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
Miodrag (Misha) Radulovacki (
Serbian Cyrillic: Миодраг Радуловачки;
Serbian Latin: Miodrag Radulovački), was a
Serbian American scientist and inventor. He was Professor of
Pharmacology in the
College of Medicine at the University of Illinois at Chicago (UIC),[1] Radulovacki's research accomplishments include: (1) the
Adenosine Sleep Theory,[2] and (2) pioneering pharmacological studies for the treatment of
sleep apnea,[3] together with research collaborator, David W. Carley,[4] (Professor of Medicine at the UIC). Radulovacki and Carley invented several
drug therapies for the treatment of sleep apnea which have been patented by the UIC. The UIC recognized them as the 2010 "Inventors of the Year."[5][6] Radulovacki published more than 170 scientific papers.[7] Radulovacki was also a Foreign Member of the
Serbian Academy of Sciences and Arts.[8]
Radulovacki graduated from the University of Belgrade School of Medicine in 1959.[11][12][13] He 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.[citation needed]
In 1966, Radulovacki accepted a teaching position with the
Physiology Department in the College of Medicine at the
University of Khartoum,
Sudan.[11] There 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
monoaminemetabolites.[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. From 1970 to 1984, at the University of Illinois, Radulovacki published a series of papers dealing with the role of monoamines in sleep.[7]
In 1970, 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] Radulovacki published more than 170 scientific papers during his career at the UIC.[7]
Scientific achievements
Adenosine Sleep Theory
In 1984, 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.
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
behavioralsleep. 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, Radulovacki started a 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.[25] Since there were no medicines to alleviate this condition, Radulovacki and Carley set out to develop a
drug treatment.[26] Their initial work focussed on an
experimentalmodel of sleep apnea in rats, initially testing the effects of adenosine compounds.[27] Eventually, they obtained positive results using serotonin and other compounds. As a result, the UIC
patented their discoveries, obtaining numerous US and international patents.[28]
Patents for sleep and sleep-related disorders include:
"Hypnotic Composition and Method of Inducing Sleep"; Inventor: Miodrag Radulovacki, US Patent 4537907, August 27, 1985. (This patent was issued to UIC before Radulovacki started his collaboration with Carley in 1993).[29]
"Pharmacological Treatment for Sleep Apnea"; Inventors: Miodrag Radulovacki and David W. Carley, US Patent 6,331,536 B1, December 18, 2001.[30]
"Neuropharmacological Treatments of Sleep-Related Breathing Disorders"; Inventors: Miodrag Radulovacki and David W. Carley, US Patent 6,555,564 B1, April 29, 2003.[31]
"Pharmacological Treatment for Sleep Apnea"; Inventors: Miodrag Radulovacki and David W. Carley, US Patent 6,727,242 B2, April 27, 2004.[32]
"Neuropharmacological Treatment of Sleep-Related Breathing Disorders"; Inventors: Miodrag Radulovacki and David W. Carley, US Patent 6,974,814 B2, December 13, 2005.[33]
"Pharmacological Treatment for Sleep Apnea"; Inventors: Miodrag Radulovacki and David W. Carley, US Patent 7,160,898 B2, January 9, 2007.[34]
"Method for Treating Sleep Apnea"; Inventors: David W. Carley and Miodrag Radulovacki, US Patent 7,705,039 B2, April 27, 2010.[35]
"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.[36]
"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.[37]
Inventor of the Year 2010
Radulovacki was named the 2010 Inventor of the Year at the University of Illinois, alongside Carley.[5] 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.[38] Their results have culminated in an IllinoisVentures-supported start-up company, Pier Pharmaceuticals, that focuses on the treatment of obstructive sleep apnea.[39]
Membership in the Serbian Academy of Sciences and Arts
In October 2003, the Serbian Academy of Sciences and Arts in Belgrade elected Radulovacki as one of its Foreign Members for his significant scientific research contributions in the fields of Neuropharmacology, sleep disorders and sleep-related breathing disorders.[8]
Yugoslav Student Summer Program
In 1990, 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.[40] The Yugoslav Student Summer Program lasted for 12 years and had 304 participants.[41]
Philanthropy
In 2005, 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.
Radulovacki made numerous contributions to his home town of
Sremski Karlovci.
In 2007, 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]
In 2009, Radulovacki restored the baroque façades of the Ecological Center in Karlovci[42][43] which occupies a historic building in the center of the town.
In 2010, Radulovacki restored the monument of 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.[44]
In 2011, Radulovacki financed the construction of a self-sustaining ecological building with
solar panels and
geothermal heat pumps in the courtyard of the Karlovci Ecological Center.[45] In recognition of Radulovacki's philanthropy, the ecological center was renamed the Ecological Center Radulovački.[citation needed]
Personal life
Radulovacki lived in
Chicago. He was a
cross-country skier.[12] He participated in several Birkebeiner-Kortelopet cross-country ski marathons in Cable-Hayward,
Wisconsin.[citation needed] 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 (Brad Radulovacki and Branko Radulovacki) and four grandchildren (Grant, Katie, Reid and Ryan).[46][47]
Selected publications
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.
PMID4705518.
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.
PMID884510.
S2CID39245160.
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.
PMID6694111.
Radulovacki, M (1985). "Role of adenosine in sleep in rats". Reviews in Clinical & Basic Pharmacology. 5 (3–4): 327–39.
PMID3916307.
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.
PMID10334159.
^Buckingham, RL; Radulovacki, M (1975). "The selective effects of alpha-methyl aromatic amino acids on brain monoamine metabolites and behavior in cats". Research Communications in Chemical Pathology and Pharmacology. 12 (2): 255–65.
PMID1197913.
^Radulovacki, Miodrag (1987).
"Adenosine and sleep". In Stefanovich, Vladimir; Okyayuz-Baklouti, I. (eds.). Role of adenosine in cerebral metabolism and blood flow. pp. 125–132.
ISBN9067640980.
^Haulicǎ, I.; Ababei, L.; Brǎnişlteanu, D.; Topoliceanu, F. (October 1973). "Preliminary data on the possible hypnogenic role of adenosine". Journal of Neurochemistry. 21 (4): 1019–1020.
doi:
10.1111/j.1471-4159.1973.tb07549.x.
PMID4754851.
S2CID46663273.