Zaštitni efekat kombinacije HI-6 i trimedoksima u miševa akutno trovanih tabunom, dihlorvosom ili heptenofosom

The aim of this study was to compare the protective effect of two individual oximes (HI-6 and trimedoxime) with their combination in mice acutely poisoned with tabun, dichlorvos or heptenophos. Oxime HI-6 did not protect experimental animals against either dichlorvos, heptenophos or tabun. Trimedoxime was very effective against all three OPs. The ED-500 doses of trimedoxime necessary to protect 50% of animals after the simultaneous administration of OPs and oxime were 42.18, 14.97 and 32.08 μmol/kg in dichlorvos, heptenophos and tabun poisoning, respectively. Half-time of efficacy in the tabun protocol was approximately three and two times longer than in the protocol for heptenophos and dichlorvos, respectively indicating also that trimedoxime is very potent in counteracting tabun toxicity. Addition of trimedoxime significantly improved the protective effect of HI-6 in acute tabun poisoning. When dichlorvos or heptenophos were used, addition of trimedoxime generally improved the antidotal effect of HI-6, but still lower protection was obtained than in the case when trimedoxime alone was administered. The investigations of different oxime combinations have indicated that application of a mixture of two oximes represents a promising antidotal approach.Cilj ovog rada je bio da se uporedi zaštitni efekat pojedinačnih oksima HI-6 i trimedoksima sa zaštitnim efektom njihove kombinacije u miševa akutno trovanih tabunom, dihlorvosom ili heptenofosom. Oksim HI-6 nije štitio eksperimentalne životinje od trovanja, ali je trimedoksim bio veoma efikasan u antagonitovanju toksičnih efekata sva tri organofosforna jedinjenja. ED-500 doze trimedoksima potrebne da zaštite 50% životinja pri istovremenoj primeni organofosfata i oksima iznosile su 42,18, 14,97 i 32,08 μmol/kg kod trovanja dihlorvosom, heptenofosom odnosno tabunom. Poluvreme efikasnosti trimedoksima u tretmanu sa tabunom bilo je dva odnosno tri puta duže od poluvremena izračunatih kod trovanja heptenofosom odnosno dihlorvosom. Dodatak trimedoksima doveo je do značajnog poboljšanja zaštitnog efekta HI-6 kod trovanja tabunom. Dodatak trimedoksima takođe je poboljšao zaštitni efekat HI-6 i kod ostala dva otrova, ali je zaštita i dalje bila najbolja kada je primenjen sam trimedoksim. Ispitivanja različitih kombinacija oksima ukazuju da je primena smeše dva oksima opravdani pristup u prevazilaženju problema nejednake efikasnosti oksima

Preživljenje bolesnika s karcinomom prostate s metastazama utvrđenim kod postavljanja dijagnoze: 14-godišnje praćenje u Općoj bolnici Karlovac

