S RELATED TO THE PHD THESIS I. Petró Éva: Normák és irányelvek szerepe a félszilárd gyógyszerformák hatóanyag kioldódásának validálásában, PhD Tudományos Nap, Szegedi Akadémiai Bizottság Székháza, 2008. november 27., Szeged II. Petró Éva, Csóka Ildikó, Erős István: Félszilárd gyógyszerformák hatóanyag kioldódásának validálása, Congressus Pharmaceuticus Hungaricus XIV., 2009. november 13-15., Budapest, Gyógyszerészet 53. 2009/11 Suppl. I., S100. (P-70.) III. Éva Petró, Ildikó Csóka, István Erős: Validation process of drug release from semisolid dosage forms. 7 World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, March 8-11 2010 Malta, Valletta (P206.) IV. Éva Petró, Ildikó Csóka, Ágnes Balogh, Gábor Blazsó, István Erős: In vitro and in vivo evaluation of drug release from semisolid dosage forms. 8 Central European Symposium on Pharmaceutical Technology and 4 International Graz Congress for Pharmaceutical Engineering, September 16-18 2010 Graz, Austria (PDD08) V. Petró Éva, Csóka Ildikó, Balogh Ágnes, Blazsó Gábor, Erős István: Félszilárd gyógyszerformák in vitro és in vivo vizsgálata, Magyar Gyógyszerésztudományi Társaság XVI. Gyógyszertechnológiai Konferencia és VIII. Gyógyszer az Ezredfordulón Konferencia, 2010. október 20-22., Siófok (EA-22) VI. Baracsi Zita, Petró Éva, Erős István, Csóka Ildikó: In vitro hatóanyag felszabadulási vizsgálatok validálása Franz vertikális diffúziós cella és USP 2 kenőcscella esetén, Magyar Gyógyszerésztudományi Társaság XVI. Gyógyszertechnológiai Konferencia és VIII. Gyógyszer az Ezredfordulón Konferencia, 2010. október 20-22., Siófok (P-3) VII. Petró Éva, Csóka Ildikó, Erős István: Félszilárd készítmények hatóanyag liberációjának meghatározására szolgáló módszerek (diffúziós cellák) összehasonlító vizsgálata, Magyar Kémikusok Egyesülete Kozmetikai Szimpózium 2010, 2010. november 18., Budapest VIII. Éva Petró, Ágnes Balogh, Gábor Blazsó, István Erős, Ildikó Csóka: In vitro and in vivo investigation of drug release from semisolid products in case of synthetic membrane and rat skin. Skin Forum 12 Annual Meeting, March 28-29 2011 Frankfurt, Germany (P24.) IX. Petró Éva, Erős István, Csóka Ildikó: In vivo-in vitro korreláció félszilárd rendszerek esetében, Magyar Kémikusok Egyesülete Kozmetikai Szimpózium 2011, 2011. november 17., Budapest X. Éva Petró, István Erős, Ildikó Csóka: Dissolution testing of semisolid dosage forms. 8 World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, March 19-22 2012, Turkey, Istanbul (P162.) XI. Petró Éva, Erős István, Csóka Ildikó: Hatóanyag felszabadulás félszilárd gyógyszerformákból – módszerek és eszközök, Molekulától a gyógyszerig, Szeged, 2012. május 24-25. XII. Petró Éva, Csóka Ildikó, Erős István: Ex vivo módszerek a biológiailag aktív anyagok liberációjának kutatásában, Magyar Kémikusok Egyesülete Kozmetikai Szimpózium 2012, 2012. november 22., Budapest XIII. Petró Éva, Erős István: Biológiailag aktív anyagok szabaddá válása krémekből, gélekből és gélemulziókból, Magyar Kémikusok Egyesülete Kozmetikai Szimpózium 2013, 2013. november 21., Budapest XIV. Petró Éva, Csóka Ildikó, Erős István: Félszilárd dermatológiai mátrixok gyógyszerleadását meghatározó tényezők, Congressus Pharmaceuticus Hungaricus XV., 2014. április 10-12., Budapest (P-116.)

