Akil Muhtar Özden (1877-1949): His life, works and contributions to Pharmacodynamics.
Abstract
Akil Muhtar Özden, who is a famous person remembered with respect in Turkish and
world medicine history, has contributed to the science world through the santonin liver
test developed, guinea pig skin reflex, digital glycosides cardiac effect definitions, and
also discovered the Muhtar Reflex. He has established the first Pharmacodynamic
Department in the modern medical school in Istanbul, and started to implement
experimental pharmacodynamic and teach Pharmacology lessons that had been taught
by Dr. A. Bernard at the beginning.
He is an intellectual scientist with his scientific studies, successful physician
personality, the importance attached to the ethics and the interest shown in political and
social events of the country, importance given to the education and his artistic
personality. He has contributed to the literature by virtue of his studies during the period
when pharmacodynamy began to develop fast across the world and has taken Turkey to
the Pharmacodynamic level of Europe.
Keywords
Akil Muhtar, Özden, Pharmaco-dynamics, Muhtar Reflex
Introduction
19th century is an era of significant developments in the fields of bacteriology and
microbiology in Europe. Also the administrators of Ottoman Empire, which had taken
necessary steps intended for the dissemination the contemporary modern medicine
widespread, have sent students for specialty education to various countries and
committees to Koch’s Clinic in Berlin and Pasteur Institute for the purpose of following
these developments. Rabies Vaccine Institution and Bacteriology laboratories had been
opened in the country by virtue of the implementation of these techniques learned at
abroad when they returned the home.(1) Meanwhile another significant development
was the opening of first Pharmaco-dynamics Department in modern medical school
developed with the contributions of Bernard, Deyke and Rieder who were supporting
the modern medical education initiated on March 14, 1827 by coming from Europe.
The first Pharmaco-dynamics tribune has been founded in Strasbourg University
Faculty of Medicine by Oswald Schmiedeberg for first time in 1872 in Europe. By
1900s, the presence of Pharmaco-dynamics has been recognized in Europe. While
Pharmaco-dynamics was developing rapidly throughout the world, its development in
Turkey has begun upon returning of Özden to Istanbul after 1908. Özden has
established Pharmaco-dynamics Institute, and started to implement experimental
Pharmaco-dynamics and teach Pharmacology lessons that had been taught by Dr. A.
Bernard at the beginning. (2) Özden has received specific traces by researching the
influence of all active substances used until that day on animals or isolated animal
organs through his serious and meticulous studies.(Picture 1,2) Pharmaco-dynamics in
Turkey has reached the scientific level in Europe thanks to him.
Özden, who is an important person remembered with respect in Turkish and world
medicine history, is also the first Turkish physician received an academic career title
abroad. (3) Özden has received the title of “Privat Dozent” in Pharmaco-dynamics
branch in Geneva University Faculty of Medicine by achieving with success the exam
for becoming an associate professorship, which he entered at a young age and in the
same period he was selected as correspondent member to the French Medical Academy.
(4) He has contributed to the science world through the santonin liver test developed,
guinea pig skin reflex, digital glycosides cardiac effect definitions. Özden is an
exemplary teacher, scientist, a man of culture and art who had taken charge in
publication boards, had studied as a teacher and as a member in scientific organizations.
