Contemporary pharmacotherapy and iatrogenic pathology

During the past few decades, the pharmaceutical industry has developed into a powerful human activity highly influencing modern medicine. Thousands of synthetic therapeuticals have been developed, and these formulations enabled the successful treatment of many diseases, some of which were considered incurable. An increase in drug consumption followed the development of the pharmaceutical industry and the introduction of synthetic drugs. The widespread use of new medicals enabled the collection of data confirming their effectiveness, but also more and more data concerning side and unwanted effects were reported. Frequent side/unwanted effect reports gave rise to development of iatrogenic pathology, a new branch of clinical pathology. The knowledge of the possible unwanted effects of drugs on macro organisms did not enable the effective withdrawal of such formulations from the market. At the beginning, the reports concerning unwanted effects were not verealed. Consequently some potentially harmful formulations were used for years without methodical analyses of their side/unwanted effects. Some potentially dangerous formulations are still on the market such as drugs containing ulcerogenic, hepatotoxic, nephrotoxic substances as well as those inducing bone marrow aplasia. The administration of these potentially dangerous formulations is understandable in the case of clear therapeutic indications allowing no alternatives. In these cases the risk of harmful side effects is greatly overwhelmed by the risk from the primary disease. Otherwise the administration of the potentially harmful drug is unjustified, especially if the indication is not a disease. Many potentially harmful drugs are formulated for use in healthy animals, recommended as growth, laying and milk stimulators, those allowing higher speed and strength in sport and racing horses, estrus inducers and suppressors. The misuse or maluse medication is highly present in sport horses daily treated with vitamin and mineral supplements, analgesics, corticosteroid and anabolic steroids. Unwanted effects of such treatments are evident sometimes shortly after application and sometimes later, influencing reproduction. The same problem is present in small animals

Delovanje haloperidola, aminooksisirćetne kiseline i (-)-nuciferina na produženje preživljavanja miševa s tetanusom

Introduction. Tetanus, also known as lockjaw, is a very dangerous, infectious, acute, usually afebrile disease characterised by muscle spasms. The causative agent of the disease is the bacterium Clostridium tetani. This pathogen produces a specifc neurotoxin, termed tetanus toxin, with two components: tetanospasmin and tetanolysin. Light chains of tetanospasmin cleavage synaptobrevin, which in turn prevent release of the inhibitory neurotransmitter GABA into the synaptic cleft. The α-motor neurons are, therefore, under no inhibitory control, as a result of which they undergo sustained excitatory discharge causing the characteristic motor spasms of tetanus. Materials and Methods. In this research, we attempted to normalise disorders caused by tetanus toxin by using haloperidol (at doses of 4, 5, 6, 7 and 8 mg/kg b.w.), alone and in combination with (-)-nuciferine (at a dose of 5 mg/kg b.w.) or aminooxyacetic acid (at a dose of 20 mg/kg b.w.). Experiments were conducted on albino mice. Experimental tetanus was induced by application of tetanus toxin. Results and Conclusions. Application of haloperidol (alone and in combination with (-)-nuciferine and aminooxyacetic acid) was carried out 24 h following the application of tetanus toxin. It was found that haloperidol, given alone in a dose of 4 mg/kg, prolonged the average survival time of mice with experimental tetanus by 24.35 h compared to the control animals. Additionally, the combination of haloperidol with (-)-nuciferine slightly, but non-signifcantly, extended survival time , while the combination of haloperidol with aminooxyacetic acid produced the best effect on extension of survival time (mice survived on average 27.74 h longer than control mice).Uvod. Tetanus je veoma opasna, akutna, obično afebrilna bolest koju karakteriše mišićni spazam. Uzročnik obolenja je bakterija Clostridium tetani, koja proizvodi specifčan neurotoksin ili tetanus toksin. Toksin se sastoji od dve komponente: tetanospazmina i tetanolizina. Laki lanac tetanospazmina cepa sinaptobrevin, što za posledicu ima sprečavanje oslobađanje inhibitornog neurotransmitera GABA u sinaptički procep. Funkcija ekscitatornih neurotransmitera ostaje očuvana, te pod njihovim uticajem dolazi do grča skeletne muskulature. Materijali i metode. U ovom istraživanju pokušali smo normalizovati poremećaje uzrokovane tetanus toksinom koristeći haloperidol (u dozama od 4, 5, 6, 7 i 8 mg/ kg t.m.), samostalno i u kombinaciji sa (-)-nuciferinom (u dozi od 5 mg/kg t.m.) i aminooksirćetnom kiselinom (u dozi od 20 mg/kg t.m.). Kompletno istraživanje je sprovedeno na albino miševima. Eksperimentalni tetanus izazvan je aplikacijom tetanus toksina. Rezultati i zaključak. Primena haloperidola (samo i u kombinaciji sa (-)-nuciferinom i aminooksirćetnom kiselinom) vršena je 24 sata nakon aplikacije tetanus toksina. Haloperidol, aplikovan u dozi od 4 mg/kg t.m., produžio je vreme preživljavanja miševa s eksperimentalnim tetanusom za oko 24.35 sati u odnosu na kontrolnu grupu životinja, te smo ovu dozu smatrali jedino opravdanom za dalja istraživanja. Kombinacija haloperidola s (-)-nuciferinom neznatno produžava vreme preživljavanja, dok je kombinacija haloperidola sa aminooksirćetnom kiselinom imala nabolji efekt na produženje ovog perioda. Period preživljavanja je produžen oko 27.74 sata u odnosu na kontrolnu grupu životinja

