Biological activity and characteristics of triamcinolone-acetonide formulated with the self-regulating drug carriers,Transfersomes

Novel formulations of the halogenated corticosteroid, triamcinolone-acetonide, based on ultradeformable mixed lipid vesicles, Transfersomes, are described. Their performance was tested in vivo using radioactive label measurements, to study the drug biodistribution, and murine ear edema, to determine the drug bioactivity. Sparse use of drug-loaded Transfersomes on the skin ensures an almost exclusive delivery of triamcinolone-acetonide into the organ, thus arguably increasing the treatment safety. Delivery of triamcinolone-acetonide in the skin with ultradeformable vesicles prolongs the anti-inflammatory drug action several times compared to drug usage in a conventional crème or an ointment, the robustness of biological response for the former being at least identical to the latter. The required dose of Transfersome-based triamcinolone-acetonide is also greatly reduced. The drug dose of 0.2 microg cm(-2) suppresses 75% of arachidonic acid-induced murine ear edema for at least 48 h. In contrast, a conventional formulation of triamcinolone-acetonide requires a 10-fold higher drug dosage to achieve a similar effect. In either case, increasing the applied corticosteroid amount delays the onset of anti-edema action.     

Biological activity and characteristics of triamcinolone-acetonide formulated with the self-regulating drug carriers, Transfersomes®

Novel formulations of the halogenated corticosteroid, triamcinolone-acetonide, based on ultradeformable mixed lipid vesicles, Transfersomes®, are described. Their performance was tested in vivo using radioactive label measurements, to study the drug biodistribution, and murine ear edema, to determine the drug bioactivity. Sparse use of drug-loaded Transfersomes® on the skin ensures an almost exclusive delivery of triamcinolone-acetonide into the organ, thus arguably increasing the treatment safety. Delivery of triamcinolone-acetonide in the skin with ultradeformable vesicles prolongs the anti-inflammatory drug action several times compared to drug usage in a conventional crème or an ointment, the robustness of biological response for the former being at least identical to the latter. The required dose of Transfersome®-based triamcinolone-acetonide is also greatly reduced. The drug dose of 0.2 μg cm⁻² suppresses 75% of arachidonic acid-induced murine ear edema for at least 48 h. In contrast, a conventional formulation of triamcinolone-acetonide requires a 10-fold higher drug dosage to achieve a similar effect. In either case, increasing the applied corticosteroid amount delays the onset of anti-edema action.     

Anti-inflammatory activity of Maytenus senegalensis root extracts and of maytenoic acid

Maytenus senegalensis (Lam.) Excell (Celastraceae) root extracts were investigated for their topical anti-inflammatory properties by measuring the inhibition of the Croton oil-induced ear oedema in mice. The highest anti-inflammatory activity was detected in the chloroform extract, which reduced the oedematous response with a potency similar to that of the NSAID reference drug indomethacin (ID(50)=84 and 93 microg/cm(2), respectively). Fractionation of the chloroform and of the hexane extracts led to the isolation of maytenoic acid (1), which exhibited a dose-dependent antiphlogistic effect (ID(50)=0.11 micromol/cm(2)) twice that of indomethacin (ID(50)=0.26 micromol/cm(2)) and only three times lower than that of hydrocortisone (ID(50)=0.04 micromol/cm(2)).     

Formulation and evaluation of ethosomes for transdermal delivery of lamivudine

The purpose of the present research was to investigate the mechanism for improved intercellular and intracellular drug delivery from ethosomes using visualization techniques and cell line study. Ethosomal formulations were prepared using lamivudine as model drug and characterized in vitro, ex vivo and in vivo. Transmission electron microscopy, scanning electron microscopy, and fluorescence microscopy were employed to determine the effect of ethosome on ultrastructure of skin. Cytotoxicity and cellular uptake of ethosome were determined using T-lymphoid cell line (MT-2). The optimized ethosomal formulation showed 25 times higher transdermal flux (68.4 +/- 3.5 microg/cm(2)/h) across the rat skin as compared with that of lamivudine solution (2.8 +/- 0.2 microg/cm(2)/h). Microscopic studies revealed that ethosomes influenced the ultrastructure of stratum corneum. Distinct regions with lamellar stacks derived from vesicles were observed in intercellular region of deeper skin layers. Results of cellular uptake study showed significantly higher intracellular uptake of ethosomes (85.7% +/- 4.5%) as compared with drug solution (24.9% +/- 1.9%). The results of the characterization studies indicate that lipid perturbation along with elasticity of ethosomes vesicles seems to be the main contributor for improved skin permeation.     