(5)
His Life
Özden was born in Istanbul on October 1, 1877. His father Mehmet Muhtar Efendi was
among the founders of Turkey Medical Academy. (6) His brothers were Dr. Celal
Muhtar and Bacteriologist Dr. Kemal Muhtar who have made significant contributions
to the Turkish Medicine. (7) He entered the Military High school of Medicine like his
both elder brothers after completing his secondary education. He had studied for one
year in Military College of Medicine in Demirkapı after receiving his graduation
certificate from High school of Medicine. (5) In those years, this college of medicine
was one of the hidden centers established so as to create an environment for opposing
the oppressive government of Sultan Abdulhamit and opening the first parliament. (8)
Having a good education was getting difficult for students due to the insufficiency of
education opportunities in the Military College of Medicine. During this process, Özden
began to flee to Europe. (5, 9) He fled to Switzerland in October 1896 before
completing his school as a young man fond of his freedom, opposing the oppressive
regime of Abdulhamit. (5) One reason for his escape was the unfair oppressive
government of Sultan Abdulhamit, and another reason was his desire to receive
education in a faculty with wider researching facilities. Özden arrived at Switzerland,
and began his education again from first class, not from the class left in Istanbul after
having registered in Geneva Faculty of Medicine in 1897 school year. (8, 9 ) Özden had
attended the courses of famous medical teachers such as Widal Georgers, Jules Dejerine
and Chauffard Anatole in Paris Hospitals by going France during 6 years of his
education in Geneva Faculty of Medicine. Özden, who completed his education in
Geneva in 1902, went to Paris with the proposal of his teacher Prof.Dr. Bard because of
the Pasteur Institute was a brilliant center about bacteriology, and had attended the
courses of Roux, Nocard, Metchnikoff and Maurice Nicolle who were the founders of
bacteriology. (10) He had worked for 18 months as an assistant to Bard in Geneva
Internal Medicine Clinic in 1903 and had prepared his doctoral thesis named as
“Contribution a L’étude de la meningite cérébrospinale a forme prolongé”. (4, 9)
First he had been polyclinic assistant to polyclinic and treatment instructor Prof. Mayor
at Geneva Faculty of Medicine in 1904, and 2 years later he had become Pharmacodynamics assistant. At the same time, he had continued as honorary assistant at hygiene
institute of Prof. Christiani. (9, 11) After completing the duration of assistantship in
Pharmaco-dynamics, he had begun to teach Practical Treatment and Medical
Curriculum courses by getting the title of Private Associate Professor. Prof. Dr. Mayor,
student of Claude Bernard interesting closely in experimental pharmacology with Prof.
Bard had major contributions in improvement of Özden’s scientific side and Pharmacodynamics side. (12) Most of the studies in Geneva based on experiments, observations
done in collaboration with successful physicians of that period, have taken part in
medical literature. His most important invention has taken place in literature as Muhtar
Reflex (Guinea Pig Dorsal Skin Reflex).
Özden married with Nina Zuraboune Odişelica of Russian nationality who was
majoring in gynecology at Geneva University in 1908 in Paris. Dr. Nina has become
Muslim and got the name of Seniye after marriage. (13)
Constitutional Monarchy has been declared in 1908 in Ottoman Empire. First faculty of
medicine has been founded with new regulations made in 1909. While the first dean of
the Faculty Cemil Topuzlu was arranging the staff of the faculty, he invited Özden
acquainted with him from Geneva to come as hygiene instructor to the Darulfunun
Faculty of Medicine opened on November 14, 1908. Özden, who was Private Associate
Professor in Switzerland when he was invited to the Faculty of Medicine, abandoned his
career at abroad and accepted the teaching post. (5) He had started to teach the
information acquired during his education in Europe to Turkish students in the medical
faculty since 1910. He showed physiological effects of medicines on animals by
utilizing a method never used until that day after establishing a modern Pharmacodynamics laboratory in the sheds present in Kadırga in the beginning years of his
teaching post. Özden was not satisfied with this, and wanted to establish a treatment
clinic connected to the Pharmaco-dynamics in order to demonstrate their effect also on
human beings by taking his instructor Prof.Dr. Mayor as an example. However, since
the realization of this under the conditions in the Faculty of Medicine was impossible,
he tried to establish a clinic as an internal medicine chief in Haseki Hospital. (14) The
first Internal Medicine opened a short time prior to the First World War, had been given
to him as a treatment clinic and he had performed his studies three days a week here.
This clinic had remained closed for two years during the war. He had served as
bacteriologist and Pathological Anatomy specialist in Haseki Hospital from 1909.
