Miodrag Radulovacki

Miodrag Radulovacki
Born	28 April 1933 Parage, Serbia
Died	27 May 2014 (aged 81) Belgrade, Serbia
Residence	United States
Nationality	Serbian
Fields	Neuropharmacology, Sleep and sleep disorders, Sleep-related breathing disorders
Institutions	University of Belgrade, Serbia UCLA – Brain Research Institute, 1964-1965 University of Khartoum, Sudan, 1967-1970 College of Medicine at the University of Illinois at Chicago (UIC), 1970 - 2014
Education	Karlovci High School, Serbia
Alma mater	Medical Faculty, University of Belgrade, Serbia, (MD), (Ph.D.)
Known for	Adenosine Sleep Theory, 1984 Pharmacological Approaches in the Treatment of Sleep Apnea Yugoslav Student Summer Program at the University of Illinois at Chicago and Champaign-Urbana, 1990-2000 The Miodrag Radulovacki Family Prize for Excellence in Basic Sciences at the UIC College of Medicine, 2005
Notable awards	Inventor of the Year Award, 2010, College of Medicine at the University of Illinois at Chicago Foreign Member of the Serbian Academy of Sciences and Arts, 2003, Belgrade, Serbia

Miodrag (Misha) Radulovacki, MD, PhD (Serbian Cyrillic: Миодраг Радуловачки; Serbian Latin: Miodrag Radulovački), was an American scientist and inventor of Serbian descent. He was Professor of Pharmacology in the College of Medicine at the University of Illinois at Chicago (UIC),^[1] Dr. Radulovacki's significant research accomplishments include: (1) the Adenosine Sleep Theory,^[2] and (2) pioneering pharmacological studies for the treatment of sleep apnea,^[3] accomplished together with his longtime research collaborator, David W. Carley,^[4] (Professor of Medicine at the UIC). Drs. Radulovacki and Carley invented several drug therapies for the treatment of sleep apnea which have been patented by the UIC. As a result, the UIC recognized them as the 2010 "Inventors of the Year."^[5][6] During his long academic career at the UIC, Dr. Radulovacki published more than 170 scientific papers.^[7] Dr. Radulovacki was also a long-time Foreign Member of the Serbian Academy of Sciences and Arts.^[8]

Early life

Miodrag Radulovacki was born on April 28, 1933, in Parage, a village in northwestern Serbia. Both of his parents were elementary school teachers. Dr. Radulovacki's father was also his first grade teacher. At the beginning of World War II, Dr. Radulovacki's father was drafted into the Yugoslav Army and was later taken prisoner by the invading Germans. From 1941 to 1944, Serbia, then part of Yugoslavia, was occupied by the German armed forces.

In 1943, when Dr. Radulovacki was 10 years old, he moved to Sremski Karlovci after his mother accepted a teaching position in the town. Sremski Karlovci (also known as Karlovci), a historic baroque Serbian town on the banks of the Danube River, had been home to the Radulovacki family for over 200 years. Dr. Radulovacki attended Karlovci High School or "Gymnasium," which is the oldest high school in Serbia.^[9][10] Karlovci High School's famous patron was the Russian czar, Peter the Great, who sent the school its first teachers and text books. Dr. Radulovacki called Karlovci Gymnasium the “Serbian Cambridge and Oxford”. Dr. Radulovacki graduated as valedictorian of the Karlovci High School Class of 1951. During his high school years, Dr. Radulovacki developed a deep interest in research and discoveries. And, in order to pursue the best clinical research opportunities, Dr. Radulovacki enrolled in the University of Belgrade School of Medicine.

Education and scientific career

Dr. Radulovacki graduated from the University of Belgrade School of Medicine in 1959.^[11][12][13] He decided to pursue an academic career in basic sciences and went on to obtain a PhD in Neurophysiology.^[12][13] The topic of his PhD thesis was: ”Sleep in Split-Brain Cats,” partly done at the Brain Research Institute at UCLA.

