Ispitivanje kinetike i mehanizma supstitucionih reakcija mononuklearnih i dinuklearnih kompleksa platine(II)

Kompleksi platine, koji se kao antitumorski agensi već duže vreme koriste u medicini, jesu cisplatina, karboplatina i oksaliplatina. Za antitumorsko dejstvo kompleksa platine odgovorne su interakcije kompleksa sa DNK molekulima. Tačan mehanizam kojim kompleksi platine ispoljavaju svoju antitumorsku aktivnost nije potpuno jasan. Smatra se da je to nastajanje bifunkcionalnog proizvoda u interakciji sa molekulom DNK. Postoji znatan broj drugih biomolekula (mali molekuli, enzimi i drugi proteini) koji mogu da reaguju sa pomenutim kompleksima platine. Pojava sporednih efekata prilikom terapije, kao što su nefrotoksičnost, gastrotoksičnost, ototoksičnost, kardiotoksičnost i neurotoksičnost, dovode se u vezu sa interakcijom između kompleksa platine i biomolekula koji sadrže atom sumpora. Upravo zbog mnogobrojnih sporednih efekata i rezistentnosti, ograničena je upotreba antitumorskih kompleksa platine u medicini. Poslednjih decenija sintetisan je znatan broj novih kompleksa, koji su strukturno slični cisplatini (klasični kompleksi platine) i kompleksa koji strukturno nisu slični cisplatini (neklasični kompleksi platine), a sve u cilju pronalaženja kompleksa koji će u odnosu na cisplatinu pokazivati manju toksičnost i rezistentnost, a veću efikasnost i rastvorljivist u vodi. Naročito je značajna sinteza neklasičnih platinskih kompleksa, kao što su kompleksi Pt(IV) koji se mogu oralno upotrebljavati, zatim sterno zaštićeni kompleksi Pt(II), polinuklearni kompleksi Pt(II), kao i kompleksi platine koji sadrže sumpor. Interakcije mononuklearnih i dinuklearnih kompleksa Pt(II) sa različitim S-donorskim i N-donorskim ligandima vrlo su značajne sa biološke i medicinske tačke gledišta. U pokušaju da definišemo odnos između strukture i funkcije nove grupe citotoksičnih i potencijalno antitumorskih jedinjenja, u okviru ove doktorske disertacije, proučavane su supstitucione reakcije mononuklearnih i dinuklearnih kompleksa Pt(II) sa različitim S-donorskim i N-donorskim biomolekulima.Platinum complexes, cisplatin, carboplatin and oxaliplatin, like anti-tumor agents, have long been used in medicine. For the antitumor activity of platinum complexes the interactions between complexes and DNA are responsible. The exact mechanism of the way how the platinum complexes exert their antitumor activity is not completely clear, it is considered that the formation of bifunctional product with DNA is responsible for the anti-tumor activity. There are a number of other biomolecules (small molecules, proteins and enzymes) that can react with platinum complexes. The occurrence of side effects during the treatment, such as nephrotoxicity, gastrotoxicity, ototoxicity, cardiotoxicity and neurotoxicity, is also associated with the interactions between platinum complexes and biomolecules containing a sulfur atom. Because of many side effects and resistance, the use of anti-tumor Pt(II) compounds in medicine is limited. In recent decades a significant number of new complexes, which are structurally similar to cisplatin (classic platinum complexes) and complexes that are not structurally similar to cisplatin (nonclassical platinum complexes) are synthesized with the aim of finding a complex that will exhibit lower toxicity and resistance, higher efficiency and solubility in water compared to cisplatin. Of particular significance is synthesis of the nonclassical platinum complexes, such as Pt(IV) complexes which can be used orally, then, the more sterically protected Pt(II) complexes, polinuclear Pt(II) complexes and platinum complexes that contain sulfur. Interaction of mononuclear and dinuclear Pt(II) complexes with various S-donor and N-donor ligands are very significant from the biological and medical point of view. In an attempt to define the relationship between structure and function of a new group of cytotoxic and potentially anticancer compounds, this doctoral thesis presents a study of the substitution reactions of mononuclear and dinuclear Pt(II) complexes with various S-donor and N-donor bio-molecules

Cerebralna mikrodijaliza: perioperacijsko praćenje i liječenje teškog neurokirurškog bolesnika

