant increase of life expectancy in Madopar+Deprenyl group regardless of the fact whether or not the significant demographic differences between the two groups were taken into account (Birkmayer, Knoll, Riederer et. al. 1985). The first longevity study with Deprenyl on the long living, robust Wistar-Logan rats, starting with two-year old males, was performed between 1985 and 1988. The study furnished unequivocal experimental evidence that prophylactic Deprenyl treatment prolongs the life of rats significantly (Knoll 1988; Knoll, Dalló and Yen 1989). The finding was soon confirmed on the short living Fischer F-344 strain of rats (Milgram, Racine, Nellis et. al. 1990). Deprenyl-induced prolongation of lifespan was later further confirmed on rats and demonstrated also on mice, Syrian hamsters, dogs and even on Drosophila melanogaster. Knoll performed with his coworkers a second longevity study with 28-week old Wistar-Logan rats between 1990 and 1994. The aim of this study was to learn how low-dose, lifelong Deprenyl treatment influences the lifespan of low and high performing rats. Out of 1,600 sexually experienced male rats the 94 sexually inactive (low performing, LP) and the 99 most sexually active (high performing, HP) rats were selected. The LP rats died significantly earlier than their HP peers and D-treatment eliminated this difference (Knoll, Yen and Miklya 1994).
In the DATATOP multicenter clinical trial (USA, Canada) in 23 University Institutions, the ability of Deprenyl and a-tocopherol - antioxidant agents that act through complementary mechanisms - were studied, expecting to delay the onset of disability necessitating levodopa therapy (the primary end point) in patients with early, untreated PD. Eight hundred subjects were randomly assigned in a two-by-two factorial design to receive Deprenyl, a-tocopherol, a combination of both drugs or placebo, and were followed up to determine the frequency of development to the end point. The study proved that the treatment of de novo parkinsonians with Deprenyl has a unique beneficial influence on the natural history of PD. Deprenyl treatment delayed significantly the need for levodopa therapy. The study also revealed that, in contrast to the expectation of the authors, a-tocopherol was ineffective. The first papers of this study were published in Science and New England Journal of Medicine in 1989 (Tetrud and Langston 1989; Parkinson Study Group 1989). The ineffectiveness of a-tocopherol in this study was explained later. Deprenyl enhances the impulse propagation mediated release of dopamine (catecholaminergic activity enhancer - CAE effect), a-tocopherol is devoid of this property (Miklya, Knoll and Knoll 2003).
In the early 1990s Knoll developed (-)-1-phenyl-2-propylaminopentane [(-)-PPAP], the Deprenyl analogue equally active with its parent compound but devoid of the MAO inhibitory property. Zoltán Török performed the chemical work in Chinoin. This study furnished direct evidence that the main effect of Deprenyl, the specific stimulation of the catecholaminergic brain engine, is unrelated to the inhibition of MAO (Knoll, Knoll, Török et. al. 1992).
Detailed analysis between 1994 and 1996 showed that PEA acts, in a dose-range below the one which is continuously releasing catecholamines from the intra-neuronal stores, to be a selective enhancer of the impulse propagation mediated release of catecholamines. Amphetamine and methamphetamine the long acting PEA-derivatives act similarly (Knoll, Miklya, Knoll et. al. 1996a). Since the catecholamine-releasing property of PEA and the amphetamines concealed their CAE effect (Knoll 2012), this property remained undetected. Deprenyl, the only PEA derivative free of the catecholamine releasing property which exerts its CAE effect in concentrations below the dose which inhibits MAO-B activity, enabled the discovery of the enhancer regulation in the catecholaminergic neurons (Knoll and Miklya 1994; Knoll, Miklya, Knoll et. al. 1996b; Knoll 1998).
The first two papers demonstrating the beneficial effect of Deprenyl in AD were published in 1987 (Martini, Pataky, Szilágyi and Venter 1987; Tariot, Goldstein, Podgorski et. al. 1987). A series of clinical studies with small sample sizes confirmed thereafter the usefulness of Deprenyl in this disease. In 1997 the first controlled trial of Deprenyl in the treatment of AD was published in New England Journal of Medicine (Sano, Ernesto, Thomas et. al. 1997).