UCLA - Brain Research Institute (1964 - 1965)

In order to gain broader experience in the field of sleep research, Dr. Radulovacki spent 18 months at the University of California, Los Angeles (UCLA) Brain Research Institute^[14] where his mentor was Ross Adey.^[15] One of the significant findings of his research at UCLA was that the electroencephalographic (EEG) pattern of sleep in cats with split brain to the pons is synchronous in both brain hemispheres, indicating the importance of the brainstem in sleep regulation.^[11][16]

University of Khartoum, Sudan (1966–1970)

In 1966, Dr. Radulovacki accepted a teaching position with the Physiology Department in the College of Medicine at the University of Khartoum, Sudan.^[11] It was there that he invented an approach for obtaining cerebrospinal fluid using a cannula to the cisterna magna in the brain of cats. The cannulation method enabled researchers to obtain cerebrospinal fluid during sleep and wakefulness for the analysis of monoamine metabolites.^[17] This approach was of interest since Michel Jouvet’s Monoamine Theory of Sleep,^[18] with serotonin as the sleep inducing agent, was dominant at the time. Later, from 1970 to 1984, at the University of Illinois, Dr. Radulovacki published a series of papers dealing with the role of monoamines in sleep.^[7]

University of Illinois at Chicago (UIC) Medical School (1970 – 2014)

In 1970, Dr. Radulovacki was recruited by Klaus Unna^[19] to join the Department of Pharmacology in the College of Medicine at the University of Illinois at Chicago as an Assistant Professor.^[11] Dr. Unna was a world authority on neuropharmacology which coincided with Dr. Radulovacki’s interest in the physiology and pharmacology of sleep. Dr. Unna came from a long line of University Professors in Hamburg, Germany who had made outstanding contributions to medicine. His grandfather invented the Unna boot, a special gauze bandage, which can be used for the treatment of venous insufficiencies of the leg. And, Dr. Unna's mother discovered and described the dermatological disease, Marie Unna hereditary hypotrichosis.

At the UIC, Dr. Unna was considered the role-model of a scientist and man who possessed great enthusiasm and a penchant for emphasizing the positive. For those who responded to his insistence on quality and creativity, life-long bonds were made. The favorite stage for fostering those bonds was Dr. Unna's garden at his home in the Chicago suburb of Hinsdale, where he brought the UIC faculty together for picnics every Saturday from June till September. Dr. Unna always emphasized the importance of research which connected with Dr. Radulovacki’s life philosophy. To reinforce this motto, in his lab, Dr. Radulovacki displayed a picture of Pablo Picasso with the text:”TO FIND IS THE THING.” With the benefit of the high caliber research environment created by Dr. Unna, Dr. Radulovacki published more than 170 scientific papers during his long academic career at the UIC.^[7]

Scientific achievements

Adenosine Sleep Theory

In 1984, Dr. Radulovacki postulated the Adenosine Sleep Theory, (JPET, 228: 268-274, 1984).^[20] The idea for adenosine’s role in sleep occurred to him after reading a paper by Sol Snyder’s group (Proc. Natl. Acad. Sci, 78: 3260-64, 1981)^[21] about the importance of adenosine receptors in the behavioral actions of methylxanthines. In the article, the authors correlated the behavioral excitation produced by theophylline in micromolar concentrations with the blockade of adenosine receptors.

Dr. Radulovacki reasoned that if the blocking of adenosine receptors produces excitation, then perhaps stimulation of the same receptors could induce sleep.^[22] He knew that experiments by John Phillis and his group (Can. J. Physiol. Pharmacol. 57:1289-1312, 1979),^[23] which utilized an iontophoretic application of adenosine in the brain, had demonstrated adenosine's depressant effect on the responses of neurons in several brain regions and that the general neurophysiological effects of adenosine were shown to be inhibitory. In addition, the preliminary experiments in dogs by Haulica et al. (J. Neurochem. 21:,1019–20, 1973)^[24] and the administration of adenosine into the brains of rats, cats and fowl suggested that adenosine was able to produce behavioral sleep. The explanation of adenosine's hypnotic effect was through its interaction with serotonin, widely believed to be a sleep inducing agent. However, since there was no suggestion how this adenosine-serotonin link was achieved, experiments highlighting the potential role of adenosine in sleep had largely been forgotten.