Cytoplasmic fungal lipases release fungicides from ultra-deformable vesicular drug carriers

The Transfersome? is a lipid vesicle that contains membrane softeners, such as Tween 80, to make it ultra-deformable. This feature makes the Transfersome? an efficient carrier for delivery of therapeutic drugs across the skin barrier. It was reported that TDT 067 (a topical formulation of 15 mg/ml terbinafine in Transfersome? vesicles) has a much more potent antifungal activity in vitro compared with conventional terbinafine, which is a water-insoluble fungicide. Here we use ultra-structural studies and live imaging in a model fungus to describe the underlying mode of action. We show that terbinafine causes local collapse of the fungal endoplasmic reticulum, which was more efficient when terbinafine was delivered in Transfersome? vesicles (TFVs). When applied in liquid culture, fluorescently labeled TFVs rapidly entered the fungal cells (T(1/2)~2 min). Entry was F-actin- and ATP-independent, indicating that it is a passive process. Ultra-structural studies showed that passage through the cell wall involves significant deformation of the vesicles, and depends on a high concentration of the surfactant Tween 80 in their membrane. Surprisingly, the TFVs collapsed into lipid droplets after entry into the cell and the terbinafine was released from their interior. With time, the lipid bodies were metabolized in an ATP-dependent fashion, suggesting that cytosolic lipases attack and degrade intruding TFVs. Indeed, the specific monoacylglycerol lipase inhibitor URB602 prevented Transfersome? degradation and neutralized the cytotoxic effect of Transfersome?-delivered terbinafine. These data suggest that (a) Transfersomes deliver the lipophilic fungicide Terbinafine to the fungal cell wall, (b) the membrane softener Tween 80 allows the passage of the Transfersomes into the fungal cell, and (c) fungal lipases digest the invading Transfersome? vesicles thereby releasing their cytotoxic content. As this mode of action of Transfersomes is independent of the drug cargo, these results demonstrate the potential of Transfersomes in the treatment of all fungal diseases.     

Feeding frequency influences crèching age in the Dalmatian pelican, Pelecanus crispus

Crèching behaviour is common in colonial seabirds; nevertheless, the factors inducing chicks to aggregate remain relatively poorly understood. It has been proposed that brood size, laying date and nest attendance are important factors in the formation of a crèche. Moreover, in most species of pelicans, chicks join crèches following the development of homoeothermy and coincident with the end of the brooding behaviour. We studied effects of feeding rate, nest attendance, brood size, laying date and homoeothermy on the age at which chicks entered the crèche at a colony of Dalmatian pelicans (Pelecanus crispus), in Srebarna, Bulgaria. Single chicks were fed more frequently than chicks from two-chick broods. Unlike American white pelicans (Pelecanus erythrorhynchos), Dalmatian pelicans maintained brooding behaviour a further 9 days after chicks had developed thermoregulation abilities. In contrast to nests with two chicks, nests with only one chick were never left unattended by the parents before the chick reached the crèching stage. Laying date, nest attendance and brood size did not affect the age that the chick entered the crèche. The age the chick entered the crèche was not correlated with the age of homoeothermy acquisition, but chicks significantly joined the crèche at younger ages when the mean number of feeds per chick per day during the rearing period in the nest was higher. This result suggests an implication of growth rate in the crèching age. Joining the crèche earlier can provide benefits that could have strong implications for the chicks’ future reproductive lives.     