Özden made the first autopsy at Haseki Hospital in Municipality Hospitals. (5, 9)
Özden had educated physicians in severe conditions of that day by serving as dean
during the years of Armistice and First World War. (15) He had worked devotedly in
order not to hinder education and patient treatments in a period when most of students
and partly teachers were enrolled because of First World War between the years of
1916-1921. (16)
Özden had given importance to the publication of Turkish medical works during his
Dean post. He had brought journals from Germany and France for medical branches to
the faculty library and encouraged the enrichment of the library. He had got the library
catalog prepared for Istanbul Faculty of Medicine in 1921. (5, 9)
He took part in 1933 University Reform advisory committee by arguing the necessity of
reform for raising the scientific level of Istanbul University. (14) Özden proposed that a
university instructor to be invited from Switzerland in order to carry out the reform
process. Prof. Dr. Albert Malche, came from Switzerland to Turkey in 1932, prepares a
report that is important for orientation and implementation of the university reform. (17)
Özden, who was appointed to the head of Institute and Treatment Clinic founded with
1933 university reform, received the title of Distinguished Professor. Moreover, he was
also appointed to the head of Medical Curriculum, Pharmaco-dynamics and treatment
chairs. He has achieved the development of pharmacology along with other instructors
who have been educated beside him to the extent of world standards concerning
education, teaching and scientific research in Turkey. Özden was selected as
correspondent member to Paris Academy of Medicine having 16 foreign members in
1938.
He had closely followed the treatment of Great Leader Ataturk, and continuously
written down the developments in recent days by looking at with the eye of a doctor.
(18) Özden has retired on age grounds on August 1, 1943 after working as Treatment
Clinic and Pharmacology instructor uninterruptedly for 37 years including two years in
Europe until 1943 from 1908. He did not make a break in his studies during the period
after retirement. He had worked as Head Physician and internal diseases specialist at the
German Hospital. He had closely followed scientific studies at abroad. He had
instructed on new discoveries, science and ethics at the Institute of Medical History and
lectured on science and ethics in order to inform young people. He also tried to inform
those who’re not physicians by writing articles and giving lectures related to medicine
and culture. He was involved in preparation of additional bind to Turkish Codex. He
was elected as a member of parliament from Republican People’s Party in 1946. (9)
He went to Switzerland hardly in the late 1947 due to Second World War, but he got
sick over there. He died at his home on the date of 12 March 1949 after caught the
disease of mediastinum lymphoma.
Özden, who had become a member of numerous national and international associations,
has published approximately 250 works in four languages including Turkish, French,
German and Bulgarian. He was interested in philosophy other than his researcher
physician identity.(19) He believes that the aim of the evolution in human generation is
intended for the development of morality and rising of the intelligence. (20) Özden was
incessantly reading, searching, and practicing his theoretical knowledge and laboratory
studies in the clinic. He also supported the education by informing the people regarding
the developments, and healing his patients besides being a successful scientist. He had
recommended young people at every opportunity when he encountered them in
explaining his opinions on a subject in a short, striking manner. He had drawn attention
to his artistic personality as well as his scientific aspect. He revealed his thought by
saying that “To make picture accustoms people to the attention” and he had watercolor,
charcoal drawings and oil paintings. (12)
His Studies
Muhtar Reflex: Özden described the “Guinea Pig Dorsal Skin Reflex” in 1907 for the
first time when he was trying the local anesthetic effect of opium alkaloids used in the
experiments on the guinea pigs and demonstrated that the impacts of local anesthesia
could be examined and various local anesthesia’s activities could be compared with
each other with the aid of guinea pig dorsal skin reflex. In his study which was prepared
when he was together with Prof. Dr. Mayor and published in “Societe de Biologie de
Paris” in 1909; he stated that the effects of opium alkaloids on sensorial nerve endings
was learned through empirical experiments by explaining this effect couldn’t be
understood exactly yet. He showed that 5% morphine solution reduced the local
tenderness even if just a pinch through experiments made by him. When touching the
shaved back of guinea pig with a needle tip, shrinking occurs on the back of the guinea
pig, as a result of the contraction of the dorsal sub-skin muscles and the animal gives a
clear reaction. The very small amount of local anesthetic injected into the skin, removes
this reflex around the application spot. It is a method showing the effects of local
