Utjecaj etanola na miorelaksirajuće djelovanje diazepama u štakora

Interaction of ethanol with benzodiazepines can lead to enhanced therapeutic anxyolytic, sedative and hypnotic effect but also can augment unwanted effects such as drowsiness, confusion, amnesia and impaired coordination. In this study we investigated the interaction between ethanol and diazepam and its influence on muscle strength in rats using the grip-strength meter. Three doses of ethanol (0.4, 0.6 and 0.8 g kg-1 of body mass, b.m.) and diazepam (0.75, 1.5 and 7.5 mg kg-1 b.m.) were used in experiments. Single substances and their combinations were tested. The myorelaxant effect of ethanol, measured as grip force (expressed in grams), was dose-dependent. The lowest dose (0.4 g kg-1 b.m.) failed to affect muscle strength while the strongest effect was observed with the highest dose of ethanol (0.8 g kg-1 b.m.) and it lasted for 75 min. Diazepam dose-dependently reduced muscle strength too. However, when ethanol was combined with diazepam (1.5 mg kg-1 b.m.), more enhanced muscle relaxation occurred than by either drug alone. Namely, two lower doses of ethanol (0.4 and 0.6 g kg-1 b.m) enhanced the myorelaxant effect of diazepam for additional 26 and 46%, respectively when measured after 15 min. The myorelaxation was the most pronounced when the highest dose of ethanol (0.8 g kg-1 b.m.) was combined with diazepam: from complete muscle relaxation observed after 15 min, it gradually decreased to 91% at 45th min and to 24% at 105th min after the beginning of the treatment. The results of this preclinical investigation showed that ethanol enhanced the muscle relaxant effect of diazepam. This enhancement as well as duration of the effect was dependent of the applied dose of ethanol.Konzumacija etanola može dovesti do pojačanog anksiolitičkog, sedativnog i hipnotskog djelovanja benzodiazepina, a može i pojačati njihove neželjene reakcije, kao što su vrtoglavica, konfuzija, amnezija i poremećena koordinacija. Cilj ovog rada bio je ispitati miorelaksirajući učinak diazepama i etanola kod štakora koristeći »metodu jačine stiska«. Također se željelo utvrditi u kojoj dozi te u kolikoj mjeri primjena etanola može pojačati djelovanje diazepama. Stoga su u ispitivanja korištene tri doze etanola (0.4, 0.6, i 0.8 g kg-1 tjelesne mase, t.m.) i diazepama (0.75, 1.5, i 7.5 mg kg-1 t.m.). Miorelaksirajuće je djelovanje ispitivano nakon jednokratne primjene obje supstance pojedinačno kao i u njihovoj kombinaciji. Miorelaksirajući učinak etanola kao i diazepama pojedinačno bio je ovisan o dozi. Što je doza bila veća, to je učinak bio jači, a vrijeme njegova trajanja bilo je dulje. Kod istodobne primjene diazepama (1.5 mg kg-1 t.m.) s različitim dozama etanola, miorelaksirajuće se djelovanje značajno pojačalo i produljilo u odnosu na ispitivane supstance pojedinačno. Pritom je učinak bio najjače izražen u prvih 15 min, a potom je postupno slabio. Naime, u tom je vremenu najmanja doza etanola korištena u ovom radu pojačala miorelaksirajuće djelovanje diazepama za dodatnih 26%, srednja za čak 46% dok je u kombinaciji s najvećom dozom etanola nastupila potpuna mišićna relaksacija koja je postupno, tijekom vremena, slabila da bi 105 min nakon primjene supstancija iznosila 24%. Stoga rezultati ovog pretkliničkog ispitivanja pokazuju da etanol, ovisno o dozi, pojačava miorelaksirajuće djelovanje diazepama kod eksperimentalnih životinja. Ono je trajalo dulje što je doza etanola u kombinaciji s diazepamom bila veća