Absence of hydrocortisone from cytoplasmic hormone-protein complexes formed in vivo after administration of biologically active doses of [3H]hydrocortisone

After administration of [³H]hydrocortisone to adrenalectomized rats, hormone-protein complexes were isolated from liver cytosol by DEAE-cellulose chromatography. After application of biologically active and inactive doses of hydrocortisone five binding components were detected eluting at the same salt concentrations as the hormone-protein complexes observed after incubation of cytosol with [³H]hydrocortisone in vitro. The isolated hormone-protein fractions were acidified and extracted with ethylacetate and the steroids were analyzed by thin-layer chromatography. No significant amount of hydrocortisone could be detected in any of the complexes formed in vivo 5–60 min after administration of biologically active doses of hydrocortisone. 3ξ,11β,17α,20ξ, 21-Pentahydroxypregnane, steroidal carboxy acids, glucuronides and a very polar conjugate of hydrocortisone were found in the different fractions. After an in vivo dose of hydrocortisone of about 1/5000th of the minimal dose required for enzyme induction, hydrocortisone could be found in all cytoplasmic hormone-protein complexes formed. In contrast to the cytoplasmic hormone-protein complexes, hydrocortisone could be readily demonstrated in nuclei isolated after the administration of biologically active doses of hormone, although acid metabolites were found to represent the main part of the radioactive compounds present in the nuclei. These acid metabolites were located in ronide on the basis of its chromatographic behavior. The biological significance of this conjugate of hydrocortisone as well as that of the extremely polar conjugate found in fraction DE-3 cannot be understood on the basis of the published data pertaining to biological functions and metabolism of glucocorticosteroids.Our finding that no ‘classical’ glucocorticosteroid receptor can be detected in rat liver cytosol raises again the question of the way in which hydrocortisone and its active metabolites enter the nucleus. On the basis of the published data, the possibility cannot be ruled out that glucocorticosteroids are transported via the endoplasmic reticulum. A transport by this way has been inferred for the uptake of sodium and inulin by liver nuclei [40–42].     

Survival of Slender-billed Gull chicks during the crèching period

Capsule Crèches formed early in the season lasted longer than those formed later, but a longer crèching period did not appear to confer higher chick survival.

Aims To investigate the ecological factors influencing the benefit to parents of crèching behaviour by measuring chick survival.

Methods Mark–recapture was used to model apparent daily survival of 505 chicks during the crèching period in three different crèches. We contrasted models with different tipping points to assess possible differences across crèches in chick survival during the first week and in the moment at which chick departures began.

Results We did not find a clear difference across crèches on daily chick survival during the first stages of the crèche. By modelling chick apparent survival as a linear function of time we showed that the latest formed crèche dispersed more rapidly.

Conclusions The two crèches formed early in the season lasted longer than the one formed later but chicks did not appear to have a higher survival over the first week of crèching. We suggest that a longer period at the crèche should result in a higher survival in the period soon after fledging because chicks leave the crèche 4–7 days older than other chicks. Furthermore, early crèches are synchronous with those of other species breeding in the same area, thus perhaps diluting predation. We discuss the limitations of our analysis and the possible implications for the community of waterbirds breeding at our study site.     

Ultradeformable lipid vesicles can penetrate the skin and other semi-permeable barriers unfragmented. Evidence from double label CLSM experiments and direct size measurements

The stability of various aggregates in the form of lipid bilayer vesicles was tested by three different methods before and after crossing different semi-permeable barriers. First, polymer membranes with pores significantly smaller than the average aggregate diameter were used as the skin barrier model; dynamic light scattering was employed to monitor vesicle size changes after barrier passage for several lipid mixtures with different bilayer elasticities. This revealed that vesicles must adapt their size and/or shape, dependent on bilayer stability and elasto-mechanics, to overcome an otherwise confining pore. For the mixed lipid aggregates with highly flexible bilayers (Transfersomes®), the change is transient and only involves vesicle shape and volume adaptation. The constancy of ultradeformable vesicle size before and after pores penetration proves this. This is remarkable in light of the very strong aggregate deformation during an enforced barrier passage. Simple phosphatidylcholine vesicles, with less flexible bilayers, lack such capability and stability. Conventional liposomes are therefore fractured during transport through a semi-permeable barrier; as reported by other researchers, liposomes are fragmented to the size of a narrow pore if sufficient pressure is applied across the barrier; otherwise, liposomes clog the pores. The precise outcome depends on trans-barrier flux and/or on relative vesicle vs. pore size. Lipid vesicles applied on the skin behave accordingly. Mixed lipid vesicles penetrate the skin if they are sufficiently deformable. If this is the case, they cross inter-cellular constrictions in the organ without significant composition or size modification. To prove this, we labelled vesicles with two different fluorescent markers and applied the suspension on intact murine skin without occlusion. The confocal laser scanning microscopy (CLSM) of the skin then revealed a practically indistinguishable distribution of both labels in the stratum corneum, corroborating the first assumption. To confirm the second postulate, we compared vesicle size in the starting suspension and in the blood after non-invasive transcutaneous aggregate delivery. Size exclusion chromatograms of sera from the mice that received ultradeformable vesicles on the skin were undistinguishable from the results measured with the original vesicle suspension. Taken together, the results support our previous postulate that ultradeformable vesicles penetrate the skin intact, that is, without permanent disintegration.     