Fruits of Hippophae rhamnoides L. has recently become a popular medicinal and nutritional herbal drug due to its beneficial constituents, mainly the high concentration of vitamin C, flavonoids, phytosterols, and carotenoids. Sea-buckthorn has been used in traditional medicine for treatment of asthma, skin diseases, gastric ulcers and lung disorders [1]. Preparations of the fruit are used nowadays in Hungary to treat allergic symptoms. To support traditional uses of sea-buckthorn berry we have investigated the in vivo anti-inflammatory effect of different extracts of the fruits and their active constituents were investigated by bioactivity-guided isolation. Aqueous and methanol extracts of the whole fruit and methanol extracts of different parts of the berries (peel, pulp, seeds) were tested on induced paw oedema test in rats. The 70% methanol peel extract was found to be the most potent, and it was further examined in different acute inflammation models induced by carrageenan, histamine, dextran, bradykinin, serotonine and by 48/80 substance to approach the mechanism of action. The extract inhibited only the 48/80 induced inflammation. The peel extract was subjected to liquid-liquid partitioning to yield chloroform, ethyl acetate, n-butanol and water soluble fractions. Only the chloroform soluble fraction was found to be active in 48/80-induced paw oedema test. The chloroform fraction was subjected then to vacuum liquid chromatography resulting 7 subfractions. In the most active subfraction high amounts of oleanolic acid (31%) and ursolic acid (19%) were detected. Both triterpenes display anti-inflammatory activity in 48/80-induced paw oedema test. Our results suggest that oleanolic acid and ursolic acid may be responsible unequivocally for the anti-allergic effect of the sea-buckthorn fruit peel extract due to their membrane stabilising effect.

This study presents the in vitro and in vivo testing of anti-inflammatory drug containing creams, hydrogels and organogels for dermal use. In vitro penetration studies were performed with products by measuring the diffused drug amount through synthetic membranes soaked in isopropyl myristate (IPM). Our developed preparations were investigated under in vitro conditions together with two marketed medicinal products used as reference preparations. In vivo studies were carried out on anaesthetized male Wistar rats; the carrageenan-induced paw oedema decreasing effect of twelve different formulations and the reference products were measured in comparison with a control group. All - previously in vitro screened - selected products reduced paw oedema in rats. Significant differences were found among the developed products both in vitro and in vivo. Correlation between the in vitro penetration studies and in vivo results were found in the case of o/w creams, organogels and hydrogels.

A tricyclic, piperidine derivative of antihistamines, loratadine, which belongs in class II of the Biopharmaceutical Classification System, was investigated. It is an ionizable drug, whose solubility depends on the gastrointestinal pH, and the bioavailability is therefore very variable. Inclusion complexes were prepared by kneading method, containing loratadine (LOR) and dimethyl-β-cyclodextrin (DIMEB) in two different molar ratios in an attempt to achieve better dissolution and therefore the better bioavailability of loratadine. The formation and physicochemical properties of the inclusion complexes were investigated by means of dissolution tests, pH-dependent solubility studies, electrospray ionization mass spectrometry and diffusion-ordered 1H NMR spectroscopy. The in vivo efficiency of the complexes was examined in rat animal experiments to confirm the better in vitro dissolution. The instrumental examinations proved the presence of total complexes in 1:1 ratio in both compositions. However, the in vitro pH-dependent solubility results, the in vivo blood levels and the greater pharmacological effect prove that excess DIMEB is needed to achieve the pH-independent and complete solubility of LOR, and therefore better and more consistent bioavailability.

The decoction of the aerial parts of Centaurea sadleriana JANKA (Asteraceae), a plant native to Hungary, is traditionally used to treat the wounds of sheep in the Southern Great Plain region. Phytochemical and pharmacological studies on this plant have not been performed so far. Only we have recently confirmed the wound healing effect of the plant on rats [1]. The objective of the present work was the in vivo and in vitro investigation of the anti-inflammatory effect of C. sadleriana and the isolation and identification of its active compounds. The concentrated methanol extract of aerial parts of C. sadleriana was partitioned using n-hexane and chloroform. These two fractions were further fractionated via VLC and the anti-inflammatory effects of the fractions were studied by in vitro (COX-1, COX-2 and LTB4 formation inhibitory activity) and in vivo (intraperitoneal and oral administration to rats) methods. Some of the fractions gained from the n-hexane extract possessed marked in vitro (70–85% LTB4 formation inhibition, 59–83% COX-1 inhibition, 80–92% COX-2 inhibition at a concentration of 50µg/ml) and in vivo anti-inflammatory effects (25–50% oedema volume reduction). Chromatographic purification (VLC, MPLC, HPLC, preparative TLC, CPC and gel filtration) of the active fractions resulted in the isolation of flavonoids, triterpenoids and lignans. Our present study confirmed the marked anti-inflammatory effect of C. sadleriana which may play role in the ethnomedicinal application of the plant.