Form of Ibuprofen with a Faster Onset of Pain Relief

Liječenje kronične boli velik je izazov u kliničkoj praksi. Jedan od razloga jest nedovoljno poznavanje neurobiologije i patofiziologije kompleksnih kroničnih bolnih stanja. Svaka kronična bol ima akutnu fazu pa se postavlja pitanje bi li pravodobna učinkovita terapija spriječila složene patofiziološke procese koji dovode do kronifikacije boli. Soli ibuprofena, primjerice ibuprofen-lizin, osiguravaju brz nastup djelovanja te intenzivniji i dugotrajniji analgetski učinak u odnosu prema standardnom obliku ibuprofena, uz smanjenje potrebe za remedikacijom.Treating chronic pain presents a great challenge in clinical practice. One of the reasons is an insufficient knowledge of neurobiology and pathophysiology of complex chronic painful conditions. Each chronic pain has an acute phase and the question is whether an efficient therapy administered in timely manner would prevent complex pathophysiological processes that lead to pain chronification. Ibuprofen salts, such as ibuprofen lysine, provide a faster onset and more intensive and longer duration of analgesia compared to the standard form of ibuprofen, with reduced need for remedication

Antinociceptivno djelovanje botulinum toksina tipa A

UVOD. Klinička opažanja ukazuju na moguće antinociceptivno djelovanje botulinum toksina tipa A (BT-A) u različitih bolnih stanja. Hipoteza ove disertacije je da BT-A ima antinociceptivno djelovanje koje uključuje interferenciju s procesima središnje senzitizacije. Ciljevi su bili: provjeriti postavljenu hipotezu, ispitati djelovanje BT-A na različite vrste eksperimentalne boli te istražiti protuupalno djelovanje. MATERIJALI I METODE. Ispitivanja su se provodila na mužjacima štakora soja Wistar. BT-A je primijenjen subkutano (u šapu štakora), intratekalno i intraneuronalno (u n. ishiadicus). Antinociceptivno djelovanje je ispitivano na eksperimentalnim modelima nociceptivne, upalne i neuropatske boli. Istraživano je djelovanje BT-A na upalni edem i ekstravazaciju proteina pri upali. Na modelu kronične mišićne hiperalgezije, ispitivano je djelovanje BT-A na sekundarnu bilateralnu hiperalgeziju. Istraživan je utjecaj inhibicije aksonalnog transporta kolhicinom i distalnom transekcijom n. ishiadicusa na djelovanje BT-A. Western blot metoda i imunohistokemija korištene su s ciljem detekcije toksina u n. ishiadicusu i senzornim ganglijima. REZULTATI. BT-A je smanjio upalnu i neuropatsku bol, dok na nociceptivnu bol nije utjecao. BT-A nije utjecao na edem, niti na ekstravazaciju proteina pri upali. BT-A je spriječio nastanak, i smanjio sekundarnu bilateralnu mehaničku hiperalgeziju. Inhibicija aksonalnog transporta kolhicinom spriječila je djelovanje subkutano primijenjenog BT-A, dok transekcija n.ishiadicusa distalno od mjesta intraneuronalnog injiciranja BT-A nije utjecala na njegovo djelovanje na kontralateralnu bol. Preliminarni rezultati imunohistokemije i Western blot metode ukazuju na moguću nazočnost kratkog lanca toksina u n. ishiadicusu i senzornim ganglijima. ZAKLJUČAK: Rezultati ove disertacije ukazuju na moguće nove primjene BT-A u liječenju bolnih neuropatija. Oni sugeriraju da antinociceptivno djelovanje BT-A uključuje interferenciju s mehanizmima središnje senzitizacije.OBJECTIVE. The hypothesis of this dissertation is that botulinum toxin type A (BT-A) has antinociceptive effect, which might include interference with mechanisms of central sensitization. MATERIALS AND METHODS. Male Wistar rats were injected with BT-A subcutaneously, intrathecally and intraneuronally. Antinociceptive effect of BT-A was investigated in nociceptive, inflammatory and neuropathic pain. The influence of BT-A on secondary bilateral hyperalgesia was explored, too. Effect of BT-A on carrageenan-induced paw edema and capsaicin-induced extravasation of proteins coupled to Evans blue was investigated. Colchicine and transection of n. ishiadicus were used as tools to prevent the axonal transport of BT-A. Western blot and immunohistochemistry were employed in order to detect the toxin in n. ishiadicus and sensory ganglia. RESULTS. BT-A decreased inflammatory and neuropathic pain, while it did not affect nociceptive pain. It did not show antiinflammatory effect. BT-A reduced bilateral secondary hyperalgesia. Colchicine prevented the effectiveness of subcutaneous BT-A, while distal transection of n. ishiadicus did not affect the influence of intraneuronal BT-A on contralateral pain. CONCLUSION. BT-A reduces inflammatory pain and symptoms of neuropathic pain. Antinociceptive effect of BT-A probably involves interference with central sensitization