anesthesia and effect differences between a variety of local anesthesia. (21) In the world
literature, this effect is known as “Muhtar Reflex” (Reflexe du Dr. Akil Muhtar), and
the method is known as “Muhtar’s Method”. (22)
Chloralose Studies: Chlorase is a substance obtained through the combination of chloral
hydrate with glucose. He made this in 1908 when he was an assistant to Prof. Mayor, it
was published in “Journal de Phsiologie et de Pathologie Générale” under the name of
“Etude expérimentale de l’état de réflectivité exagéréé déterminé par le chloralose”. He
demonstrated that Chlorase is among the substances making convulsion on the basis of
experiments conducted after describing effect mechanisms and stimulatory effect on the
spinal cord and narcotic effect on centers with high levels of Chlorase. For this reason,
it causes convulsion forming substances to potentiate. Chlorase reflex is a medicine
anesthetizing the animal without disrupting the reflexes. It is an anesthetic substance
emerged as a result of the effort for researching an anesthetic substance not touching the
reflexes due to entire anesthesia make difficulties for being able to explain the events in
studies because of inhibiting the reflexes. It has been proved that chlorase is an ideal
anesthetic for making experiments on animals. (23)
Digital Studies: Özden have got considerable studies on cardiology and made valuable
discoveries. He has revealed that the effects of drugs do not start late contrary to what
previously thought by researching the influential mechanisms of medicine affecting the
heart in human beings and animals. (11, 14 ) The effect of digital objects had been
accepted to start 10-20 hours after taking the drug, before this pharmacological and
clinically relevant study. He demonstrated through clinical trials that the effect of digital
objects namely digitoxin is seen after a short time as 1-3 hours after being taken by
cardiac patients, in humans by means of pulse records done with Uskoff tool. (22, 24).
The digital, which was used by people as diuretic, has been used as heart medicine by
Scotch William Withering in 1785 for the first time. This drug’s Pharmaco-dynamicss
and effects on patients have been started to be examined at the beginning of 20th
century. A glycoside called digitalin has been derived by Nativella in 1869 for the first
time from its digital leaves.
Özden Özden has showed for the first time in the world that pulse amplitudes of pulse
traces start to rise within two hours after giving the digital by using Uskoff tool on
patients with cardiac insufficiency. (14, 25) The first work on this subject has been
published in Paris in Bulletin de la société the therapeutique de in 1914. It is more
vasoconstrictor than strophant for digitoxin vessels. (26) Özden has showed that
strophanthin affects more quickly compared to the digital by comparing these two
medicaments’ effect on heart with the traces received by means of Uskoff tool, it is
excreted more quickly from the body and it doesn’t have any contractionary effect on
coronary vessels at low doses. He has examined the history of digital and strophantus,
their physiological effects, effects on patients and said that it was impossible to
eliminate asystole fits in the heart muscle, the patients must be given digital on a regular
basis and in adequate amounts in order to prevent recurrence of the seizure. He
explained the circumstances that are harmful for using this medicament by drawing
attention to the sensitivity that may arise in patients against this medicament. He has
published this in German with the name of “Digitalis und Strophantus bei Herzchwache
von Prof.Dr. Özden”. In this article, the issues have been emphasized such as
physiological effects of digital and strophantus, the situations harmful for using the
medicament by drawing attention to the sensitivity that may arise in patients against the
medicament. (23)
Özden has discussed the medical effect of the digital in the article which was enriched
with electro samples and experiments written by taking into consideration the works of
authors and physicians like Prof. R. Heinz, Prof.Heubner, Abert Robin, Alfred Martinet,
Gaston Lion. In Özden’s opinion, all authors accept that digital has a slow effect. In
Gaston Lion’s opinion, “digital’s physiological effect cannot be compared with its
medical effect. This object’s effect on patients is not same with the effect on healthy
humans and animals. “Prof.Dr. Heinz has said that the first effect of the digital is seen
after 12 hours or a longer duration when it is administered orally. Özden says that the
digital’s effect is seen fast through the experiments made on animals, and if this effect
on patients is considered to appear 1 day later, then physiological effect and medical
effect should be different from each other. Özden has wrote in the paper sent to Paris
Scientific Treatment Society in 1914 and published in the journal of the same
institution, the fallacy of the idea i.e. the digital’s effect starts after 1-2 hours even
administered orally. Some authors accepts that slow running of the heart depends on the
narrowing of arteries with the effect of digital and so that both the rise of blood pressure
