- Email: [email protected]
An extraordinary relationship involving MIF-1 and other peptides
G Model
ARTICLE IN PRESS
PEP-69430; No. of Pages 2
Peptides xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Peptides journal homepage: www.elsevier.com/locate/peptides
An extraordinary relationship involving MIF-1 and other peptides Rudolph H. Ehrensing ∗ Department of Psychiatry, Ochsner Medical Center, New Orleans, LA, USA
a r t i c l e
i n f o
Article history: Received 9 March 2015 Received in revised form 14 March 2015 Accepted 16 March 2015 Available online xxx Keywords: AJ Kastin Peptides Depression MIF-1 TRH MSH/ACTH4-10
a b s t r a c t In commemoration of Abba J. Kastin’s exceptional service as the founding editor for the international journal Peptides, I review our collaborative work on how neuropeptides are involved in depression and other neuropsychiatric behavior. A special focus is on MIF-1 (prolyl-leucyl-glycinamide) that was discovered in the Kastin laboratory and shown effective to treat human depression with greater efficacy and faster onset of action than traditional antidepressants at the time of clinical trial. My personal reflection of the evolving changes of translational research on neuropeptides will hopefully provide some insight to young investigators. © 2015 Elsevier Inc. All rights reserved.
Abba and I have had an unusually positive collegial research relationship for over 40 years. While good from the start, during those decades, it has grown steadily in mutual trust and respect professionally and, on a personal level, in fraternal affection for one another. In all these 40 plus years we have never had an argument and neither of us can remember even a serious disagreement. Minor disagreements were quickly resolved by each listening to the other and one of us agreeing with the other or coming to a mutually acceptable decision. Back in 1971 Abba was a well-known and experienced endocrine investigator and I was a young, inexperienced psychiatric researcher. But both of us had the as yet unaccepted idea that peptides could have a direct effect on the brain, i.e, peptides affect emotions, mood, and psychiatric conditions. Abba’s interest in this was well published at that time. For my part, I was conducting a fully approved clinical study of oxytocin and its possible affect on hospitalized patients with schizophrenia. I first heard of Abba in 1972. Dr. Lyle Miller, my colleague in the Department of Psychiatry at Louisiana State University, commented that on Saturday mornings Abba would sit down and write several research papers. Since I was a slow writer, I clearly remember saying to myself that Abba would be someone I would like to work with if I had the chance. Abba called me for the first time just weeks later. Because of Lyle Miller’s remarks, I had no hesitation even though I had not yet met him in person to say “yes” that I
∗ Tel.: +1 5048973244. E-mail address: [email protected]
was very interested in joining him in a clinical study that involved a peptide and mental depression. Abba played an important role in my career at the Ochsner Clinic. In 1973 I learned that Ochsner was looking for a new head of the Department of Psychiatry. When I discussed this with Abba, he offered to call Frank Riddick, an endocrinologist friend, who was soon to become the Medical Director of the Clinic and who had at that time the position I would have in the future, evaluating potential new staff. Abba called and relayed my desire that Frank call me, which he did. I joined the staff at Ochsner and with the steady and unwavering support from Frank I rebuilt the Psychiatry department. First impressions can be very influential and Frank’s first impression of me was the very positive recommendation to him from Abba, someone he highly respected. Later Frank asked me to be acting Medical Director in his absence and to take over professional personal matters which I did for the next 20 years while continuing to practice and do research with Abba. In September 2013 I received Ochsner’ s highest award, the Life Time Achievement Award, only awarded five times since it was begun a decade ago. Both Abba and Frank were there and in my acceptance speech I was able to recognize the important roles each had played in my career and in my life and thank them. I cherish the pictures of both of them with me at that ceremony. Frank was a prior recipient of the award. He died a year later. After that invitation to do research with him in 1972, my research collaboration with Abba continued. The next two decades of study involved MIF-1 (prolyl-leucyl-glycinamide) and mental depression. We conducted three double-blind clinical studies. The results showed that most patients had a significant improvement
http://dx.doi.org/10.1016/j.peptides.2015.03.013 0196-9781/© 2015 Elsevier Inc. All rights reserved.