Based on his finding that tryptamine is like PEA, a natural enhancer of the impulse propagation mediated release of transmitters from the catecholaminergic and serotonergic neurons, Knoll developed R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane [(-)-BPAP], a tryptamine-derived selective enhancer substance which exerts this effect in femto-picomolar concentrations. The chemical part of the SAR study was performed with a group of chemists in the research laboratory of the Fujimoto Pharmaceutical Corporation (Osaka) led by Fumio Yoneda (Knoll, Yoneda, Knoll et. al. 1999). (-)-BPAP is an about 100 times more potent CAE substance than Deprenyl and acts even more potently on the serotonergic neurons. Deprenyl is an almost selective CAE substance. With the development of (-)-BPAP the proper experimental tool is now available to search hitherto unknown enhancer-sensitive regulations in the brain.
References:
Birkmayer W, Riederer P, Ambrozi L, Youdim MBH. Implications of combined treatment with "Madopar" and L-Deprenyl in Parkinson's disease. The Lancet 1977; i: 439-43.
Birkmayer W, Knoll J, Riederer P, Youdim MBH, Hars V, Marton V. Increased life expectancy resulting from addition of L-deprenyl to Madopar treatment in Parkinson's disease: a longterm study. Journal Neural Transmission 1985;64:113-27.
Bodkin JA, Amsterdam JK. Transdermal selegiline in major depression: a double-blind, placebo-controlled, parallel-group study in outpatients. American Journal of Psychiatry 2002; 159:1869-75.
Carrillo MC, Kanai S, Nokubo M, Kitani K. (-)Deprenyl induces activities of both superoxide dismutase and catalase but not of glutathion peroxidase in the striatum of young male rats. Life Sciences 1991;48:517-21.
Dunn S (Ed.) Dachau 29 April, The Rainbow Liberation Memoires. Lubbock: Texas Tech University Press; 1998.
Ebadi M, Sharma S, Shavali S, El Refaey H. Neuroprotective actions of selegiline. Journal of Neuroscience Research 2002;67:285-9.
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.
Knoll J. The Theory of Active Reflexes. An Analysis of Some Fundamental Mechanisms of Higher Nervous Activity. Budapest: Publishing House of the Hungarian Academy of Sciences; New York: Hafner Publishing Company; 1969. (inhn.org.publications, February 27, 2014).
Knoll J. The possible mechanism of action of (-)deprenyl in Parkinson's disease. Journal Neural Transmission 1978;43:177-98.
Knoll J. Selective inhibition of B type monoamine oxidase in the brain: a drug strategy to improve the quality of life in senescence. In: JA Keverling Buisman (Ed), Strategy in Drug Research. Amsterdam: Elsevier; 1982, pp 107-35.
Knoll J. The facilitation of dopaminergic activity in the aged brain by (-)deprenyl. A proposal for a strategy to improve the quality of life in senescence. Mechanisms of Ageing and Development 1985;30:109-22.
Knoll J. R-(-)Deprenyl (Selegiline, MoverganR) facilitates the activity of the nigrostriatal dopaminergic neuron. Journal Neural Transmission 1987;25:45-66.
Knoll J. The striatal dopamine dependency of lifespan in male rats. Longevity study with
(-)deprenyl. Mechanisms of Ageing and Development 1988; 46:237-62.
Knoll J. (-)Deprenyl (selegiline) a catecholaminergic activity enhancer (CAE) substance acting in the brain. Pharmacology & Toxicology 1998; 82:57-66.
Knoll J. The Brain and Its Self. A Neurochemical Concept of the Innate and Acquired Drives. Berlin/Heidelberg/New York: Springer; 2005. inhn.org.publications, January 23, 2014.
Knoll J. How Selegiline((-)-Deprenyl) Slows Brain Aging. Bentham e-Books; 2012. inhn.org.publications, September 5, 2013.
Knoll J, Magyar K. Some puzzling effects of monoamine oxidase inhibitors. Advances in Biochemical Psychopharmacology 1972;5:393-408.
Knoll J, Miklya I. Multiple, small dose administration of (-)deprenyl enhances catecholaminergic activity and diminishes serotoninergic activity in the brain and these effects are unrelated to MAO-B inhibition. Archives internationales de Pharmacodynamie et de Thérapie 1994;328:1-15.