The early signs of brain ischemia are key indicators of secondary brain injury and their recognition on time can ultimately save life. Direct recording of cerebral ischemia is possible using the method of cerebral microdialysis (CM). This paper presents results of the five-year experience in applying this method at University Department of Neurosurgery, Sarajevo University Clinical Center in Sarajevo. In this observational prospective clinical study, the treatment and outcome of 51 patients with subarachnoid hemorrhage (SAH) and traumatic intracranial hemorrhage (tICH) undergoing neurosurgery and consequently treated conservatively at Neurosurgical Intensive Care Unit (NICU) were analyzed. All patients were followed up by unified monitoring at NICU and additionally by the CM method. Between December 2006 and September 2010, CM monitoring was performed in 51 patients: 18 patients with SAH and 33 patients with tICH. In all patients, samples were obtained on 367 occasions, yielding a total of 3314 samples for biochemical parameters (mean 64.98 per patient, range 42-114 samples). Positive correlation was found between glucose level and outcome at one-year follow up (when glucose level was lower, the patient Glasgow Outcome Scale (GOS) score was worse). The correlation coefficient for glycerol was negative (r=-0.81), and so was for the lactate/pyruvate ratio. There was a significant difference in patient outcome in favor of the group of patients monitored by use of CM in terms of poor and good outcome graded according to GOS score 12 months after the injury compared with the group of patients not monitored with CM (P<0.028). According to our experience, we believe that CM enables early initiation of appropriate therapeutic strategies to overcome cerebral ischemia and secondary brain damage, eventually leading to better patient outcome.Rani znaci ishemije mozga su ključni pokazatelji sekundarnih moždanih oštećenja i njihovo prepoznavanje na vrijeme može u konačnici spasiti život. Izravna registracija moždane ishemije moguća je metodom cerebralne mikrodijalize (CM). U radu su prikazani rezultati petogodišnjeg iskustva u primjeni ove metode na Klinici za neurokirurgiju Kliničkog centra Univerziteta u Sarajevu. U prospektivnoj opservacijskoj kliničkoj studiji pratilo se liječenje i ishod u 51 bolesnika sa subarahnoidnim krvarenjem (SAH) i traumatskim intrakranijskim krvarenjem (tICH) koji su bili podvrgnuti neurokirurškoj operaciji, a potom konzervativno liječeni u Neurokirurškoj jedinici intenzivnog liječenja (NICU). Kod svih bolesnika je provedeno standardno praćenje u NICU i dodatno su praćeni metodom CM. U razdoblju od prosinca 2006. do rujna 2010. praćenje pomoću CM provedeno je u 51 bolesnika: 18 bolesnika sa SAH i 33 bolesnika s tICH. U svih bolesnika uzorci su uzeti 367 puta, ukupno 3314 uzoraka biokemijskih parametara (prosječno 64,98 po bolesniku, raspon 42-114). Nađena je pozitivna korelacija između razine glukoze i ishoda u bolesnika nakon godinu dana praćenja; kada je razina glukoze bila niža, zbir GOS (Glasgow Outcome Scale) bolesnika bio je lošiji. Za glicerol je koeficijent korelacije bio negativan (r = – 0,81). Negativna korelacija zabilježena je također za omjer laktat/piruvat. Postojala je značajna razlika u ishodu bolesnika u korist skupine bolesnika koji su praćeni pomoću CM u smislu lošeg i dobrog ishoda, prema zbiru GOS, 12 mjeseci nakon ozljede, u usporedbi s rezultatima bolesnika koji nisu praćeni pomoću CM (P<0,028). Prema dosadašnjem iskustvu, vjerujemo da CM omogućava rano pokretanje odgovarajućih terapijskih strategija za prevladavanje cerebralne ishemije i sekundarnih oštećenja mozga, što konačno vodi boljem ishodu bolesnika

New natural products from Clinopodium thymifolium (Scop.) Kuntze (Lamiaceae)

Clinopodium thymifolium (Scop.) Kuntze (syn. Micromeria thymifolia (Scop.) Fritsch) is an aromatic plant species widespread in the Mediterranean region, from north-eastern Italy across the Western Balkans to Hungary and Albania [1,2]. C. thymifolium has been used in folk medicine of the Mediterranean area for a long time [3]. Also, due to a high content of the essential oil in its leaves, it is used as a condiment and sometimes used in cooking [4,5]. For this reason, and the marked tendency to broaden the use of condiments and spices, some efforts are being made to introduce this plant as a new crop species (currently successfully cultivated in northern Italy) [4]. The beneficial effects of Lamiaceae species on human health have been frequently ascribed to essential-oil ingredients. Volatiles of C. thymifolium have been well studied – previous studies showed that the qualitative compositions of the investigated C. thymifolium oils were very mutually similar and dominated by oxygenated p-menthane monoterpenoids [6,7]. However, in this work, a comprehensive chemical analysis, in combination with detailed spectral analyses and chemical synthesis of selected compounds, has led to the identification of a series of esters of menthol stereoisomers in C. thymifolium essential oil, including some new natural products