Please cite this article in press as: Ehrensing RH. An extraordinary relationship involving MIF-1 and other peptides. Peptides (2015), http://dx.doi.org/10.1016/j.peptides.2015.03.013
G Model PEP-69430; No. of Pages 2 2
ARTICLE IN PRESS R.H. Ehrensing / Peptides xxx (2015) xxx–xxx
in depression after receiving MIF-1 for only 2–3 days with the improvement lasting as long as six months in some patients, the longest duration of any of the follow-ups we did. Moreover, there were no side effects as observed with the use of traditional antidepressants. MIF-1 was given orally and subcutaneously in studies that involved inpatients or outpatients or both. As things unfolded, MIF-1 turned into an orphan drug – an interesting story worth telling in a brief form and because it was important in Abba and my relationship. Abbott Laboratories in the late 1960s and early 1970s had a “use patent” for MIF-1 in depression and other CNS conditions. Abbott had performed the extensive toxicology studies and activity of MIF-1 in animal models of depression. They had funded our first two studies. However before they had received the data from the second study (which was very positive), Abbott decided not to proceed with any further studies. As best we could fathom, this was a “corporate business decision to get out of peptides all together”. Nonetheless, the physician clinical monitor at Abbott was impressed with the potential of MIF-1. When he moved to Wallace Laboratories, he persuaded that pharmaceutical company to obtain the rights to MIF-1 from Abbott. Wallace Laboratories funded two inpatient studies. One enrolled seriously depressed inpatients in a state hospital. MIF-1 showed significant positive effect in reducing depression. The other study was conducted in a Veterans Administration hospital. The patients in that study were described by the authors as giving absurd and perseveratory responses on self-rating forms which precluded their use. Nonetheless the authors concluded that MIF-1 was ineffective as an antidepressant. An additional outpatient study by Wallace was equivocal. Thus, Wallace stopped funding research with MIF1. In the 1980s we decided to continue research with MIF-1 in depression and obtained our own Investigational New Drug (IND) application from the Food and Drug Administration (FDA). We carried out a study using a subcutaneous small dose of MIF-1. This study was very positive.
During this period we also researched other aspects of MIF-1. We found that it blocked the analgesic effects of morphine in both animal and human studies, resembling what could be described as an “endogenous naloxone”. Furthermore, in the animal studies there was a curvilinear dose–response curve. This “therapeutic window” as we discussed in our first paper on MIF-1 and depression turned out to be typical and characteristic of the action of many peptides. While most of our research focused on MIF-1, we investigated other peptides: TRH, LHRH, Tyr-MIF-1, enkephalin, and MSH/ACTH 4-10 In the early 1990s a small pharmaceutical company developed a patentable analog of MIF-1. This is a pentapeptide which they named “nemifitide”. We coauthored a few small clinical trials that showed positive effect of nemifitide in treating depression. The company then began large scale clinical trials and long term toxicology studies. While the large scale clinical trial was turning out positive, toxicology testing in beagle dogs showed formation of vacuoles in the brain. The FDA halted clinical testing of nemifitide. Subsequent long term testing in rhesus monkeys showed no such effect on the brain. However, the small company had lost momentum and the remaining years of patent protection had decreased to the point where no large pharmaceutical company would participate in the development of nemifitide. Eventually this small company went bankrupt several years ago. Over the years we were asked what the mechanism of action of MIF-1 might be, how it affected the brain. There were many studies that had ruled out various mechanisms of action. In 2010 studies in Abba’s lab demonstrated that MIF increased c-Fos expression in brain regions involved in the regulation of mood, anxiety, depression, and memory. At the end of our careers, we both hope that somehow MIF-1 with its rapid onset of action could become available to the public for the alleviation of mental depression. But regardless of whatever happens to MIF-1, what Abba and I have received from our research together is a deep, deep friendship filled with respect and affection that has a value beyond all measure.