Knoll J, Ecsery Z, Kelemen K, Nievel J, Knoll B. Phenylisopropylmethyl-propinylamine HCL (E-250) egy új hatásspektrumú pszichoenergetikum. MTA V. Osztály Közleményei 1964; 15: 231-8 (in Hungarian).
Knoll J, Ecsery 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;18:109-12.
Knoll J, Dalló J, Yen TT. Striatal dopamine, sexual activity and lifespan. Longevity of rats treated with (-)deprenyl. Life Sciences 1989;45:525-31.
Knoll J, Knoll B, Török Z, Timar J, Yasar S. The pharmacology of 1-phenyl-2-propylaminopentane (PPAP), a deprenyl-derived new spectrum psychostimulant. Archives internationales de Pharmacodynamie et de Thérapie 1992;316:5-29.
Knoll J, Yen TT, Miklya I. Sexually low performing male rats die earlier than their high performing peers and (-)deprenyl treatment eliminates this difference. Life Sciences 1994; 54:1047-57.
Knoll J, Miklya I, Knoll B, Markó R, Rácz D. Phenylethylamine and tyramine are mixed-acting sympathomimetic amines in the brain. Life Sciences 1996a;58:2101-14.
Knoll J, Miklya I, Knoll B, Markó R, Kelemen K. (-)Deprenyl and (-)1-phenyl-2-propylaminopentane, [(-)PPAP], act primarily as potent stimulants of action potential-transmitter release coupling in the catecholaminergic neurons. Life Sciences 1996b; 58:817-27.
Knoll J, Yoneda F, Knoll B, Ohde H, Miklya I (-)l-(Benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain. British Journal of Pharmacology 1999;128:1723-32.
Lancet Editorial (1982) Deprenyl in Parkinson’s Disease. The Lancet 1982; ii: 695-6.
Martini E, Pataky I, Szilágyi K, Venter V. Brief information on an early phase-II study with
(-)deprenyl in demented patients. Pharmacopsychiatry 1987;20:256-7.
Miklya I, Knoll B, Knoll J. A pharmacological analysis elucidating why, in contrast to
(-)-deprenyl (selegiline) a-tocopherol was ineffective in the DATATOP study. Life Sciences 2003;72:2641-8.
Milgram MW, Racine RJ, Nellis P, Mendoca A, Ivy GO. Maintenance on
L-(-)deprenyl prolongs life in aged male rats. Life Sciences 1990;47:415-20.
Parkinson Study Group. Effect of (-)deprenyl on the progression disability in early Parkinson's disease. New England Journal of Medicine 1989;321:1364-71.
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.
Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman CW, Pfeiffer E, Schneider LS, Thal LJ. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. New England Journal of Medicine 1997;336:1216-22.
Shimazu S, Tanigawa A, Sato N, Yoneda F, Hayashi K, Knoll J. Enhancer substances: Selegiline and R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane, [(-)-BPAP] enhance the neurotrophic factor synthesis on cultured mouse astrocytes. Life Sciences 2003;72:2785-92.
Tariot PN, Goldstein B, Podgorski CA, Cox C, Frambes N. Short-term administration of selegiline for mild-to-moderate dementia of the Alzheimer’s type A. Journal of Geriatric Psychiatry 1998;6:145-54.
Tetrud JW, Langston JW. The effect of (-)deprenyl (selegiline) on the natural history of Parkinson's disease. Science 1989;245:519-522.
Tringer L, Haits G, Varga E. The effect of (-)E-250, (-)L-phenyl-isopropylmethyl- propinyl-amine HCl, in depression. In: G Leszkovszky (Ed), 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: B Dumbovich (Ed), 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.
March 13, 2014
Ervin Varga’s comment
When I try to relate my memories about the birth of deprenyl, I have to remind myself that I worked as Associate Professor in Budapest at the Semmelweis University Psychiatric Clinic. I was trained and conditioned to be a clinician with a narrow focus on my patients. I was both a neurologist and a psychiatrist, but I was neither biochemist nor pharmacologist. My exclusive interest was diagnostic evaluation and treatment of patients under my care.
