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Tbilisi State Medical University I.Kutateladze Institute of Pharmacochemistry

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CREATIVE WAY
Pharmacology is of an ancient tradition in Georgia. It became one of the most important fields of medical sciences in our country. This fact was reflected in medicinal books Ustsoro Karabadini, Tsigni Saakimoi and Samkurnalo Tsigni Karabadini, written as far back as the Middle Ages, and later in Iadigar Daudi (XVI century). Far more, than one idea is associated with Medea’s name, Colch King’s daughter, who was the founder of Ancient Greek phytotherapy. 
But the foundation for Georgian scientific pharmacy was laid only after opening of Tbilisi State University. At that time Acad. Iovel Kutateladze, already a well-known scientist, was invited by Ivane Javakhishvili to be the Head of the Department of Pharmacy and Pharmacology. He came back to Tbilisi from Odessa in 1921. Acad. I. Kutateladze also founded the Chemical-Pharmaceutical Department, on the base of which the Pharmaceutical Faculty was established in 1928. In 1930, from the University, Tbilisi State Medical Institute was detached and there was opened the Parmacochemical Faculty. In 1937 it was transformed into an independent Pharmaceutical Institute. Acad. I. Kutateladze was the Head of the Faculty and, later, of the Institute.
This way, the pharmaceutical education was established in Georgia. At the same time with the pedagogic work, Acad. I. Kutateladze together with his group carried out scientific research and achieved such results that in 11 years it became possible to establish an independent scientific body. 
By Decree No.63 of the People’s Commissariat of Health of the Georgian SSR of 5 May 1932, Tbilisi Research Institute of Pharmacochemistry was established. In 1932-1940, the Institute was in the system of Georgian People’s Commissariat of Health, in 1940-1946 – of the Georgian Pharmacochemical Industry, in 1946-1958 – of the USSR Ministry of Health and in 1959-1960 – of the Georgian Ministry of Health. By Decree No.108 of the Council of Ministers of the Georgian SSR of 2 March 1961, the Institute was placed under the authority of the Georgian Academy of Sciences.
From the date of its establishment to1963, Acad. Iovel Kutateladze, the Honored Scientist and the founder of pharmaceutical education and pharmacochemical field of science in Georgia, headed the Institute. When he died, the Institute was named after its founder.
In 1964-1972, the Director of the Institute was Acad. Vladimir Asatiani, the Honored Scientist, the founder of medical biochemistry, biochemical pharmacology and mountain climate biochemistry.

Academician Ether Kemertelidze, the Honored Scientist, has headed the Institute in 1972-2005. Since 2005 she is a Head of the Laboratory of Steroids and Cardiac Glycosides.
Side by side with Acad. Iovel Kutateladze there worked the following scientists: Academicians A.Aladashvili and V.Asatiani, Professors N.Maskhulia, E.Abol, V.Shotadze, A.Mshvidobadze, G.Vashadze, D.Gedevanishvili, V.Chumburidze, A.Plisov and K.Mujiri; Assistant Professors I.Burjanadze, L.Ramishvili, T.Kachukhashvili, N.Zhgenti, T.Mekhuzla et al. Of special note is the activity of Ivane Javakhishvili who headed the terminological investigation in the Institute (1933-1938). Later, at different times, there worked Acad. I.Sosnovsky and N.Ketskhoveli, Prof. A.Gakhokidze, V.Gersamia, A.Yatsenko-Khmelevski, V.Goguadze, N.Aneli, S.Kobaladze, T.Gibradze and Ts.Dalakishvili; Assist.Prof. V.Bostoganashvili, L.Chkhatarashvili, T.Pkheidze, A.Gotsiridze et al. They contributed a lot to the development of pharmacochemistry in Georgia. 
From the establishment of the Institute of Pharmacochemistry, the purposeful investigation of natural resources of Georgia began and the firm foundation of the pharmacochemical field of science was laid.
I.Kutateladze Institute of Pharmacochemistry of the Georgian Academy of Sciences is the leading institution in the field of production of medicinal preparations in Georgia. The basic line of the Institute is investigation of biologically active substances of plant and mineral origin, study of their chemical properties and pharmacological efficiency, development of the technologies and analysis methods and, as a result, creation of medicinal preparations.
 Solution of the problems related to creation of new remedies determined the complex structure of the Institute and the trends of fundamental research in various fields of science. An integral system from seeking for biologically active substances (BAS) to production of obtained remedies has been formed. At the Institute, there are carried out investigations in the field of pharmacochemistry, chemistry of natural compounds, organic and analytical chemistry, medicine, biology and technology. Lately chemical modification of natural substances has been started. The sphere of scientific research was extended, new structural units were formed, and the number of employees, which made 300 people in 1985, grew systematically. At present, there work 133 employees, including 1 academician, 9 doctors and 50 candidates of science. 
The scientists of the Institute have achieved significant results in fundamental and applied research. About 70 medicinal preparations, which were used in medical practice at different times, have been recommended for application.