Please cite this article in press as: Ehrensing RH. An extraordinary relationship involving MIF-1 and other peptides. Peptides (2015), http://dx.doi.org/10.1016/j.peptides.2015.03.013
ARTICLE IN PRESS
PEP-69430; No. of Pages 2
Peptides xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Peptides journal homepage: www.elsevier.com/locate/peptides
An extraordinary relationship involving MIF-1 and other peptides Rudolph H. Ehrensing ∗ Department of Psychiatry, Ochsner Medical Center, New Orleans, LA, USA
a r t i c l e
i n f o
Article history: Received 9 March 2015 Received in revised form 14 March 2015 Accepted 16 March 2015 Available online xxx Keywords: AJ Kastin Peptides Depression MIF-1 TRH MSH/ACTH4-10
a b s t r a c t In commemoration of Abba J. Kastin’s exceptional service as the founding editor for the international journal Peptides, I review our collaborative work on how neuropeptides are involved in depression and other neuropsychiatric behavior. A special focus is on MIF-1 (prolyl-leucyl-glycinamide) that was discovered in the Kastin laboratory and shown effective to treat human depression with greater efficacy and faster onset of action than traditional antidepressants at the time of clinical trial. My personal reflection of the evolving changes of translational research on neuropeptides will hopefully provide some insight to young investigators. © 2015 Elsevier Inc. All rights reserved.
Abba and I have had an unusually positive collegial research relationship for over 40 years. While good from the start, during those decades, it has grown steadily in mutual trust and respect professionally and, on a personal level, in fraternal affection for one another. In all these 40 plus years we have never had an argument and neither of us can remember even a serious disagreement. Minor disagreements were quickly resolved by each listening to the other and one of us agreeing with the other or coming to a mutually acceptable decision. Back in 1971 Abba was a well-known and experienced endocrine investigator and I was a young, inexperienced psychiatric researcher. But both of us had the as yet unaccepted idea that peptides could have a direct effect on the brain, i.e, peptides affect emotions, mood, and psychiatric conditions. Abba’s interest in this was well published at that time. For my part, I was conducting a fully approved clinical study of oxytocin and its possible affect on hospitalized patients with schizophrenia. I first heard of Abba in 1972. Dr. Lyle Miller, my colleague in the Department of Psychiatry at Louisiana State University, commented that on Saturday mornings Abba would sit down and write several research papers. Since I was a slow writer, I clearly remember saying to myself that Abba would be someone I would like to work with if I had the chance. Abba called me for the first time just weeks later. Because of Lyle Miller’s remarks, I had no hesitation even though I had not yet met him in person to say “yes” that I
∗ Tel.: +1 5048973244. E-mail address: [email protected]
was very interested in joining him in a clinical study that involved a peptide and mental depression. Abba played an important role in my career at the Ochsner Clinic. In 1973 I learned that Ochsner was looking for a new head of the Department of Psychiatry. When I discussed this with Abba, he offered to call Frank Riddick, an endocrinologist friend, who was soon to become the Medical Director of the Clinic and who had at that time the position I would have in the future, evaluating potential new staff. Abba called and relayed my desire that Frank call me, which he did. I joined the staff at Ochsner and with the steady and unwavering support from Frank I rebuilt the Psychiatry department. First impressions can be very influential and Frank’s first impression of me was the very positive recommendation to him from Abba, someone he highly respected. Later Frank asked me to be acting Medical Director in his absence and to take over professional personal matters which I did for the next 20 years while continuing to practice and do research with Abba. In September 2013 I received Ochsner’ s highest award, the Life Time Achievement Award, only awarded five times since it was begun a decade ago. Both Abba and Frank were there and in my acceptance speech I was able to recognize the important roles each had played in my career and in my life and thank them. I cherish the pictures of both of them with me at that ceremony. Frank was a prior recipient of the award. He died a year later. After that invitation to do research with him in 1972, my research collaboration with Abba continued. The next two decades of study involved MIF-1 (prolyl-leucyl-glycinamide) and mental depression. We conducted three double-blind clinical studies. The results showed that most patients had a significant improvement
http://dx.doi.org/10.1016/j.peptides.2015.03.013 0196-9781/© 2015 Elsevier Inc. All rights reserved.