Poisoning of domestic animals with heavy metals

The term heavy metal refers to a metal that has a relatively high density and is toxic for animal and human organism at low concentrations. Heavy metals are natural components of the Earth's crust. They cannot be degraded or destroyed. To a small extent they enter animal organism via food, drinking water and air. Some heavy metals (e.g cooper, iron, chromium, zinc) are essential in very low concentrations for the survival of all forms of life. These are described as essential trace elements. However, when they are present in greater quantities, like the heavy metals lead, cadmium and mercury which are already toxic in very low concentrations, they can cause metabolic anomalies or poisoning. Heavy metal poisoning of domestic animals could result, for instance, from drinking-water contamination, high ambient air concentrations near emission sources, or intake via the food chain. Heavy metals are dangerous because they tend to bioaccumulate in a biological organism over time. Manifestation of toxicity of individual heavy metals varies considerably, depending on dose and time of exposure, species, gender and environmental and nutritional factors. Large differences exist between the effects of a single exposure to a high concentration, and chronic exposures to lower doses. The aim of this work is to present the source of poisoning and toxicity of some heavy metals (lead, mercury, cadmium, thallium, arsenic), as well as new data about effects of those heavy metals on the health of domestic animals.

Ispitivanje genotoksičnog efekta Carbadoxa in vitro i in vivo

Due to its bactericidal activity Carbadox is used for treatment of swine dysentery and salmonellosis. Also, it can be used as a factor for growth stimulation. Carbadox is the only drug for certain health problems in swine production. At the same time Carbadox is slowly metabolized. The aim of this work was an examination of Carbadox genotoxicity in vivo and in vitro. In vitro genotoxicity of different doses of Carbadox was examined on cultured human peripheral blood lymphocytes. Damage to chromosomal DNA was observed under the microscope as sister chromatid exchanges (SCEs). In vivo genotoxicity of Carbadox was examined on metaphase chromosomes from bone marrow cells of BALB/c strain male mice. Experimental animals were intragastrically treated with three different doses of Carbadox. In addition there were negative and a positive control groups of mice. Animals in the positive control were treated with a known clastogenic agent, cyclophosphamide, in a dose of 0,4 mg/kg b.w. In vivo genotoxicity of Carbadox was examined through eight experimental cycles. The results showed that this preparation with an antimicrobial mode of action induced damage to chromosomal DNA in human lymphocytes as well as structural and numerical chromosomal changes in bone marrow cells of BALB/c mice. All the examined concentrations of Carbadox significantly increased SCEs and consistently manifested a dose-dependent pattern. Also, all the examined doses caused karyotypic changes in vivo inducing numerical and structural chromosomal aberrations in mouse bone marrow cells. There was a positive correlation between the number of bone marrow cells with cytogenetic changes and the dose of Carbadox. It could be concluded that Carbadox expressed potential genotoxicity, especially at the highest investigated doses.Carbadox je sintetsko organsko jedinjenje (Metil-3(2quinoksal-metilen) karbozat-N1-N4 dioksid) sa baktericidnim dejstvom koje se koristi u suzbijanju svinjske dizenterije i salmoneloze i kao faktor koji stimuliše rast. Zbog spore metaboličke obrade i dugog zadržavanja u organizmu tretiranih životinja, a još vise zbog njegovog toksičnog, citotoksičnog i kancerogenog dejstva, Carbadox u novije vreme predmet detaljnih proučavanja. U ovom radu su izneti rezultati in vitro ispitivanja efekta Carbadoxa na limfocite periferne krvi čoveka praćenjem promena na nivou molekula DNK na osnovu učestalosti razmene sestrinskih hromatida. Citogenetička ispitivanja uticaja Carbadoxa, posle intragastrične aplikacije, na nastanak hromozomskih promena u ćelijama kostne srži obavljena su na miševima BALB/c soja. Hromozomi za kariotipsku analizu su dobijeni korišćenjem direktne metode ispiranja srži dugih cevastih kostiju. Rezultati ispitivanja efekata različitih doza Carbadoxa in vitro na limfocitima čoveka i in vivo na ćelijama kostne srži miševa BALB/c ukazali su da ovaj antibiotik poseduje visok genotoksični potencijal i jasno manifestuje mutageni efekat