The decoction of the aerial parts of Centaurea sadleriana JANKA (Asteraceae), a plant native to Hungary, is traditionally used to treat the wounds of sheep in the Southern Great Plain region. Phytochemical and pharmacological studies on this plant have not been performed so far. Our preliminary in vitro pharmacological screening has revealed that the extract of the aerial parts of C. sadleriana possess a marked anti-inflammatory effect.

The objective of the study in rats was to investigate the anti-inflammatory effects of pure meloxicam (ME) with different particle sizes and of physical mixtures of the binary ME-mannitol system. The level of local inflammation was significantly decreased when the amount of mannitol was the highest and the particle size of ME was the lowest as well as the components had the interparticulate interaction. The same results were achieved in in vitro experiments.

Anti-inflammatory efficacy of the fermented wheat germ extract (FWGE, Avemar) in the rat adjuvant arthritis (AA) model was examined. To Wistar rats with AA, different doses of FWGE and anti-inflammatory drugs (indomethacin, dexamethasone) as monotherapies were administered and FWGE and either diclofenac or dexamethasone were also given in combination. Besides plethysmographies of the paws, histological investigations of synovial tissues were also performed along with detection of CD4+ and CD8+ T lymphocytes. Gene expressions of COX-1 and 2 were determined by real-time polymerase chain reaction (PCR). FWGE monotherapy significantly inhibited the development of the secondary (immune-mediated) response in AA, and dexamethasone and indomethacin exerted inhibitory effects in a degree comparable to that of FWGE. Histological analysis of the affected joints confirmed the results. FWGE inhibited COX-1 and -2, while indomethacin enhanced COX-2 gene expressions. FWGE had an additive interaction with diclofenac. It is concluded that FWGE has significant anti-inflammatory efficacy confirmed by plethysmography, histology, and real-time PCR.

OBJECTIVE:To investigate the effect of the fermented wheat germ extract (Avemar)in patients with severe rheumatoid arthritis (RA).METHODS:Fifteen female RA (Steinbrocker II-III) patients, who had unsuccessfully tried two different DMARD treatments, were enrolled in an open-label, 1-year long, pilot clinical study. DMARD and steroid therapies were recorded and continued. All patients received Avemar as additional therapy. For measurement of efficacy the Ritchie Index, the Health Assessment Questionnaire (HAQ) and the assessment of morning stiffness were applied. Patients were evaluated at baseline, 6 and 12 months. For statistical analyses the Wilcoxon test was used.RESULTS:At both 6 and 12 months, Ritchie index, HAQ and morning stiffness showed significant improvements compared with the baseline values. Dosages of steroids could be reduced in about half of the patients. No side effects of Avemar were observed.CONCLUSION:Supplementation of standard therapies with a continuous administration of Avemar is beneficial for RA patients.

Purpose: The selective contribution of neuronal gap junction (GJ) communication via connexin 36 (Cx36) channels to epileptogenesis and to the maintenance and propagation of seizures was investigated in both the primary focus and the mirror focus by using pharmacologic approaches with the 4-aminopyridine in vivo epilepsy model.Methods: ECoG recording was performed on anesthetized adult rats, in which either quinine, a selective blocker of Cx36, or the broad-spectrum GJ blockers carbenoxolone and octanol were applied locally, before the induction or at already active epileptic foci.Results: The blockade of Cx36 channels by quinine before the induction of epileptiform activity slightly reduced the epileptogenesis. When quinine was applied after 25-30 repetitions of seizures, a new discharge pattern appeared with frequencies > 15 Hz at the initiation of seizures. In spite of the increased number of seizures, the summated ictal activity decreased, because of the significant reduction in the duration of the seizures. The amplitudes of the seizure discharges of all the patterns decreased, with the exception of those with frequencies of 11-12 Hz. The blockade of Cx36 channels and the global blockade of the GJ channels resulted in qualitatively different modifications in ictogenesis.Conclusions: The blockade of Cx36 channels at the already active epileptic focus has an anticonvulsive effect and modifies the manifestation of the 1- to 18-Hz seizure discharges. Our findings indicate that the GJ communication via Cx36 channels is differently involved in the synchronization of the activities of the networks generating seizure discharges with different frequencies. Additionally, we conclude that both neuronal and glial GJ communication contribute to the manifestation and propagation of seizures in the adult rat neocortex.