Despite a very favorable stage migration, there are still patients with bone and/or nodal metastasis at the time of initial diagnosis of prostate cancer (CaP). The incidence of these patients varies significantly from country to country depending on whether or not programs for CaP screening are implemented in their health policy. In contrast to vast interest for prognosis of patients who develop metastasis after radical treatment of presumed localised CaP, there are only a few studies in recent literature analyzing survival of patients diagnosed with metastasis at initial presentation. In our study, we analyzed 128 patients with CaP in whom metastasis were assessed at the time of diagnosis. Ninety-five (74.2%) of all metastatic patients had bone metastasis (T1-4N0M1), 17 (13.3%) had metastasis in lymph nodes (T1-4N1M0) and in 16 (12.5%) patients metastasis were assessed both in bones and lymph nodes (T1-4N1M1). Patients with both bone and nodal metastasis (T1-4N1M1) had a significantly higher average PSA value and significantly higher average Gleason score. The median time to progression for all pateints was 12 (1-86) months while the median survival time was 18 (1-135) months. The tumor-specific survival of the patients with both bone and nodal metastasis (T1-4N1M1) was significantly worse than the survival of the patients with only bone or only nodal involvement. In conclusion, despite the introduction of new hormonal and cytotoxic agents and strategies, prognosis for patients with metastatic prostate cancer remains poor, especially if they initially present with both bone and nodal metastasis.Unatoč tendenciji otkrivanja karcinoma prostate u sve ranijem stadiju, i dalje se javljaju bolesnici s koštanim i/ili limfnim metastazama utvrđenim u trenutku postavljanja dijagnoze primarnog tumora. Pojavnost ovih bolesnika bitno se razlikuje od zemlje do zemlje ovisno o primjeni probira na karcinom prostate u zdravstvenom sustavu. Za razliku od širokog zanimanja za prognozu bolesnika koji su razvili metastaze karcinoma prostate nakon radikalnog liječenja, suvremena literatura nudi svega nekoliko istraživanja koja se bave preživljenjem bolesnika kod kojih su metastaze utvrđene u trenutku postavljanja dijagnoze. U našem istraživanju analizirali smo 128 bolesnika koji su imali metastaze u trenutku postavljanja dijagnoze karcinoma prostate. Kod 95 (74,2%) bolesnika metastaze su utvrđene u kostima (T1-4N0M1), kod 17 (13,3%) u limfnim čvorovima dok su kod16 (12,5%) bolesnika metastaze u trenutku postavljanja dijagnoze primarnog tumora bile prisutne i u kostima i u limfnim čvorovima (T1-4N1M1). Bolesnici koji su imali i koštane i limfne metastaze(T1 4N1M1) imali su značajno višu prosječnu vrijednost PSA te znatno viši prosječni Gleason score. Srednje vrijeme do progresije bolesti iznosilo je za sve bolesnike 12 (1-86) mjeseci, dok je prosječno trajanje života iznosilo 18 (1-135) mjeseci. Prosječno preživljenje bolesnika koji su imali i koštane i limfne metastaze (T1-4N1M1) bilo je značajno kra}e u odnosu na bolesnike koji su imali samo koštane ili samo limfne metastaze. U zaključku ističemo da prognoza bolesnika s metastatskom boleš}u utvrđenom prilikom postavljanja dijagnoze karcinoma prostate, usprkos uvođenju novih hormonskih i citotoksičnih lijekova i novih strategija, ostaje loša, posebno za bolesnike s metastazama i u kostima i u limfnim čvorovima

Nerandomizirana usporedba rezultata radikalne prostatektomije i radikalnog zračenja u liječenju bolesnika s karcinomom prostate 14-godišnje praćenje u Općoj bolnici Krlovac