In the 1960s Hungary was a communist country. We had limited access to literature or exchange with Western colleagues. But since the discoveries of the phenothiazines and tricyclic antidepressants in the 1950s, we became involved in drug trials. They were unsophisticated clinical trials, especially Phase 1 studies with unknown substances, reviewed only by pharmacologists without clinical experience.
At the same time, we had complete freedom with little involvement with drug companies or ethics committees. We were not restrained by cost issues, because there were no grants. Healthcare in Hungary in those days was free. Doing research, we were on our own. Depression was the target of our research. Tricyclic antidepressants were fine for many patients, but it took time until they improved and the severity of their depression simply did not permit us to wait. So, we went for ECT. The chairman of my Department was Professor Gyula Nyirö, who with Meduna introduced convulsive treatment in the 1930s. It was still the treatment of choice in severe delusional cases or when we were concerned about suicide. There was need for a faster acting antidepressant, since ECT was not applicable to frail patients with involutional depression. We still did not use muscle relaxants with anesthesia.
I remember my discussion with Joseph Knoll, my old friend and classmate, about the available choices. That was the time when endorphin became the vogue and opiates promised the route to developing the ultimate antidepressant. Knoll did not believe this and went on the catecholamine path.
He wanted me to examine a group of new substances, phenylethylamines, which he combined with pargyline (all I knew was that this was a sedative antihypertensive drug). The combination of a stimulant with a sedative reminded me of the once famous Brom Caffeine tablets.
Sometime in 1964 Knoll started to send me experimental samples. First, I took such tablets myself for 1-2 days, and since it seemed harmless, I gave it to patients. If I remember, I gave 5 mg tablets and when no change was noticed, I increased the dose to 15 mg/day, but for no longer than another 5-6 days. When still no improvement was noticeable, I stopped the experimental drug and continued either with Tofranil or ECT. This went on with five different patients, one after the other, without any result until the 6th patient showed marked improvement after only 4 days. It was as dramatic as an ECT treatment. I called Knoll, told him the last sample was an antidepressant.
The rest is well described by Dr. Miklya.
August 7, 2014
Ildiko Miklya’s reply to ErvinVarga’s comment
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, Ecseri, Kelemen 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, Vizi and Somogyi 1968). 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. Vizi and Somogyi 1968 paper also two other Hungarian studies are mentioned which confirmed that E-250 was devoid of the 'cheese effect' (Kardos and Füredi 1966). 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 a 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, Glover , Reynolds et. al. 1978; Sandler, Glover , Ashford and Stern 1978).
Let me again thank you for sharing with us the story of the first experiences with deprenyl in humans.
References:
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, Vizi and Somogyi 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;18:109-12.
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.
November 27, 2014
Samuel Gershon’s comment on Ildiko Miklya’s reply to ErvinVarga’s comment
I agree with Dr. Miklya that early clinical research with selegiline in psychiatry was done at a difficult time in Hungary. However, I don’t think that the difficulties encountered in the introduction of deprenyl in the treatment of depression can be attributed entirely to those difficulties. In my Psychopharmacology Research Unit at New York University we also did open studies, like the Hungarian investigators, with selegiline in the 1970s and we found that it had only a minimal effect in inpatient depression. Probably an even more important contributing factor was that the Hungarian investigators were not able to provide findings from double-blind controlled studies. This alone would explain the little interest in the drug outside of Hungary. Finally, I think the most important contributing factor to the delay in the introduction of selegiline in the treatment of depression was the publicity of other antidepressants in the West. The intensity and the funding for advertising a new claimed therapeutic agent in the USA is colossal. Direct advertising of drugs in some countries is still prohibited whereas in the USA it is perfected to the extent that a patient with a particular set of depressive symptoms could ask their doctor to prescribe one or another antidepressant.