Antinociceptive action of botulinum toxin type A in carrageenan-induced mirror pain

"Mirror pain" or mirror-image pain (MP) is pain opposite to the side of injury. Mechanism and frequency in humans are not known. There is no consent on therapy. Here we report that unilaterally injected botulinum toxin type A (BT-A) has bilateral effect in experimental MP, thus deserves to be investigated as therapy for this condition. We examined the localization of BT-A's bilateral antinociceptive action in MP induced by 3 % carrageenan intramuscular injection in Wistar rats. BT-A was applied peripherally (5 U/kg), into ipsilateral or contralateral hind paw pad (i.pl.) and centrally (1 U/kg), at spinal (intrathecally, i.t.) or supraspinal (intracisternally, i.c.) level. Additionally, we examined the involvement of central opioid and GABAergic systems, as well as the contribution of peripheral capsaicin-sensitive neurons to BT-A's bilateral antinociceptive effect. Ipsilateral i.pl. and i.t. BT-A reduced the bilateral mechanical sensitivity to von Frey filaments, while contralateral i.pl. and i.c. treatments had no effect on either tested side. Bilateral antinociceptive effect of ipsilateral i.pl. BT-A was prevented by μ-opioid antagonist naloxonazine (1.5 μg/10 μl) and GABAA antagonist bicuculline (1 μg/10 μl) if applied at the spinal level, in contrast to supraspinal application of the same doses. Local treatment of sciatic nerve with 2 % capsaicin 5 days following BT-A i.pl. injection caused desensitization of sciatic capsaicin-sensitive fibers, but did not affect bilateral antinociceptive effect of BT-A and the presence of cleaved SNAP-25 at the spinal cord slices. Present experiments suggest segmental actions of peripheral BT-A at spinal level, which are probably not solely dependent on capsaicin-sensitive neurons

Primjena eteričnih ulja za masažu

Many plant species have been used for the massage mainly in the form of essential oils. The most common oils are obtained from the following plant species: Lavandula angustifolia, Rosmarinus officinalis, Mentha x piperita, Melaleuca alternifolia, Eucalyptus globulus, Citrus limon, Citrus aurantium ssp. dulcis, Citrus reticulata, Cinnamomum zeylanicum, Syzygium aromaticum, Pinus silvestris and Pelargonium x asperum. Applications of essential oils for therapeutic purporses are numerous (i.e., wellbeing, labour, infections, dementia and anxiety treatment) but often they have not been scientifically validated

Antidepresivni učinak Hipericum perforatum L. mjeren pomoću dvije eksperimentalne metode na miševima

The pharmacological approach to the treatment of depression includes a long-term employment of antidepressants, either in the form of monotherapy or as a combination of several antidepressants with various mechanisms of action. Hypericum perforatum L. (St. John\u27s wort) is the only natural antidepressant. Several constituents of the extract, such as hypericin and hyperforin seem to be important for this effect. H. perforatum is considered to be an effective alternative to other therapeutic agents in the treatment of mild to moderate depression. The paper describes the investigation of the antidepressant effect of H. perforatum (doses 7, 35 and 70 mg kg-1 b.m.) on mice using the forced-swimming and tail suspension methods. As an indicator of the antidepressant effect, it was shown that the immobility time of animals in the forced-swimming and tail-suspension experiments was shorter, i.e. the activity of the animals was higher. With single doses of extract suspension increasing from 7, over 35 to 70 mg kg-1 of extract suspension, the antidepressant effect increased in proportion by 10.1%, 25.8% and 38.6% in the swimming method, and by 12.7%, 16.5% and 24.5% in the tai-suspension method compared to controls. H. perforatum extract displays a dose-dependent antidepressant effect at a dose as low as 7 mg kg-1. Both models have proved to be equally valuable for demonstration of substances with a potential antidepressant effect.Farmakološki pristup liječenju depresije uključuje dugotrajnu prijmjenu antidepresiva, pri čemu se oni mogu primjenjivati kao monoterapija ili pak kao kombinacija više lijekova s različitim mehanizmima djelovanje. Hipericum perforatum L. (gospina trava) je jedini prirodni antidepresiv koji je djelotvoran u liječenju depresivnih poremećaja blagog i srednje jakog intenziteta. Za antidepresivno djelovanje gospine trave čini se da su najzaslužniji hipericin i hiperforin. U ovom radu ispitivan je antidepresivni učinak niskih doza ekstrakta H. perforatum i to: 7, 35 i 70 mg kg-1 na miševima pomoću metode «prinudnog plivanja» i «vješanja za rep». Kao pokazatelj antidepresivnog djelovanja mjereno je vrijeme mirovanja životinja- što je ono bilo kraće, aktivnost životinja je bila veća, pa je antidepresivni učinak bio jači. Povećanjem doze sa 7 mg kg-1 na 35 odnosno 70 mg kg-1, antidepresivni učinak ekstrakta H. perforatum bio je veći u odnosu na kontrolnu skupinu životinja i to za 10,1%, 25,8% i 38,6% u metodi plivanja, odnosno za 12,7%, 16,5% i 24,5% u metodi vješanja za rep. Rezultati ovog rada ukazuju na antidepresivno djelovanje ekstrakta gospine trave već nakon jednokratne primjene niskih doza u oba korištena eksperimentalna modela