Radical prostatectomy (RP) and radical external radiotherapy (RT) are standard curative options for patients with localized prostate cancer (CaP). There are no conclusive randomized studies comparing these two methods in terms of oncological outcome. The aim of our nonrandomized study was to compare oncological outcome of our patients with localized CaP treated surgically with those underwent RT. We analyzed 115 consecutive patients with newly diagnosed localized CaP in Karlovac General Hospital from January 1994 to January 2008. Sixty four (55.7%) underwent RP and 51 (44.3%) external RT. The patients in RP group were significantly younger and with lower serum prostate-specific antigen (PSA) value, while there was no significant difference between the patients in RP and RT group in term of pathologic stage, pathologic grade (Gleason score) and risk group distribution. The median follow-up was 44 months (range 5-168). There was no difference in PSA recurrence rate between the patients in RP and RT group. Time to PSA recurrence was significantly shorter after RP (median 16 months, range 2-86) than after RT (median 36, range 10-73). The overall 5-year PSA recurrence-free survival rate, estimated by Kaplan-Meier method was 57.2%. There was no difference in PSA recurrence-free survival between the patients in RP and RT group. Although nonrandomized and with a limited follow-up, our study supports a general consensus that there is no significant difference in oncological outcome between the patients with localized CaP treated with RP and those submitted to RT.Radikalna prostatektomija i radikalno perkutano zračenje standardne su metode liječenja bolesnika s lokaliziranim karcinomom prostate. Ne postoje zaključna randomizirana istraživanja koja uspoređuju onkološki ishod bolesnika liječenih ovim dvjema metodama. Cilj našeg nerandomiziranog ispitivanja bio je usporediti onkološke rezultate liječenja bolesnika s lokaliziranim karcinomom prostate liječenih kirurški s onima podvrgnutim radikalnom zračenju prostate. Analizirali smo 115 susljednih bolesnika s novodijagnosticiranim lokaliziranim karcinomom prostate u Općoj bolnici Karlovac u razdoblju od siječnja 1994. do siječnja 2008. Šezdeset jedan pacijent (55,7%) podvrgnut je radikalnoj prostatektomiji, a 51 (44.7%) radioterapiji. Pacijenti podvrgnuti radikalnoj prostatektomiji bili su značajno mlađi i imali značajno nižu vrijednost serumskog PSA, dok nije bilo značajne razlike između terapijskih skupina po pitanju patološkog stadija, patološkog gradusa (Gleason score) i distribucije po skupinama prema stupnju rizika. Medijan praćenja bolesnika iznosio je 44 mjeseca (raspon 5-168). Nije utvrđena značajna razlika u incidenciji PSA recidiva među terapijskim skupinama bolesnika.Vrijeme do pojave PSA recidiva bilo je značajno kraće kod bolesnika nakon radikalne prostatektomije (medijan 16 mjeseci, raspon 2-86), nego kod bolesnika nakon radikalne radioterapije (medijan 36 mjeseci, raspon 10-73). Ukupno stopa 5-godišnjeg preživljenja bez porasta PSA, procijenjena Kaplan Meierovom metodom, iznosila je 57,2%. Nije utvrđena razlika u preživljenu bez biokemijskog recidiva između bolesnika nakon radikalne prostatektomije i onih podvrgnutih radikalnoj radioterapiji. Iako nerandomizirano i s praćenjem bolesnika ograničenog trajanja, naše ispitivanje podupire opće prihvaćeni stav da nema značajnih razlika po pitanju onkološkog ishoda između bolesnika s lokaliziranim karcinomom prostate liječenih radikalnom prostatektomijom i onih podvrgnutih radikalnom zračenju prostate

Preživljenje bolesnika s karcinomom prostate s metastazama utvrđenim kod postavljanja dijagnoze: 14-godišnje praćenje u Općoj bolnici Karlovac