and reduces the heart beat as a result of this highness stimulating the Nervus vagus
center. However, Özden argues that this theory is not correct, the digital in fewer
quantities don’t shrink the vessels, causes the heart to slow down by affecting the heart,
consequently the medical effect of the digital belongs to this cycle. He put forth that the
first effect of the digital is to replicate pulse amplitude through clinical experiments on
the digital, and this effect shows itself four five hours after first taking by a systolic
patient and in accordance with the experiments made on animals, the digital has real
Pharmaco-dynamics effect and the clinical symptoms written by various researchers are
side effect of the digital. Özden has published the effects of medicines like
Acetylcholine, padutine, cardiazol deriphyllin, glucose on heart and circulatory system
along with the traces taken during experiments. (14)
Liver failure test with santonin: It is important due to the contribution to the clinic by
Özden although not being a Pharmaco-dynamics study. He examined the studies made
until that day by seeing the importance of knowing the extent how the liver fulfills its
function in some diseases. The color of the urine turns yellow in santonin areas. The
yellow painted urine turns red color with the aid of alkaline. It is possible to get an idea
about to what extent the liver can perform detoxification function in the clinic by
utilizing the amount of oxysantonin that is excreted by urine and turns red with the aid
of alkaline. However, it had not been known that the color of santonin turns where in
the body. They have understood that the yellow substance was formed in the bile and
the liver had an effect in the conversion event through the animal experiments
conducted with his friends. They started to research from 1913 by thinking that they can
use this as a liver function test in liver diseases. A study titled as Santonin Experience in
Determination of Antitoxic Task of Liver has been published in Presse Médicale
Magazine in 1933. (21) He stated that the santonin administered orally passes to the bile
after a short time and excreted from kidneys by changing into oxysantonin and this
excretion is different in healthy people and liver patients. (23) They detected that they
found a large number of yellow substances in the bile 30-40 minutes after putting the
santonin in the stomach with the experiments made on the guinea pigs and this
substance is also excreted by urine after 15-25 minutes. (27) This method, which has
been mentioned as santonin test in classical books by utilizing the excretion in the form
of oxysantonin by the urine after the santonin turns into oxysantonin in the liver during
the periods in the absence of main methods that can explore the liver functions in 1930s,
had been used successfully in several countries for many years. (28) This test was used
in clinics in South America with France and Germany. (29)
Özden has researched the peripheral circulation with the Maximal Venous Pressure
Operation and with an objective method for the first time. This method provides
information about the suction power of heart and peripheral circulation. If the
sphygmomanometer put on the arm squeezes in a manner not to exceed the arterial
pressure, the pressure in the vein gradually rises. It is a method showing the passage of
the blood coming from the arteries at the height of this pressure to the vein by means of
arterioles. From this point of view, if the arteriole system is stable, the pressure in the
vein is high, if not healthy then the pressure in the vein is low. In this way, peripheral
circulation has been researched with an objective method. (30)
Conclusion
Özden, the pioneer of experimental pharmacology in Turkey, has made studies that are
regarded as invention, entered in world literature of medicine. Özden, who showed that
the sensitivity of the pain was eliminated in the animals anesthetized with Kloralos
studies, on the contrary the sensitivity against mechanical excitations increased, has also
discovered the Muhtar Reflex. He had researched the effects of influential mechanisms
of digital medicaments affecting the heart in human beings and animals and has
revealed that the impact of these medicaments do not start late contrary to what
supposed previously. Özden has proved that pulse traces, pulse amplitude began to rise
within two hours after administering the digital to the patients with cardiac insufficiency
by using Uskoff tool, discovered the test of determination of liver failure with Santonin
and published.
He is an intellectual scientist with his scientific studies, successful physician
personality, the importance attached to the ethics and the interest shown by political and
social events of the country, importance given to the education and his artistic
personality. He had contributed to the literature by virtue of his studies during the
period when Pharmaco-dynamicss began to develop fast across the world and has taken
Turkey to the Pharmaco-dynamics level of Europe.
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Picture 1 A horizontal Kymograph used by Özden between 1930-35
Picture 2 Kymographs with coil spring used by Özden