Please cite this article in press as: Ehrensing RH. An extraordinary relationship involving MIF-1 and other peptides. Peptides (2015), http://dx.doi.org/10.1016/j.peptides.2015.03.013
G Model PEP-69430; No. of Pages 2 2
ARTICLE IN PRESS R.H. Ehrensing / Peptides xxx (2015) xxx–xxx
in depression after receiving MIF-1 for only 2–3 days with the improvement lasting as long as six months in some patients, the longest duration of any of the follow-ups we did. Moreover, there were no side effects as observed with the use of traditional antidepressants. MIF-1 was given orally and subcutaneously in studies that involved inpatients or outpatients or both. As things unfolded, MIF-1 turned into an orphan drug – an interesting story worth telling in a brief form and because it was important in Abba and my relationship. Abbott Laboratories in the late 1960s and early 1970s had a “use patent” for MIF-1 in depression and other CNS conditions. Abbott had performed the extensive toxicology studies and activity of MIF-1 in animal models of depression. They had funded our first two studies. However before they had received the data from the second study (which was very positive), Abbott decided not to proceed with any further studies. As best we could fathom, this was a “corporate business decision to get out of peptides all together”. Nonetheless, the physician clinical monitor at Abbott was impressed with the potential of MIF-1. When he moved to Wallace Laboratories, he persuaded that pharmaceutical company to obtain the rights to MIF-1 from Abbott. Wallace Laboratories funded two inpatient studies. One enrolled seriously depressed inpatients in a state hospital. MIF-1 showed significant positive effect in reducing depression. The other study was conducted in a Veterans Administration hospital. The patients in that study were described by the authors as giving absurd and perseveratory responses on self-rating forms which precluded their use. Nonetheless the authors concluded that MIF-1 was ineffective as an antidepressant. An additional outpatient study by Wallace was equivocal. Thus, Wallace stopped funding research with MIF1. In the 1980s we decided to continue research with MIF-1 in depression and obtained our own Investigational New Drug (IND) application from the Food and Drug Administration (FDA). We carried out a study using a subcutaneous small dose of MIF-1. This study was very positive.
During this period we also researched other aspects of MIF-1. We found that it blocked the analgesic effects of morphine in both animal and human studies, resembling what could be described as an “endogenous naloxone”. Furthermore, in the animal studies there was a curvilinear dose–response curve. This “therapeutic window” as we discussed in our first paper on MIF-1 and depression turned out to be typical and characteristic of the action of many peptides. While most of our research focused on MIF-1, we investigated other peptides: TRH, LHRH, Tyr-MIF-1, enkephalin, and MSH/ACTH 4-10 In the early 1990s a small pharmaceutical company developed a patentable analog of MIF-1. This is a pentapeptide which they named “nemifitide”. We coauthored a few small clinical trials that showed positive effect of nemifitide in treating depression. The company then began large scale clinical trials and long term toxicology studies. While the large scale clinical trial was turning out positive, toxicology testing in beagle dogs showed formation of vacuoles in the brain. The FDA halted clinical testing of nemifitide. Subsequent long term testing in rhesus monkeys showed no such effect on the brain. However, the small company had lost momentum and the remaining years of patent protection had decreased to the point where no large pharmaceutical company would participate in the development of nemifitide. Eventually this small company went bankrupt several years ago. Over the years we were asked what the mechanism of action of MIF-1 might be, how it affected the brain. There were many studies that had ruled out various mechanisms of action. In 2010 studies in Abba’s lab demonstrated that MIF increased c-Fos expression in brain regions involved in the regulation of mood, anxiety, depression, and memory. At the end of our careers, we both hope that somehow MIF-1 with its rapid onset of action could become available to the public for the alleviation of mental depression. But regardless of whatever happens to MIF-1, what Abba and I have received from our research together is a deep, deep friendship filled with respect and affection that has a value beyond all measure.
Please cite this article in press as: Ehrensing RH. An extraordinary relationship involving MIF-1 and other peptides. Peptides (2015), http://dx.doi.org/10.1016/j.peptides.2015.03.013