The earlier works carried out at the Institute provided the basis for establishment of Tbilisi Chemical-Pharmaceutical Plant and Batumi Caffeine Plant. The preparations and technologies offered by the Institute were introduced there. The technology of production of caffeine from tea manufacture residues and raw materials left after tea bush trimming was developed. For 40 years Batumi Caffeine Plant supplied the former Soviet Union with natural caffeine and even exported it abroad. Tealbin, a remedy against gastroenteric diseases, was also introduced into production there. At that time, a significant fact was the development of the technology for production of natural tannin from the leaves of the fustic and sumac, which was introduced at Tbilisi Chemical-Pharmaceutical Plant. The Plant also produced the following remedies prepared in the Institute: Elargol, a colloid silver preparation, being a strong antiseptic; highly efficient antihelminthic preparations Filicol and Filixan; Quinet, a malaricidal preparation; drastic cardiovascular remedies Digalen-Neo, Periplocin, Satituran, Digicil and Digicilen.

A new medicinal form – natural juice of raw plants, created at the Institute 55 years ago, was acknowledged in contemporary phytotherapy worldwide. The natural juices prepared at the Institute were used

The specialists of the Institute justified the possibility of application of mineral water Lugela in medicine instead of 10% calcium chloride solution. Tbilisi Chemical-Pharmaceutical Plant is still producing tablets of antiepileptic Gluferal.
I.Kutateladze was the first who suggested application of bentonite in medicine. From clays of Askani Deposit (Ozurgeti region of Georgia), preparations Tikha-Askane and Askancol were produced. Besides versatile medical application, they are also universal base for production of soft medicinal forms. On the base of Tikha-Askane there were developed preparations Cincascol, Cincascan, Ikhtascan, Streptascan, and Bentobol etc. New medicinal forms, so-called dry ointments in the form of tablets, were invented.
Acad. I. Kutateladze carried out important investigations on the history of pharmacy; he published several books on chemical, botanic and pharmaceutical terminology with Georgian-Russian-Latin references.