Research collaboration with David W. Carley

In 1993, Dr. Radulovacki started a long and fruitful collaboration with David W. Carley, a Professor of Medicine, Bioengineering and Pharmacology at the UIC. Their research efforts focused on developing pharmacological approaches for the treatment of sleep apnea. Sleep apnea, an involuntary cessation of breathing that occurs during sleep, affects at least 3% to 5% of the adult population in the United States. In addition, the prevalence of sleep-related apnea is dramatically elevated in the elderly, ranging from 28% to 67% of that population.^[25] Sleep apnea can lead to high blood pressure, cardiovascular disease, memory problems, weight gain, headaches and death.^[26] Since there were no medicines to alleviate this condition, Drs. Radulovacki and Carley set out to develop a drug treatment.^[27] Their initial work focussed on an experimental model of sleep apnea in rats, initially testing the effects of adenosine compounds.^[28] Eventually, they obtained positive results using serotonin and other compounds. As a result, the UIC patented their discoveries, obtaining numerous US and international patents.^[29]

Patents for sleep and sleep-related disorders include:

1. “Hypnotic Composition and Method of Inducing Sleep”; Inventor: Miodrag Radulovacki, US Patent 4537907, August 27, 1985. (This patent was issued to UIC before Dr. Radulovacki started his collaboration with Dr. Carley in 1993).^[30]
2. “Pharmacological Treatment for Sleep Apnea”; Inventors: Miodrag Radulovacki and David W. Carley, US Patent 6,331,536 B1, December 18, 2001.^[31]
3. “Neuropharmacological Treatments of Sleep-Related Breathing Disorders”; Inventors: Miodrag Radulovacki and David W. Carley, US Patent 6,555,564 B1, April 29, 2003.^[32]
4. “Pharmacological Treatment for Sleep Apnea”; Inventors: Miodrag Radulovacki and David W. Carley, US Patent 6,727,242 B2, April 27, 2004.^[33]
5. “Neuropharmacological Treatment of Sleep-Related Breathing Disorders”; Inventors: Miodrag Radulovacki and David W. Carley, US Patent 6,974,814 B2, December 13, 2005.^[34]
6. “Pharmacological Treatment for Sleep Apnea”; Inventors: Miodrag Radulovacki and David W. Carley, US Patent 7,160,898 B2, January 9, 2007.^[35]
7. “Method for Treating Sleep Apnea”; Inventors: David W. Carley and Miodrag Radulovacki, US Patent 7,705,039 B2, April 27, 2010.^[36]
8. "Methods for treating sleep disorders by cholecystokinin (CCK) receptor B antagonists”: Inventors: David W. Carley and Miodrag Radulovacki, US Patent 8,053,413 B2, Nov. 8, 2011.^[37]
9. "Pharmacological treatments for sleep disorders (apnoe) with prostanoid receptor antagonists", Inventors: David W. Carley and Miodrag Radulovacki, US Patent 8,076,315, Dec. 13, 2011.^[38]

Inventor of the Year 2010

Dr. Radulovacki was named the 2010 Inventor of the Year at the University of Illinois, alongside his research collaborator, Dr. David Carley.^[5] Drs. Radulovacki and Carley were honored by the University of Illinois for producing a dozen potential treatments for sleep apnea, many of which are now under consideration for commercial development.^[39] Their ground-breaking results have culminated in an IllinoisVentures-supported start-up company, Pier Pharmaceuticals, that focuses on the treatment of obstructive sleep apnea.^[40]

Membership in the Serbian Academy of Sciences and Arts

In October 2003, the Serbian Academy of Sciences and Arts in Belgrade elected Dr. Radulovacki as one of its Foreign Members. Dr. Radulovacki received this distinction for his significant scientific research contributions in the fields of Neuropharmacology, sleep disorders and sleep-related breathing disorders.^[8] Other foreign scientists elected to the Serbian Academy of Sciences and Arts that same year were Noam Chomsky^[41] from MIT and Nobel Laureate, Stanley Prusiner.^[42]