Utvrđivanje histaminskih receptora h1 tipa u tankom crevu brojlera primenom histamina i nekih njegovih agonista i antagonista

Histamine is a biologically active amine (biogenic amine) that has a broad spectra of physiologic and pathologic reactions in the organism. Its effects are shown through 4 types of specific receptors (H1, H2, H3 and H4). Histamine is one of the main causes of intestine disorders and the occurrence of diarrhea, both of which are very common in broilers. Whilst there is no information in scientific literature about the presence of histaminic receptors in smooth muscles of the small intestine wall of broilers (duodenum, jejunum and ileum), we tried to determine their presence, distribution and type in this kind of muscles. Investigations were carried out on isolated smooth muscles of the circular and longitudinal layer of the broiler small intestine (strip dimension 3-4 mm x 2 cm). The muscle strip was then placed in an isolated organ bath and the contractions obtained were registered with isometric transducers on a two-channel printer. This was done following the addition of histamine, betahistine (H1 agonist), and mepiramine (H1 antagonist). Muscle vitality was checked by adding acethylcholine chloride. Using the obtained results, it can be concluded that H1 types of histaminergic receptors are present in smooth muscles of the small intestine of broilers. .Histamin je biološki aktivni amin (biogeni amin) koji ima širok spektar fizioloških i patoloških delovanja u organizmu. Svoje delovanje ispoljava preko četiri tipa specifičnih receptora (H1, H2, H3i H4). Histamin je jedan od glavnih uzroka poremećaja funkcije creva i nastanka proliva, koji su kod brojlera česti. Pošto u stručnoj literaturi nema podataka o zastupljenosti histaminskih receptora u glatkoj muskulaturi zida tankog creva (duodenuma, jejunuma i ileuma) brojlera, pokušali smo utvrditi njihovu zastupljenost, distribuciju i vrstu u ovoj muskulaturi. Ispitivanja su vršena na izoliranoj glatkoj muskulaturi cirkularnog i longitudinalnog sloja sva tri dela tankog creva brojlera (strip dimenzija 3-4 mm x 2 cm). Mišićni strip je postavljen u kupatilo za izolirane organe, a izazvane kontrakcije su registrovane na dvokanalnom pisaču izometrijskim transdjuserima, nakon dodavanja histamina, betahistina (H1 agonist) i mepiramina (H1 antagonist). Vitalnost glatke muskulature tankog creva brojlera smo proveravali dodavanjem acetilholina. Na osnovu dobijenih rezultata se može zaključiti da su histaminergični receptori H1 tipa zastupljeni u glatkoj muskulaturi sva tri segmenta tankog creva brojlera

Utvrđivanje serotonergičnih receptora 5HT1A tipa u tankom crijevu brojlera primjenom serotonina i njegovih agonista i antagonista

Serotonin or 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter synthesised from L-tryptophan in serotonergic neurons and enterochromaffin cells of the gastrointestinal tract. This neurotransmitter is widely distributed in the animal and plant kingdom and regulates some central and peripheral functions through several types of specific serotonergic (5-HT) receptors. Since it is known that the effect of serotonin, especially in pathological conditions, is very important, we believe that determining the types of receptors for this substance would make it possible to use their agonist or antagonists, which would undoubtedly enhance the pharmacotherapy of functional disruption of the small intestine in broilers. Investigations were carried out on isolated smooth muscle strips of the circular and longitudinal layer of the broiler small intestine (strip dimension 3-4 mm x 2 cm). The muscle strips were placed in an isolated organ bath. The mechanical activity of the preparations was recorded via an isotonic force transducer coupled to a pen recorder. This was done following the addition of serotonin (nonselective 5-HT agonist), 8-OH-DPAT (selective 5-HT1A agonist) and spiroxatrin (selective 5-HT1A antagonist). The sensitivity of the tissues to acetylcholine was tested before starting the experiments. Using the obtained results, it can be concluded that 5HT1A type receptors are present in smooth muscles of the broiler small intestine, duodenum and ileum, especially in the longitudinal smooth muscle layer which reacted with contractions even to low serotonin concentration (10-6), but not in the jejunum.Serotonin ili 5-hidroksitriptamin (5-HT) je monoaminski neurotransmiter kojeg iz L-triptofana sintetišu serotonergični neuroni i enterohrmofine ćelije gastrointestinalnog trakta. Ovaj neurotransmiter se nalazi kod velikog broja životinja i biljaka i reguliše neke centralne i periferne funkcije posredstvom nekoliko tipova specifičnih serotonergičnih (5- HT) receptora. Pošto je poznato da je efekat serotonina,posebno u patološkim uslovima, veoma značajan, mi mislimo da određivanje tipa receptora za ovu supstancu može učiniti mogućom upotrebu njenih agonista ili antagonista, što bi nedvosmisleno povećalo farmakoterapiju poremećaja funkcije tankog creva kod brojlera. Istraživanja su izvršena na izolovanim trakama glatkih mišića kružnog i uzdužnog sloja tankog creva brojlera (dimenzije trake 3-4 mm x 2 cm). Trake mišića su bile stavljane u kupatila za izolovane organe. Mehanička aktivnost preparata je registrovana pomoću izotoničnog transdjusera povezanog sa štampačem. Registrovanje je vršeno posle dodavanja serotonina (neselektivni 5-HT agonist), 8-OH-DPAT (selektivni agonist) i spiroksatrina (selektivni 5-HT1A antagonist). Osetljivost tkiva na acetilholin testirana je pre početka eksperimenta. Imajući u vidu dobijene rezultate može se zaključiti da su receptori 5HT1A tipa prisutni u glatkim mišićima tankog creva brojlera, duodenumu i ileumu, posebno u uzdužnom sloju glatkih mišića koji je reagovao kontrakcijama čak i na niske koncentracije serotonina (10-6), ali ne i u jejunumu