In view of their good skin tolerability, glyceryl fatty acid esters were used as organogelators, and their effects in the topical penetration of piroxicam (Px) were investigated. The in vivo skin penetration was evaluated by measuring the anti-inflammatory effect in rats, where we found that Px incorporated into glyceryl fatty acid ester organogels exhibited a significantly greater inhibition of oedema than that of the placebo control either when applied locally (p < 0.001), or via transdermal absorption (p < 0.01 and < 0.05, respectively). As the Px concentration was increased, the extent of oedema inhibition rose in accordance with a power law. Comparisons with traditional galenic organogels and a marketed product revealed that the relative biological availability of Px was better from glyceryl fatty acid ester organogels, except when calculated for D1 versus T2 and T3. In order to predict the extent of in vivo skin absorption, we measured the penetration coefficient and the in vitro penetration. In accordance with theory, the extent of in vivo oedema inhibition increased as P(oct/w) increased, and maximum inhibition was observed at logP = 2.0211. However, the in vitro penetration through a synthetic membrane did not correlate with the in vivo results, the reason for which might be the different natures of the model barriers.

Pycnogenol was applied topically to experimental wounds inflicted on healthy rats by means of a branding iron. The wound-healing time was taken as the number of days required for 50% of the scabs to separate spontaneously from the animals. Application of a gel formulation containing 1% Pycnogenol significantly shortened the wound healing time, by 1.6 days compared with the group treated with gel only (15.4 days). The application of 2% Pycnogenol decreased the healing time by almost 3 days, while 5% Pycnogenol further accelerated the wound-healing process. In parallel, Pycnogenol gels reduced the diameter of the scars remaining following complete scab loss in a concentration-dependent manner. In conclusion, Pycnogenol is a potent active ingredient for the treatment of minor injuries.

Eight macrocyclic diterpenoids were isolated from whole plants of E. esula, E. salicifolia and E. serrulata. The chemical structures of the compounds were elucidated by mass spectrometry, high-field nuclear magnetic resonance techniques. Spectral analyses revealed that the compounds are new members of the group of jatrophane diterpenes except compound 5, which is based on a modified 5-13 fused jatrophane skeleton. All compounds are highly functionalized with acetyl, benzoyl, isobutanoyl and nicotinoyl groups. The crude dichloromethane extracts and the pure compounds were subjected to pro-inflammatory assay. The extracts exhibited mouse irritant activity, with ID504h values of 56-325 µg per ear. Compounds 1-4 were inactive up to a dose of 200 µg per ear, indicating that the jatrophane-type compounds do not play a significant role in the skin irritant activity of Euphorbia species. The antiproliferative and multidrug-resistance-reversing (mdr) activities of compounds 1-8 were evaluated on mouse lymphoma cells. The compounds inhibited cell growth. The growth inhibitory activity of compounds 2, 3, 4, 5, 7 and 8 was more potent against human mdr gene-transfected cells (IC50 values of 1.4-3.3 µg/ml) than against parental cells (IC50 values of 5.6-9.8 µg/ml). Only compound 1 displayed a marginal antiproliferative effect in both tests.

This article evaluated the influence of vehicle compositions on topical drug availability. In vitro drug release and in vivo experiments were performed in case of the hydrophilic ketamine hydrochloride and the lipophilic piroxicam. Ketamine hydrochloride is a NMDA receptor antagonist that has been useful for anesthesia and analgesia. The study of transdermal ketamine delivery is a novelty, because nobody has investigated the hypnotic effects of ketamine after this administration route. In vitro measurements gave a good basis for screening among the developed products. The physiological changes after ketamine administration showed, that there were significant differences among the parameters tested (breathing rate, duration of sleep) from the developed products (hydrogel, lyotropic liquid crystal and o/w cream) compared to the reference product (Carbopol gel). The in vivo feedback for piroxicam was the measurement of the anti-inflammatory activity by edema inhibition percentage. Significant differences were measured in case of the developed systems compared to the reference.

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Experiments with male mice (28-32 g) of the CFLP strain showed that cinnarizine in doses of 2.5, 5.0 or 10.0 mg kg-1 significantly inhibited the extent of ear oedema induced by croton oil, capsaicin or dithranol, in a dose-dependent manner. In rats of the Wistar strain, oedema was induced in the hind paw by subplantar injection of carrageenin, and simultaneously by the application of croton oil to the inner surface of the ear. Preliminary cinnarizine treatment (5, 10 or 20 mg kg-1) inhibited the development of both types of oedema, to a statistically significant extent, in a dose-dependent manner.