Despite a very favorable stage migration, there are still patients with bone and/or nodal metastasis at the time of initial diagnosis of prostate cancer (CaP). The incidence of these patients varies significantly from country to country depending on whether or not programs for CaP screening are implemented in their health policy. In contrast to vast interest for prognosis of patients who develop metastasis after radical treatment of presumed localised CaP, there are only a few studies in recent literature analyzing survival of patients diagnosed with metastasis at initial presentation. In our study, we analyzed 128 patients with CaP in whom metastasis were assessed at the time of diagnosis. Ninety-five (74.2%) of all metastatic patients had bone metastasis (T1-4N0M1), 17 (13.3%) had metastasis in lymph nodes (T1-4N1M0) and in 16 (12.5%) patients metastasis were assessed both in bones and lymph nodes (T1-4N1M1). Patients with both bone and nodal metastasis (T1-4N1M1) had a significantly higher average PSA value and significantly higher average Gleason score. The median time to progression for all pateints was 12 (1-86) months while the median survival time was 18 (1-135) months. The tumor-specific survival of the patients with both bone and nodal metastasis (T1-4N1M1) was significantly worse than the survival of the patients with only bone or only nodal involvement. In conclusion, despite the introduction of new hormonal and cytotoxic agents and strategies, prognosis for patients with metastatic prostate cancer remains poor, especially if they initially present with both bone and nodal metastasis.Unatoč tendenciji otkrivanja karcinoma prostate u sve ranijem stadiju, i dalje se javljaju bolesnici s koštanim i/ili limfnim metastazama utvrđenim u trenutku postavljanja dijagnoze primarnog tumora. Pojavnost ovih bolesnika bitno se razlikuje od zemlje do zemlje ovisno o primjeni probira na karcinom prostate u zdravstvenom sustavu. Za razliku od širokog zanimanja za prognozu bolesnika koji su razvili metastaze karcinoma prostate nakon radikalnog liječenja, suvremena literatura nudi svega nekoliko istraživanja koja se bave preživljenjem bolesnika kod kojih su metastaze utvrđene u trenutku postavljanja dijagnoze. U našem istraživanju analizirali smo 128 bolesnika koji su imali metastaze u trenutku postavljanja dijagnoze karcinoma prostate. Kod 95 (74,2%) bolesnika metastaze su utvrđene u kostima (T1-4N0M1), kod 17 (13,3%) u limfnim čvorovima dok su kod16 (12,5%) bolesnika metastaze u trenutku postavljanja dijagnoze primarnog tumora bile prisutne i u kostima i u limfnim čvorovima (T1-4N1M1). Bolesnici koji su imali i koštane i limfne metastaze(T1 4N1M1) imali su značajno višu prosječnu vrijednost PSA te znatno viši prosječni Gleason score. Srednje vrijeme do progresije bolesti iznosilo je za sve bolesnike 12 (1-86) mjeseci, dok je prosječno trajanje života iznosilo 18 (1-135) mjeseci. Prosječno preživljenje bolesnika koji su imali i koštane i limfne metastaze (T1-4N1M1) bilo je značajno kra}e u odnosu na bolesnike koji su imali samo koštane ili samo limfne metastaze. U zaključku ističemo da prognoza bolesnika s metastatskom boleš}u utvrđenom prilikom postavljanja dijagnoze karcinoma prostate, usprkos uvođenju novih hormonskih i citotoksičnih lijekova i novih strategija, ostaje loša, posebno za bolesnike s metastazama i u kostima i u limfnim čvorovima

Nerandomizirana usporedba rezultata radikalne prostatektomije i radikalnog zračenja u liječenju bolesnika s karcinomom prostate 14-godišnje praćenje u Općoj bolnici Krlovac