The preparations used to be tested at the Clinical Department of the Institute, which was headed by Acad. Alexander Aladashvili. There worked well-known therapeutists: Prof. M.Kandelaki, V.Gersamia and I.Javakhishvili; Assistant Prof. I.Parma, N.Gambashidze, T.Gedevanishvili et al. In 1978 the Department of Experimental and Clinical Pharmacotherapy with its own therapeutic clinic (50 beds) was transferred from Tbilisi State Medical Institute to the Institute of Pharmacochemistry. Prof. Sergo Kobaladze headed the Department. After his death in 1989, the Department was headed by Assistant Prof. Tengiz Tsertsvadze and, later, since 1991 - by Assistant Prof. Archil Kobaladze. The Department was the base organization of the Pharmacological Committee of the USSR Ministry of Health. The studies carried out at the Department promoted introduction into medical practice of such medicines as Voltaren, Corvaton, Tribusponin, Causuron, Fatsiflogin etc. and extension of application of Brufen, Trental, Lidocaine and Cordarone. The remedies prepared in the Institute were tested in various specialized clinics of the former USSR. Application of the new preparations in medical practice and their commercial production were performed by the corresponding Orders of the USSR Ministry of Health. Nowadays the registration of the preparations produced in the Institute is performed by the Georgian Ministry of Trade, Health and Social Affairs and the Ministry of Health of Russian Federation. 
By means of pharmacobotanic expeditions and purposeful trips which had been undertaken every year since the foundation of the Institute, the flora growing on the territory of Georgia was studied substantially; the areas of basic plants were studied and the natural resources were registered; a rich herbarium was collected. An interesting investigation concerning the anatomy of higher plants was carried out.
The Institute possesses several testing fields of medicinal plants in various geographical zones of Georgia: the 20 ha area in Tbilisi; the 162 ha in Shiraki region, in the vicinity of the villages of Kasristskali and Vashlovani. In 1975-1992 ,there was a testing field point of 3.5 ha in the village of Shebelda, Gulripshi region. In 1992, Kobuleti Experiment Station was joined to the Institute. Until then the station has been the Transcaucasian Regional Station of the All-Union Research Institute of Medicinal and Aromatic Plants. 
Biological specific features of growth/development of the plants were studied; agricultural recommendations on their growth were worked out. the works on introduction of 70 plants were carried out and 50 species of medicinal plants were introduced into culture on the testing fields of the Institute. Thus, a firm foundation for production of medicinal preparations was laid.
The Experimental and Production Base occupies an important place in the Institute structure. There are improved and implemented the technologies for production of the recommended preparations; there are produced the preparations for clinical tests and mass consumption. 
As the result of the analysis of about 400 species of wild and introduced plants, there have been revealed a lot of plant species of a unique composition and interesting pharmacological effect.
From the plants there were extracted and identified about 1000 substances of various chemical classes: alkaloids, cardenolids, bufadienolids, coumarins, furo- and isocoumarins, hydrolyzable and condensed tannides, lignans, neolignans, antraquinones and polysaccharides.
Among them, there were 95 structurally new organic substances, the chemical structure of which was determined. In more than 200 plant species, there were studied neutral and polar lipids, 22 kinds of terpenoids and volatile oils, polysaccharides, proteolytic enzymes and lectins. A significant number of the extracted substances or preparations on their base are physiologically effective.
While studying the dynamics of active substance accumulation from the first stage of plant ontogenesis and in different phases of vegetation, some specific features of the active substance biogenesis were observed. Determination of the relationship between the chemical structure and biological activity created perspectives for purposeful screening for the remedies of a desired effect.
Academicians I.Kutateladze and V.Asatiani laid the foundation for pharmaceutical and biochemical analysis in our country. Later, the research in the field of physical, chemical and biological analysis of natural and synthetic substances was significantly extended using up-to-date progressive methods. At that time, there were being created theoretical prerequisites for application of nuclear magnetic resonance (NMR) spectroscopy for solving the structural problems of molecular biophysical chemistry. At the same time, in 1978-1993 the Department of Spectroscopy of the Institute operated as the Republican NMR Center.
Based on the up-to-date research data, there were developed ion-exchange technologies of selective and polybuffer extraction and complex formation of plant substances. Significant results were obtained in the field of biopharmaceutical investigation, especially for production of finished disperse forms. Since 1970-ies, dozens of original medicinal preparations, biologically active food additives, biochemical reagents and effective plant growth stimulators have been prepared at the Institute. The basic issues referred to their production have been studied and their manufacture has been organized. 
Colchicinum speciosum Stv. – preparation Colchicin (tablets) based on Colchicinum s. bulb alkaloid, is the only remedy of the periodic disease. It is also used for treatment of amyloidosis and gout. 
Carica papaya L. – from papaya fruit latex, proteolytic enzymatic preparation Caripazym in the form of lyophilized powder was produced. Caripazym is recommended for treatment of pussy ulcers and deep burns. It has found wide application especially in neurosurgery and traumatology, in the cases of spinal osteochondrosis, arthritis, cerebral and spinal arachnoiditis, vertebral hernia and discogenic radiculitis etc. Caripazym is used effectively in stomatology for treatment of chronic paradontitis, pulpitis, gingivitis, paradontosis and aphthous and necrotizing ulcerative stomatitis. At first the papaya was cultivated at Gagra Point of the Central Botanic Garden of the USSR Academy of Sciences, then in the greenhouse based on thermal waters of Ohurei (Ochamchiri region). At present the papaya is being grown at Kobuleti Station of Medicinal Plants.
Astragalus falcatus L. - From the leaves and blossoms of the Astragalus f., a glycoside – robinin was extracted and, on its base, preparation Flaronin (tablets) was produced. The preparation is widely used in the cases of renal insufficiency with uremia. 
One of the important problems of medicinal industry was solved: there was produced a paying raw material for synthesis of hormonal steroids. This was tigogenin prepared from Yucca gloriosa L. In co-operation with the All-Union Research Chemical-Pharmaceutical Institute it was established that tigogenin transforms easily into initial products of the 5α-row steroid hormones: 5α-pregnenolone and 5α-androstanol. From them, there were synthesized dihydrotestosterone, medandrosterenol, mesterenol, altesin and parcuran bromide. There were also produced the preparations for treatment of tuberculosis, malignant tumors, arrhythmia etc. Transformation of tigogenin into 5α-pregnenolone and then its synthesis into medandrostenoloin on an industrial scale was carried out at Moscow Chemical-Pharmaceutical Plant “Akrichin”. Tigogenin was produced at the stand equipment of Batumi Chemical-Pharmaceutical Plant. There has been developed a project of constructing the tigogenin-producting section with the capacity of 15 tons a year at Akhmeta Bioplant of Tbilisi Chemical-Pharmaceutical Plant. The raw material of tigogenin – the mound-lily yucca is cultivated on the area of 162 ha in the Shiraki Valley.
Tribulus terrestris L. – On the base of steroid glycosides of the puncture vine, preparation Tribusponin (tablets) was produced. Tribusponin is a non-specific anabolic remedy for prevention and treatment of arteriosclerosis; it regulates functioning of cardiovascular and alimentary systems. The Tribusponin substance used to be produced at Chimkent Chemical-Pharmaceutical Plant (Kazakhstan) and the finished form – at Tbilisi Chemical-Pharmaceutical Plant. At present Tribusponin is produced at the Experimental and Production Base of the Institute. From steroid glycosides of Tribulus t. there was also prepared Terestrin – a generative function stimulator. 
Digitalis ciliata Trautv. – The technologies of producting drastic cardiac remedies Digitoxin and Acetyldigitoxin from the Caucasian endemic – ciliated foxglove – have been developed. 
Hedera caucasigena Pojark. – From the Caucasian ivy leaves, bronchospasmolytic preparation Causuron (drops), which is effectively used for treatment of respiratory tract inflammation, was produced.
Fatsia japonica (Thunb) Decne et Phanch. – From triterpene glycosides extracted from the leaves of Fatsia japonica, nonsteroid antirheumatic remedy Fatsiflogin was prepared. It has analgesic, anti-inflammatory effect and is recommended for the treatment of rheumatic arthritis, spondyloarthritis, ankylosing spondylitis, osteochondrosis, tendinitis and tendovaginitis, gout, myalgia and pains in soft tissues and the locomotor apparatus. Fatsiflogin is of a wide therapeutic action and has no adverse effects. 
Paliurus spina-christii Mill. – From the fruit of the Jerusalem thorn, widely spread in the Caucasus, effective hepatoprotective and bile-expelling remedy Tsarubol (capsules) was prepared. Tsarubol consists of phenolic compounds and lipids of the plant fruit.
Rhamnus frangulae L. – Preparation Ramnil (tablets), produced from oxymethylanthraquinone of the alder buckthorn bark, holds a firm place in treatment of gastrointestinal malfunctions.
There was prepared Psoranthron (ointment) – 1,8-dihydroxy 9-anthrone, which is a high-performance remedy against psoriasis.