Yugoslav Student Summer Program

In 1990, Dr. Radulovacki initiated the Yugoslav Student Summer Program at the University of Illinois at Chicago (UIC) and the University of Illinois at Champaign-Urbana (UIUC) after the creation of International Linkage Agreements between the UIC and the Universities of Belgrade and Novi Sad in Yugoslavia.^[43] The motivating force behind this program was to bring outstanding students from these Yugoslav Universities to the UIC and the UIUC for one month in order to introduce them to graduate programs and advanced research. The Yugoslav Student Summer Program was successful due to its strict system of pre-selection and final selection of participants. Participants were chosen on the basis of their academic success - only students with an average grade of 9.00 and higher (where the top grade was 10.00) were able to apply. The final selection was done by Dr. Radulovacki on the basis of supplemental English writing tests that he developed and which were administered every December at the two Yugoslav Universities.^[44]

The Yugoslav Student Summer Program lasted for 12 years and had 304 participants.^[45] As a result of the Summer Program, at one point, over 100 students from Yugoslavia had been enrolled at the UIC and the UIUC graduate programs with full teaching assistantships.

According to the official Radulovacki Scholarship page as of 2014 there have been efforts to revive the Summer Student Program.

Philanthropy

Dr. Radulovacki was also a philanthropist. In 2005, Dr. Radulovacki established the Miodrag Radulovacki Family Prize for Excellence in Basic Sciences at the University of Illinois College of Medicine at Chicago.^[11] The purpose of the prize, given annually, is to honor a fourth year Medical student who displays a high degree of intellectual integrity and who has demonstrated strong academic achievement. The prize consists of a plaque and a check for $1,000.

In addition to the establishment of a scholarship at the UIC, Dr. Radulovacki made numerous contributions to his home town of Sremski Karlovci, a city with a rich history located on the banks of the Danube River in Serbia. Throughout its history, Sremski Karlovci has been a leading Serbian cultural center, home to the first Serbian high school and the first Serbian Orthodox Theological Seminary (established soon after the founding of the Russian Orthodox Seminary in Kiev). Sremski Karlovci was, for several centuries, the seat of the Serbian Patriarchy and has also served as the site for a number of important Serbian National Assemblies.^[46]

Four Lions Fountain, Sremski Karlovci, Serbia

• In 2007, Dr. Radulovacki restored the symbol of Sremski Karlovci, a baroque fountain called the Four Lions Fountain, located in the central square of the city.^[9][10] The fountain was built in 1792 by the Italian architect Giuseppe Aprile. It survived both world wars but was in complete disrepair. The fountain has been authentically reconstructed and augmented by elegant lighting.
• In 2009, Dr. Radulovacki restored the baroque façades of the Ecological Center in Karlovci^[47][48] which occupies a historic building in the center of the town. The Ecological Center, among other things, serves as an educational center for young people and has with 42 beds.^[9][10] The owners of the Ecological Center, Vojvodina Environmental Movement, moved to Karlovci from Novi Sad, the capital of the northern Serbian province of Vojvodina (Voyvodina), in order to accommodate participants in the national and international youth educational activities held annually in Karlovci.
• In 2010, Dr. Radulovacki restored the monument of a popular Serbian poet, Branko Radičević (Radichevich), at Stražilovo (Strazhilovo) which is located on a mountain-top surrounded by forests in the Fruška Gora (Frushka Gora) National Park near Karlovci.^[49] Only two Serbian poets have their graves and monuments on the top of mountains: Petar Petrović Njegoš (Petar Petrovich Nyegosh) on the top of Lovćen (Lovchen) mountain in Montenegro and Branko Radičević at Stražilovo.
• In 2011, Dr. Radulovacki also financed the construction of a self-sustaining ecological building with solar panels and geothermal heat pumps in the courtyard of the Karlovci Ecological Center.^[50] In recognition of Dr. Radulovacki's philanthropy, the ecological center was renamed, the Ecological Center Radulovački.