Efekti pinacidila - otvarača kalijumovih kanala na kontrakcije izolovanog negravidnog uterusa pacova izazvane kalijum hloridom

The effects of K+ channel opener, pinacidil on contractions provoked by contraction-stimulating KCl were investigated on isolated uterus of non-pregnant rats in oestrus. Pinacidil produced a more potent inhibition of 20 mM KCl-elicited contractions (pD2 = 6.57 μM) than of 40 or 80mMKCl-elicited contractions (pD2=5.11 and 5.19 μM, respectively). Glibenclamide, a selective blocker of adenosine triphosphate (ATP)-sensitive K+ (KATP) channels, antagonized the pinacidil-induced inhibition of contractions elicited by 20 mM KCl in a competitive manner. However, the pinacidil-induced inhibition of contractions provoked by 40 and 80 mM KCl glibenclamide was unable to prevent them. Pinacidil ability to completely relax the non-pregnant uterus pre-contracted with K+-rich solution suggests that K+ channelindependent mechanism(s) also plays a part in its relaxant effect.U ovom radu su prikazani efekti pinacidila, koji ima osobinu da otvara kalijumove kanale, na kontrakcije izazvane kalijum hloridom na modelu izolovanog negravidnog uterusa ženki pacova tokom estrusa. Pinacidil dovodi do snažnije inhibicije kontrakcija izazvanih sa 20mM KCl (pD2= 6.57 μM) u poređenju sa kontrakcijama izazvanim sa 40 ili 80 mM KCl (pD2 = 5.11 i 5.19 μM). Poznato je da je glibenclamid selektivni blokator adenozin-3-fosfat senzitivnih K+ (KATP) kanala antagonizuje pinacidilom indukovanu kompetitivnu inhibiciju kontrakcija izazvanih pomoću 20 mM KCl-a. Međutim, pinacidilom indukovana inhibicija kontrakcija, izazvanih sa 40 i 80 mM KCl-a nije se mogla prevenirati glibenclamidom. Sposobnost pinacidila da dovede do potpune relaksacije negravidnog uterusa ženki pacova pre kontrakcije izazvane rastvorom kalijuma ukazuje na to da u relaksaciji učestvuje i mehanizam nezavisan od kalijumovih kanala

NOVI LEK U VETERINARSKOJ KLINIČKOJ PRAKSI – OKLACITINIB MALEAT

Uvođenjem novog leka oklacitinib maleata u veterinarsku kliničku praksu napravljenje značajan pomak u lečenju alergijskog i kliničkih slučajeva atopijskog dermatitisa(posebno pratećeg svraba) kod pasa.U lečenju ovih bolesti do sada su se najčešće koristili glukokortikoidi, ciklosporin iantihistaminici. Pokazalo se da ciklosporin ima sličnu aktivnost kao i glukokortikoidi,dok je aktivnost antihistaminika slabija. Novi lek oklacitinib maleat ima antiinflamatornii antipruritični efekt sličan onom koji izazivaju glukokortikoidi i ciklosporin, alimu (za razliku od njih) efekt brže nastupa, što mu daje veliku prednost.Oklacitinib je imunomodulator i ima specifičan mehanizam delovanja. Deluje takošto inhibira aktivnost enzima janus kinaza (pre svega JAK1 i JAK3), od kojih zavisifunkcija proinflamatornih i pruritogenih citokina.Oklacitinib je prilično bezbedan lek, ukoliko se koristi u kraćem vremenskom periodui u preporučenim dozama

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