Cotinus coggygria L. – From hydrolyzsable tannides of the smoke tree leaves, fungicidal remedy Tanifucin (ointment) and antimicrobial remedy Microgalinia (ointment) were prepared.
Rhododendron Ungernii Trautv. – Phenolic compounds from the leaves of Rhododendron Un., a Caucasian endemic, provide complete inhibition of the herpes simplex virus. Preparation Rodopes (ointment) produced from this plant is recommended for treatment of herpes. By its therapeutic effect Rodopes is compatible with Zovirax, a well-known synthetic preparation. 
The capsulated form of the valerian was approved for application in medical practice. This form offers a few advantages over the tincture. 
From Tikha-Askane, universal base Talos for production of both lipophilic and lyophilic ointments, baby powder Baya and antacid Bentobol (Tikha-Askane tablets) for treatment of wind and gastrointestinal bacteriosis were prepared.
There were also produced biologically active food additives: hypoglycemic Saturin, Ginkgo-Max for regulation of the central nervous system function etc.
There were developed original technologies for production of important biochemical agents and manufacturing of the following agents was organized: Digitonin – steroid glycoside from foxglove seeds, Emodin and chrysophanic acid from the residues of Rambol production, chemically pure tannin and colchicine; medicinal preparation standards etc.
From tea seeds, there was extracted triterpenic glycoside of an interesting effect – Teasaponin, which is a nonionic detergent, a veterinary vaccine adjuvant and a diagnostic means. Teasaponin was introduced in the production of high-speed X-ray films.
Elixir Medea for treatment of pyorrhea and disposable enema Extralax are also worthy of notice.