Radical prostatectomy (RP) and radical external radiotherapy (RT) are standard curative options for patients with localized prostate cancer (CaP). There are no conclusive randomized studies comparing these two methods in terms of oncological outcome. The aim of our nonrandomized study was to compare oncological outcome of our patients with localized CaP treated surgically with those underwent RT. We analyzed 115 consecutive patients with newly diagnosed localized CaP in Karlovac General Hospital from January 1994 to January 2008. Sixty four (55.7%) underwent RP and 51 (44.3%) external RT. The patients in RP group were significantly younger and with lower serum prostate-specific antigen (PSA) value, while there was no significant difference between the patients in RP and RT group in term of pathologic stage, pathologic grade (Gleason score) and risk group distribution. The median follow-up was 44 months (range 5-168). There was no difference in PSA recurrence rate between the patients in RP and RT group. Time to PSA recurrence was significantly shorter after RP (median 16 months, range 2-86) than after RT (median 36, range 10-73). The overall 5-year PSA recurrence-free survival rate, estimated by Kaplan-Meier method was 57.2%. There was no difference in PSA recurrence-free survival between the patients in RP and RT group. Although nonrandomized and with a limited follow-up, our study supports a general consensus that there is no significant difference in oncological outcome between the patients with localized CaP treated with RP and those submitted to RT.Radikalna prostatektomija i radikalno perkutano zračenje standardne su metode liječenja bolesnika s lokaliziranim karcinomom prostate. Ne postoje zaključna randomizirana istraživanja koja uspoređuju onkološki ishod bolesnika liječenih ovim dvjema metodama. Cilj našeg nerandomiziranog ispitivanja bio je usporediti onkološke rezultate liječenja bolesnika s lokaliziranim karcinomom prostate liječenih kirurški s onima podvrgnutim radikalnom zračenju prostate. Analizirali smo 115 susljednih bolesnika s novodijagnosticiranim lokaliziranim karcinomom prostate u Općoj bolnici Karlovac u razdoblju od siječnja 1994. do siječnja 2008. Šezdeset jedan pacijent (55,7%) podvrgnut je radikalnoj prostatektomiji, a 51 (44.7%) radioterapiji. Pacijenti podvrgnuti radikalnoj prostatektomiji bili su značajno mlađi i imali značajno nižu vrijednost serumskog PSA, dok nije bilo značajne razlike između terapijskih skupina po pitanju patološkog stadija, patološkog gradusa (Gleason score) i distribucije po skupinama prema stupnju rizika. Medijan praćenja bolesnika iznosio je 44 mjeseca (raspon 5-168). Nije utvrđena značajna razlika u incidenciji PSA recidiva među terapijskim skupinama bolesnika.Vrijeme do pojave PSA recidiva bilo je značajno kraće kod bolesnika nakon radikalne prostatektomije (medijan 16 mjeseci, raspon 2-86), nego kod bolesnika nakon radikalne radioterapije (medijan 36 mjeseci, raspon 10-73). Ukupno stopa 5-godišnjeg preživljenja bez porasta PSA, procijenjena Kaplan Meierovom metodom, iznosila je 57,2%. Nije utvrđena razlika u preživljenu bez biokemijskog recidiva između bolesnika nakon radikalne prostatektomije i onih podvrgnutih radikalnoj radioterapiji. Iako nerandomizirano i s praćenjem bolesnika ograničenog trajanja, naše ispitivanje podupire opće prihvaćeni stav da nema značajnih razlika po pitanju onkološkog ishoda između bolesnika s lokaliziranim karcinomom prostate liječenih radikalnom prostatektomijom i onih podvrgnutih radikalnom zračenju prostate

Simultaneous determination of amoxicillin and clavulanic acid in the human plasma by high performance liquid chromatography: Mass spectrometry (UPLC/MS)

Background/Aim. Quantitative analysis of amoxicillin and clavulanic acid in biological matrices requires sensitive and specific methods which allow determination of therapeutic concentration in μg/mL range. Analytical methods for determination of their concentrations in body fluids described in literature include high performance liquid chromatography coupled to UV detector (HPLC-UV) and liquid chromatography-mass spectrometry (LC-MS). The aim of this study was to develop sensitive and specific ultra performance liquid chromatography/ mass spectrometry (UPLC/MS) method which could be used for the spectral identification and quantification of the low concentrations of amoxicillin and clavulanic acid in the human plasma. Method. A sensitive and specific UPLC/MS method for amoxicillin and clavulanic acid determination was developed in this study. The samples were taken from the adult healthy volunteers receiving per os one tablet of amoxicillin (875 mg) in combination with clavulanic acid (125 mg). Results. Plasma samples were pretreated by direct deproteinization with perchloric acid. Quantification limit of 0.01 μg/ml for both amoxicillin and clavulanic acid was achieved. The method was reproducible day by day (RSD < 7 %). Analytical recoveries for amoxicillin ranged from 98.82% to 100.9% (for concentrations of 1, 5 and 20 μg/mL), and recoveries for clavulanic acid were 99,89% to 100.1% (for concentrations of 1, 2 and 5 μg/mL). This assay was successfully applied to a pilot pharmacokinetic study in healthy volunteers after a single-oral administration of amoxicillin/ clavulanic combination. The determined plasma concentrations of both amoxicillin and clavulanic acid were in the range of the expected values upon the literature data for HPLC-UV and LC-MS methods. Conclusion. The described method provided a few advantages comparing with LC/MS-MS method. The method is faster using running time of 5 minute, has lower limit of quantification (LOQ ) and it could be used in pharmacokinetic studies of both amoxicillin and clavulanic acid