December 11, 2014
Ildiko Miklya’s reply to Samuel Gershon’s comment on her reply to ErvinVarga’s comment
Thank you Professor Gershon for commenting on my reply to Dr. Varga. It was in 1979 when I started working in the Knoll Institute. Deprenyl was already used as an experimental tool in MAO research as the first selective inhibitor of B-type MAO. It was in 1977 when Birkmayer’s group demonstrated in their Lancet paper that deprenyl deserves attention as a unique therapeutic agent. Levodopa treatment in Parkinson’s disease had various side effects. Birkmayer and Hornykiewicz tried to achieve a levodopa-sparing effect by the concurrent administration of levodopa with a MAO-inhibitor. They were compelled to terminate this trial because the combination elicited hypertensive attacks. Since selegiline was the unique MAO inhibitor free of the cheese effect, Birkmayer combined selegiline with levodopa and a levodopa-sparing effect was achieved in patients without side effects (Birkmayer, Riederer, Ambrozi and Youdim 1977). The levodopa-sparing effect of selegiline is related to the selective inhibition of B-type MAO. The Lancet Editorial “Deprenyl in Parkinson’s Disease” in 1982 catalyzed thereafter the widespread use of deprenyl in Parkinson’s disease. The antidepressant effect of deprenyl published first by Dr. Varga in 1965 was first confirmed by you in 1980. Your paper with Mann, published in Life Sciences appeared 15 years after the first Varga paper. Yours was the first study that confirmed the beneficial antidepressant effect of deprenyl in the West. But only in 2006 was deprenyl (Emsam) registered in the USA as an antidepressant. By now it is successfully used in therapy. In my reply to Dr. Varga’s comment, I tried to explain that in the early 1960s, when Professor Knoll developed deprenyl and clarified its unique pharmacological spectrum, this important discovery passed almost unnoticed. Only in the mid-1970s when the chances to develop personal contacts with colleagues in the West, did opportunities for Hungarian scientists brighten. I feel honored by and appreciate your informative comment.
References:
Birkmayer W, Riederer P, Ambrozi L, Youdim MBH. Implication of combined treatment with “Madopar” and L-deprenyl in Parkinson's disease. Lancet 1:439-43.
Mann D, Gershon S. A selective monoamine oxidase-B inhibitor in endogenous depression. Life Sciences, 1980;26:877-82.
Varga E. Vorläufiger Bericht über die Wirkung des Präparats E-250 (phenyl-isopropyl-methyl-propinylamine-chlorhydrat). In: Dumbovich B. (Ed), III. Conferentia Hungarica pro Therapia et Investigatione in Pharmacologia, Akadémiai Kiadó (Publishing House of the Hungarian Academy of Sciences), Budapest, pp. 197-201.
Ervin Varga’s comment on Samuel Gershon’s comment on Ildiko Miklya’s reply to Samuel Gershon’s comment
Last time we had a discussion on deprenyl (D) was in the company of George Simpson and Arthur Sugerman, while Don Gallant introduced his famous crepes. I appreciate your convincing comment concerning the destructive effect of marketing. As far as your negative comment on D’s antidepressive effect - the answer is more complicated. I am not aware of any blind comparative study on D. Even if so, an intriguing question in clinical psychopharmacology is how the same drug may produce a different outcome in different blinded studies. An important meta-analysis of efficacy studies comparing new generation antidepressants in Lancet (2009) showed clinically important differences among commonly prescribed antidepressants. The therapeutic value and the popularity of a drug does not go necessarily hand-in-hand. We clinicians are relatively humble, when it comes to administering treatment. It is only occasionally that our first choice of drug lifts severe depression in patients. And I have had patients who did not respond to any antidepressant but to D although that is not always the case. I trust the drug because it has been tested by other psychiatrists as required by the FDA, but the ultimate judgment must be based upon actual clinical response in patients. I remember our discussion and I admired your logic and forthright expression of your opinion. I feel honored to be involved in scientific interaction with you.
January 29, 2015
Samuel Gershon’s reply to Ervin Varga’s comment on his comment on Ildiko Miklya’s reply to Ervin Varga’s comment
I am sure that your first-hand observation of the clinical effects of Deprenyl are very important and possibly the field does not have the data currently to define the really objective efficacy of Deprenyl. The FDA requires at least two double-blind randomized clinical trials to establish efficacy and if you have a wealthy company to support the studies on a compound they could do nine clinical trials; if only two show significant efficacy they win the game and have a marketable product. This game has been played with many claimed “antidepressants” and that is why we are in a mess.
February 19, 2015
March 26, 2020