Personal life

Dr. Radulovacki lived in Chicago. He was an avid cross country skier^[12] and belonged to the Lake Shore Ski and Sports Club.^[51] He participated in several Birkebeiner-Kortelopet cross-country ski marathons in Cable-Hayward, Wisconsin. Dr. Radulovacki died on May 27, 2014 in Belgrade, Serbia, while on two-week trip to promote his philanthropic projects. He is survived by two sons and four grandchildren.^[52]

Selected publications

1. Radulovacki, M (1973). "5-Hydroxyindoleacetic acid in cerebrospinal fluid: Measurements in wakefulness, slow-wave and paradoxical sleep". Brain Research. 50 (2): 484–8. doi:10.1016/0006-8993(73)90757-9. PMID 4705518. 
2. Kovacević, R; Radulovacki, M (1976). "Monoamine changes in the brain of cats during slow-wave sleep". Science. 193 (4257): 1025–7. doi:10.1126/science.948760. PMID 948760. 
3. Radulovacki, M; Buckingham, RL; Chen, EH; Kovacević, R (1977). "Similar effects of tryptophan and sleep on cisternal cerebrospinal fluid 5-hydroxyindoleacetic and homovanillic acids in cats". Brain Research. 129 (2): 371–4. doi:10.1016/0006-8993(77)90018-X. PMID 884510. 
4. Radulovacki, M; Walovitch, R; Yanik, G (1980). "Caffeine produces REM sleep rebound in rats". Brain Research. 201 (2): 497–500. doi:10.1016/0006-8993(80)91060-4. PMID 7417859. 
5. Radulovacki, M; Zak, R (1981). "Amphetamine abolishes REM sleep rebound in rats: Effect of single injection". Brain Research. 217 (2): 420–4. doi:10.1016/0006-8993(81)90022-6. PMID 7248800. 
6. Radulovacki, M; Virus, RM; Djuricic-Nedelson, M; Green, RD (1984). "Adenosine analogs and sleep in rats". The Journal of Pharmacology and Experimental Therapeutics. 228 (2): 268–74. PMID 6694111. 
7. Radulovacki, M (1985). "Role of adenosine in sleep in rats". Reviews in clinical & basic pharmacology. 5 (3–4): 327–39. PMID 3916307. 
8. Radulovacki, M (2005). "Adenosine sleep theory: How I postulated it". Neurological research. 27 (2): 137–8. doi:10.1179/016164105X21814. PMID 15829175. 
9. Radulovacki, M; Trbovic, SM; Carley, DW (1998). "Serotonin 5-HT3-receptor antagonist GR 38032F suppresses sleep apneas in rats". Sleep. 21 (2): 131–6. PMID 9542796. 
10. Carley, DW; Radulovacki, M (1999). "Role of peripheral serotonin in the regulation of central sleep apneas in rats". Chest. 115 (5): 1397–401. doi:10.1378/chest.115.5.1397. PMID 10334159. 
11. Prasad, B; Radulovacki, M; Olopade, C; Herdegen, JJ; Logan, T; Carley, DW (2010). "Prospective trial of efficacy and safety of ondansetron and fluoxetine in patients with obstructive sleep apnea syndrome". Sleep. 33 (7): 982–9. PMC 2894441. PMID 20614859. 

Related publications

• Ryan, CM; Bradley, TD (2005). "Pathogenesis of obstructive sleep apnea". Journal of applied physiology (Bethesda, Md. : 1985). 99 (6): 2440–50. doi:10.1152/japplphysiol.00772.2005. PMID 16288102. 
• Stone, KL; Ewing, SK; Ancoli-Israel, S; Ensrud, KE; Redline, S; Bauer, DC; Cauley, JA; Hillier, TA; Cummings, SR (2009). "Self-reported sleep and nap habits and risk of mortality in a large cohort of older women". Journal of the American Geriatrics Society. 57 (4): 604–11. doi:10.1111/j.1532-5415.2008.02171.x. PMC 2927342. PMID 19220560. 

References