Neuspeh sprečavanja razvoja intermedijernog sindroma kod akutnog trovanja organofosfornim insekticidima primenom oksima i atropina

Introduction. Intermediate syndrome (IMS) was described a few decades ago, however, there is still a controversy regarding its exact etiology, risk factors, diagnostic parameters and required therapy. Considering that acute poisonings are treated in different types of medical institutions this serious complication of organophosphate insecticide (OPI) poisoning is frequently overlooked. The aim of this paper was to present a case of IMS in organophosphate poisoning, which, we believe, provides additional data on the use of oxime or atropine. Case report. After a well-resolved cholinergic crisis, the patient developed clinical presentation of IMS within the first 72 h from deliberate malathion ingestion. The signs of IMS were weakness of proximal limb muscles and muscles innervated by motor cranial nerves, followed by the weakness of respiratory muscles and serious respiratory insufficiency. Malathion and its active metabolite were confirmed by analytical procedure (liquid chromatography-mass spectrometry). Pralidoxime methylsulphate, adiministered as a continuous infusion until day 8 (total dose 38.4 g), and atropine until the day 10 (total dose 922 mg) did not prevent the development of IMS, hence the mechanical ventilation that was stopped after 27 h had to be continued until the day 10. Conclusion. Continuous pralidoxime methylsulphate infusion with atropine did not prevent the development of IMS, most likely due to the delayed treatment and insufficient oxime dose but also because of chemical structure and lipophilicity of ingested OPI. A prolonged intensive care monitoring and respiratory care are the key management for the intermediate syndrome.Uvod. Intermedijerni sindrom (IMS) opisan je pre nekoliko decenija, međutim i dalje postoje kontroverze u vezi sa njegovom etiologijom, faktorima rizika, dijagnostičkim parametrima i potrebnom terapijom. S obzirom na to da se akutna trovanja leče u medicinskim ustanovama različitog tipa, ova teška komplikacija akutnih trovanja organofosfornim insekticidima (OFI) često se ne prepoznaje. Cilj rada bio je da se prikaže slučaj akutnog trovanja organofosfornim insekticidom koji će dati dodatne podatke o upotrebi oksima i atropina. Prikaz bolesnika. Nakon kupirane holinergičke krize kod bolesnika, 72 h od namerne ingestije malationa, došlo je do razvoja kliničke slike IMS. Znaci IMS su uključivali slabost mišića gornjih ekstremiteta i mišića inervisanih motornim kranijalnim nervima, što je bilo praćeno slabošću respiratorne muskulature i teškom respiratornom insuficijencijom. Malation i njegov aktivni metabolit potvrđeni su analitičkom procedurom (tečna hromatografijamasena spektrometrija). Kontinuiranom infuzijom pralidoksim metilsulfata do osmog dana (ukupno 38,4 g) i atropina do desetog dana (ukupna doza 922 mg), nije sprečen razvoj IMS, te je mehanička ventilacija, koja je prekinuta nakon 27 h, morala biti nastavljena do desetog dana. Zaključak. Kontinuiranom infuzijom pralidoksim-metilsulfata i atropina nije sprečen razvoj IMS, najverovatnije zbog odloženog početka lečenja i nedovoljne doze primenjenog oksima, ali i hemijske strukture i lipofilnosti ingestiranog OFI. Istaknut je značaj produžene opservacije u jedinici intenzivne nege i respiratorne podrške u lečenju intermedijernog sindroma

Toksikokinetika i korelacija koncentracija karbamazepina u salivi i serumu kod akutnog trovanja