Ispitivanje kinetike i mehanizma supstitucionih reakcija mononuklearnih i dinuklearnih kompleksa platine(II)

Kompleksi platine, koji se kao antitumorski agensi već duže vreme koriste u medicini, jesu cisplatina, karboplatina i oksaliplatina. Za antitumorsko dejstvo kompleksa platine odgovorne su interakcije kompleksa sa DNK molekulima. Tačan mehanizam kojim kompleksi platine ispoljavaju svoju antitumorsku aktivnost nije potpuno jasan. Smatra se da je to nastajanje bifunkcionalnog proizvoda u interakciji sa molekulom DNK. Postoji znatan broj drugih biomolekula (mali molekuli, enzimi i drugi proteini) koji mogu da reaguju sa pomenutim kompleksima platine. Pojava sporednih efekata prilikom terapije, kao što su nefrotoksičnost, gastrotoksičnost, ototoksičnost, kardiotoksičnost i neurotoksičnost, dovode se u vezu sa interakcijom između kompleksa platine i biomolekula koji sadrže atom sumpora. Upravo zbog mnogobrojnih sporednih efekata i rezistentnosti, ograničena je upotreba antitumorskih kompleksa platine u medicini. Poslednjih decenija sintetisan je znatan broj novih kompleksa, koji su strukturno slični cisplatini (klasični kompleksi platine) i kompleksa koji strukturno nisu slični cisplatini (neklasični kompleksi platine), a sve u cilju pronalaženja kompleksa koji će u odnosu na cisplatinu pokazivati manju toksičnost i rezistentnost, a veću efikasnost i rastvorljivist u vodi. Naročito je značajna sinteza neklasičnih platinskih kompleksa, kao što su kompleksi Pt(IV) koji se mogu oralno upotrebljavati, zatim sterno zaštićeni kompleksi Pt(II), polinuklearni kompleksi Pt(II), kao i kompleksi platine koji sadrže sumpor. Interakcije mononuklearnih i dinuklearnih kompleksa Pt(II) sa različitim S-donorskim i N-donorskim ligandima vrlo su značajne sa biološke i medicinske tačke gledišta. U pokušaju da definišemo odnos između strukture i funkcije nove grupe citotoksičnih i potencijalno antitumorskih jedinjenja, u okviru ove doktorske disertacije, proučavane su supstitucione reakcije mononuklearnih i dinuklearnih kompleksa Pt(II) sa različitim S-donorskim i N-donorskim biomolekulima.Platinum complexes, cisplatin, carboplatin and oxaliplatin, like anti-tumor agents, have long been used in medicine. For the antitumor activity of platinum complexes the interactions between complexes and DNA are responsible. The exact mechanism of the way how the platinum complexes exert their antitumor activity is not completely clear, it is considered that the formation of bifunctional product with DNA is responsible for the anti-tumor activity. There are a number of other biomolecules (small molecules, proteins and enzymes) that can react with platinum complexes. The occurrence of side effects during the treatment, such as nephrotoxicity, gastrotoxicity, ototoxicity, cardiotoxicity and neurotoxicity, is also associated with the interactions between platinum complexes and biomolecules containing a sulfur atom. Because of many side effects and resistance, the use of anti-tumor Pt(II) compounds in medicine is limited. In recent decades a significant number of new complexes, which are structurally similar to cisplatin (classic platinum complexes) and complexes that are not structurally similar to cisplatin (nonclassical platinum complexes) are synthesized with the aim of finding a complex that will exhibit lower toxicity and resistance, higher efficiency and solubility in water compared to cisplatin. Of particular significance is synthesis of the nonclassical platinum complexes, such as Pt(IV) complexes which can be used orally, then, the more sterically protected Pt(II) complexes, polinuclear Pt(II) complexes and platinum complexes that contain sulfur. Interaction of mononuclear and dinuclear Pt(II) complexes with various S-donor and N-donor ligands are very significant from the biological and medical point of view. In an attempt to define the relationship between structure and function of a new group of cytotoxic and potentially anticancer compounds, this doctoral thesis presents a study of the substitution reactions of mononuclear and dinuclear Pt(II) complexes with various S-donor and N-donor bio-molecules