Using biologically active plant substances, cosmetic-prophylactic compositions were made up. Tbilisi Iveria Perfumery produced creams Dila, Papaya, Nunisi and Tbilisuri, a mask-cream based on Tikha-Askane; toothpastes Lugela, Dila and Tbilisuri. Plant lipids from the seeds of the fir, grape and corkwood were supplied for application in perfumery and pharmacy.

The investigation in the field of allelochemistry has been carried out. Preparation Alexin produced from the steroid saponins of yucca blossoms is an effective stimulator of agricultural plants. Pretreatment of seeds with its low-concentration water solution (25-50 mg/l) increases the yield of the wheat, barley, kidney bean and soybean by 30-50% and of the potato, tomato and aubergine – by 20-35%; improves the product quality; reduces the vegetation period; makes plants more resistant to weather and microorganisms. Alexin is subject to biological degradation, it is nontoxic and environment friendly.

The specialists of the Institute systematically take part in International conferences on chemistry of natural substances, pharmacy, biopharmacy, technology, pharmacology and technology. The Institute of Pharmacochemistry, for its part, has been an organizer of a number of International Conferences and Symposia. There were held the International Conferences on the problems of clinical and experimental pharmacotherapy of medicinal preparations (in 1972, 1979, 1981, 1982 and 1990), on cardiovascular remedies (1982), phenolic compounds (1976), indoles (1981, 1986, 1991) and on the chemistry and biology of carbohydrates (1972, 1987); the International Workshop on 5α-Steroids (1981 and 1984); the VII-th Soviet-Indian Symposium on the Chemistry of Natural Substances (1983); the International Immunopharmacological Symposium (1990); the First International Congress of Pharmacists (2002) etc.

Meticulous attention is paid to training the personnel. At the Institute, 22 Doctors’ and 135 Candidates’ Theses have been implemented and maintained. Since 1993 there has been working the Degree-Granting Dissertation Council of Pharmaceutical Science (Far.15.01.No.1). The Council awards the degrees on two specialities: Technology of Medicines and Organization of Pharmaceutical Business, and Pharmaceutical Chemistry and Pharmacognozy.
The Institute maintains scientific relations with similar-profile scientific institutions of the CIS and foreign countries in the field of chemistry and biology of natural substances. The specialists of the Institute have received the grants from the INTAS, ISTC and NATO.
Professor Gui Balansard, Head of the Department of Pharmacognozy and Homoeopathy of the University of Marseille was elected as Foreign Member of the Georgian Academy of Sciences in the field of pharmacochemistry.
With consideration of state importance of the Institute’s achievements and potential possibilities, in 1979-1985 five Government’s Decrees were issued with the aim to strengthen the material and technical base of the research, development and production of new medicinal preparations.
That provided for expansion of the Institute’s testing fields of medicinal plants, formation of new structural units, staffing, improving equipment for laboratories and Experimental and Production Base etc. The 3500 m2 building had been constructed for manufacture of the medicinal preparations, which was to be put into service in 1992. Construction of a laboratory building, a substance production section etc. has remained unrealized.
On the 50-th anniversary of the Institute of Pharmacochemistry, the Institute and its 8 specialists were awarded Government’s Diplomas and 2 specialists were conferred the rank of the Honored Scientist.
The diversity of the Georgian flora and mineral raw materials gives a broad opportunity to reveal biologically active substances.
The I.Kutateladze Institute of Pharmacochemistry continues the purposeful research in the field of effective medicinal preparations of natural origin with the aim to restore the pharmaceutical industry, which is traditional and important for our country, basing on national natural resources, available production facilities and scientific potential.


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