Background/Aim. Saliva is a body fluid which, like serum, can be used for determination of concentrations of certain drugs, both in pharmacotherapy as well as in acute poisonings. The aim of this study was to determine carbamazepine concentrations in both saliva and serum in acute poisoning in order to show if there is a correlation between the obtained values, as well as to monitor toxicokinetics of carbamazepine in body fluides. Methods. Saliva and serum samples were obtained from 26 patients treated with carbamazepine and 20 patients acutely poisoned by the drug immediately after their admission in the Emergency Toxicology Unit. Determination of salivary and serum carbamazepine concentrations was performed by the validated high pressure liquid chromatographyultraviolet (HPLC-UV) method. Results. A significant correlation of salivary and serum carbamazepine concentrations in both therapeutic application and acute poisoning (r = 0.9481 and 0.9117, respectively) was confirmed. In acute poisonings the mean ratio between salivary and serum concentrations of carbamazepine (0.43) was similar to the mean ratio after its administration in therapeutic doses (0.39), but there were high inter-individual variations in carbamazepine concentrations in the acutely poisoned patients, as a consequence of different ingested doses of the drug. In acute poisoning the halftime of carbamazepine in saliva and serum was 12.57 h and 6.76 h, respectively. Conclusion. Our results suggest a possible use of saliva as an alternative biological material for determination of carbamazepine concentrations in therapeutic application and acute poisoning as well, and a possible extrapolation of the results obtained in saliva to serum concentrations of carbamazepine.Uvod/Cilj. Slično serumu, saliva je biološki materijal koji se može primeniti za određivanje koncentracije lekova kako nakon terapijske primene, tako i u akutnom trovanju. Cilj ovog rada bio je da se odrede koncentracije karbamazepina u salivi i serumu u akutnom trovanju da bi se pokazalo da li postoji korelacija između dobijenih vrednosti, kao i da se isprati toksikokinetika karbamazepina u salivi i serumu. Metode. Uzorci salive i seruma uzeti su od 26 bolesnika na terapiji karbamazepinom i 20 bolesnika akutno otrovanih ovim lekom nakon prijema u toksikološku ambulantu. Određivanje koncentracije karbamazepina vršeno je validovanom metodom visokoefikasne tečne hromatografije sa ultravioletnom detekcijom (HPLC-UV). Rezultati. Potvrđena je značajna korelacija koncentracija karbamazepina u salivi i serumu nakon terapijske primene (r = 0,9481), kao i u akutnom trovanju ovim lekom (r = 0,9117). Prosečni odnos koncentracija karbamazepina u salivi i serumu u akutnim trovanjima (0,43) bio je sličan odgovarajućem parametru nakon terapijske primene leka (0,39), ali je bilo većih interindividualnih razlika u koncentracijama leka u akutnim trovanjima, zbog, najverovatnije, razlika u ingestiranim dozama karbamazepina. U akutnim trovanjima poluvreme eliminacije karbamazepina u serumu bilo je 12,57 h, a u salivi 6,76 h. Zaključak. Dobijeni rezultati govore o mogućoj primeni salive kao biološkog materijala za određivanje koncentracije karbamazepina tokom terapijske primene i u akutnom trovanju, kao i o mogućoj ekstrapolaciji vrednosti koncentracija karbamazepina u salivi na serumske koncentracije ovog leka

Pharmacodynamic and pharmacokinetic effects of flumazenil and theophylline application in rats acutely intoxicated by diazepam