Pharmacogenomics – the key to personalized medicine

Different rates of drug metabolism and the effect of commonly prescribed drugs are often seen in clinical practice. Some of these differences can be predicted if the patient’s genetic profile is known by pharmacogenomic analysis, which done once, provides lifetime benefits. In the United States, adverse drug reactions are the fourth leading cause of death, costing their healthcare system about $136 billion annually. By implementing pharmacogenomic testing early in clinical algorithms, debilitating and potentially life-threatening side-effects can be predicted and avoided, which is particularly important in settings of pain therapy and anesthesia. In St. Catherine Specialty Hospital, this approach is readily advocated for our patients. Through the use of the RightMed panel, 25 genes coding for enzymes and other proteins important for drug function, are analyzed, and a pharmacogenomic-driven approach is taken by selecting the right drug, in the right dose, for the right patient

Pharmacogenomics – the key to personalized medicine

Different rates of drug metabolism and the effect of commonly prescribed drugs are often seen in clinical practice. Some of these differences can be predicted if the patient’s genetic profile is known by pharmacogenomic analysis, which done once, provides lifetime benefits. In the United States, adverse drug reactions are the fourth leading cause of death, costing their healthcare system about $136 billion annually. By implementing pharmacogenomic testing early in clinical algorithms, debilitating and potentially life-threatening side-effects can be predicted and avoided, which is particularly important in settings of pain therapy and anesthesia. In St. Catherine Specialty Hospital, this approach is readily advocated for our patients. Through the use of the RightMed panel, 25 genes coding for enzymes and other proteins important for drug function, are analyzed, and a pharmacogenomic-driven approach is taken by selecting the right drug, in the right dose, for the right patient

Central Action of Peripherally Applied Botulinum Toxin Type A on Pain and Dural Protein Extravasation in Rat Model of Trigeminal Neuropathy

BACKGROUND: Infraorbital nerve constriction (IoNC) is an experimental model of trigeminal neuropathy. We investigated if IoNC is accompanied by dural extravasation and if botulinum toxin type A (BoNT/A) can reduce pain and dural extravasation in this model. ----- METHODOLOGY/PRINCIPAL FINDINGS: Rats which developed mechanical allodynia 14 days after the IoNC were injected with BoNT/A (3.5 U/kg) into vibrissal pad. Allodynia was tested by von Frey filaments and dural extravasation was measured as colorimetric absorbance of Evans blue - plasma protein complexes. Presence of dural extravasation was also examined in orofacial formalin-induced pain. Unilateral IoNC, as well as formalin injection, produced bilateral dural extravasation. Single unilateral BoNT/A injection bilaterally reduced IoNC induced dural extravasation, as well as allodynia (lasting more than 2 weeks). Similarly, BoNT/A reduced formalin-induced pain and dural extravasation. Effects of BoNT/A on pain and dural extravasation in IoNC model were dependent on axonal transport through sensory neurons, as evidenced by colchicine injections (5 mM, 2 µl) into the trigeminal ganglion completely preventing BoNT/A effects. ----- CONCLUSIONS/SIGNIFICANCE: Two different types of pain, IoNC and formalin, are accompanied by dural extravasation. The lasting effect of a unilateral injection of BoNT/A in experimental animals suggests that BoNT/A might have a long-term beneficial effect in craniofacial pain associated with dural neurogenic inflammation. Bilateral effects of BoNT/A and dependence on retrograde axonal transport suggest a central site of its action