Background/Aim. The majority of symptoms and signs of acute diazepam poisoning are the consequence of its sedative effect on the CNS affecting selectively polisynaptic routes by stimulating inhibitory action of GABA. The aim of the present study was to examine the effects of combined application of theophylline and flumazenil on sedation and impaired motor function activity in acute diazepam poisoning in rats. Methods. Male Wistar rats were divided in four main groups and treated as follows: group I - with increasing doses of diazepam in order to produce the highest level of sedation and motor activity impairment; group II - diazepam + different doses of flumazenil; group III - diazepam + different doses of theophylline; group IV - diazepam + combined application of theophylline and flumazenil. Concentrations of diazepam and its metabolites were measured with LC-MS. The experiment was performed on a commercial apparatus for spontaneous motor-activity registration (LKBFarad, Sweden). Assessment of diazepam- induced neurotoxic effects and effects after theophylline and flumazenil application was performed with rotarod test on a commercial apparatus (Automatic treadmill for rats, Ugo Basile, Italy). Results. Diazepam in doses of 10 mg/kg and 15 mg/kg produced long-time and reproducible pharmacodynamic effects. Single application of flumazenil or theophylline antagonized effects of diazepam, but not completely. Combined application of flumazenile and theophylline resulted in best effects on diazepaminduced impairment of motoric activity and sedation. As a result of theopylline application there was better elimination of diazepam and its metabolites. Conclusion. Combined application of flumazenil and theophylline resulted in the best antidotal effects in the treatment of diazepam poisoned rats. These effects are a result of different mechanisms of their action, longer half-life of theophylline in relation to that of flumezenil and presumably the diuretic effect of theophylline

Mehanizmi toksičnog dejstva i interakcije polihlorovanih bifenila i polibromovanih difenil etara

Polychlorinated biphenyls (PCBs) and brominated flame retardants, polybrominated diphenylethers (PBDEs), are widespread environmental contaminants as a result of anthropogenic activities and due to their persistency and resistance to degradation. Both groups of chemicals are placed on the list of persistent organic pollutants (POPs), covered by the Stockholm convention which is aimed to limit or ban the production, use, emission, import and export of POPs in order to protect human health and the environment. Taking into account the structural similarity between PCBs and PBDEs, and the known effects of PCBs, these two groups of chemicals could have similar mechanisms of action. Also, because of real simultaneous exposure to these compounds, an examination of possible interactions is of great importance. Interactions of the compounds from these groups are likely at the system level of hormones, particularly thyroid and reproductive ones. As there are mechanisms of adverse effects of both groups of chemicals on the nervous system, including functional, neurological and behavioral changes, there are influences on neurotransmiters, changes in signal transduction and apoptosis. There are interactions affecting the occurrence of metabolic disorders as well. Data on the toxicity of mixtures of PCBs and PBDEs, as well as interactions of these chemicals would contribute to the processes of risk evaluation and risk characterisation.Polihlorovani bifenili (PCBs) i bromovani usporivači gorenja, polibromovani difenil etri (PBDEs) su široko rasprostranjeni u životnoj sredini kao posledica antropogenih aktivnosti i zahvaljujući njihovoj postojanosti i otpornosti na degradaciju. Obe grupe jedinjenja se nalaze na listi perzistentnih organskih zagađivača (POPs) usvojenoj Stokholmskom konvencijom sa ciljem da zabrani ili ograniči proizvodnju, upotrebu, emisiju ili uvoz i izvoz toksičnih supstanci označenih kao POPs u svrhu zaštite zdravlja ljudi i životne sredine. Uzimajući u obzir strukturnu sličnost između PBDEs i PCBs, kao i činjenicu da je istovremena ekspozicija ovim jedinjenima realna, ispitivanja njihovih interakcija su od značaja za predviđanje rezultujućeg efekta. Saznanja u oblasti toksikologije smeša, takođe doprinose procesu evaluacije i karakterizacije rizika. Interakcije jedinjenja iz ovih grupa su verovatne na nivou endokrinog sistema, naročito tiroidnog i reproduktivnog. S obzirom na mehanizme toksičnosti obe grupe supstanci za nervni sistem, uključujući funkcionalne promene, neurološke poremećaje i promene u ponašanju, moguće je očekivati njihove interakcije i na sistemima neurotransmitera, promene u prenosu signala i izazivanje apoptoze, kao i na pojavu metaboličkih poremećaja