Mammary skin oedema: a new prognostic indicator for breast cancer.

Mammary skin thickening shown on the mammogram was measured in 220 patients with non-inflammatory breast cancer, and the mean skin oedema was derived by taking the mean of five measurements from separate sites on the breast (upper part, lower part, medial part, lateral part, and areola) after subtracting the corresponding figures from the opposite (normal) breast. The prevalence of appreciable oedema (greater than 0.25 mm) was 70% for tumours less than 1 cm and 100% for tumours more than 3 cm in diameter. This measure of oedema correlated positively and significantly with tumour size and lymph node status. In a minimum of 60 months'' follow up patients developing recurrence had significantly higher oedema values. The amount of oedema also predicted recurrence better than lymph node status, tumour size, or tumour stage. Oedema and tumour size, information available preoperatively, provide a simple means of assessing prognosis before definitive treatment.     

Postfledging crèche behavior in the European shag

Formation of a postfledgling crèche in the European shag Phalacrocorax aristotelis on the Cíes Islands (northwest Spain) was studied. There was no relationship between the number of birds in a crèche and environmental temperature. Moreover, the number of juveniles in the crèche was not correlated with adult peck rate per juvenile. Also, predation was not reported on the studied population. Therefore, their postfledging crèche did not serve as protection from thermal stress, aggressiveness of adults, or predators. In the crèche studied, fledglings are faithful to their perch, which serves as a functional unit where they form a group consisting of stable members. I postulate that there may be advantages in the formation of crèches, which allow adults to be able to locate their young and continue their postfledging parental care and also enable chicks to exercise and develop fishing skills. Adults remained in the crèche during the entire period, but their number depended on the hour and tide, which would be associated with the effectiveness of fishing according to these factors. Moreover, crèches may facilitate finding mates and forming feeding groups. Received: October 19, 2000 / Accepted: February 28, 2001     

Transformation/neodifferentiation of human skin fibroblasts by acute oncornaviruses and dexamethasone

We demonstrated that the Kirsten murine sarcoma virus (KiMSV) and the Harvey murine sarcoma virus (HaMSV) converted human skin fibroblasts (HSF) into adipocytes. Adipocytic conversion of HSF by KiMSV and HaMSV was dependent on the presence of glucocorticosteroids. The Kirsten murine leukemia virus, the Harvey murine sarcoma [corrected] virus and the amphotropic helper virus (AP292) were ineffective by themselves. Balb murine sarcoma virus and Moloney murine sarcoma virus were, to a lesser degree, able to effect adipocytic conversion of HSF. In contrast, the feline sarcoma virus and the simian sarcoma virus did not cause this conversion. Together, the results suggest a role for certain oncogenes and glucocorticosteroids in the transformation/neodifferentiation of human cells.     

Evaluation of Meloxicam-Loaded Cationic Transfersomes as Transdermal Drug Delivery Carriers

The aim of this study is to develop meloxicam (MX)-loaded cationic transfersomes as skin delivery carriers and to investigate the influence of formulation factors such as cholesterol and cationic surfactants on the physicochemical properties of transfersomes (i.e., particle size, size distribution, droplet surface charge and morphology), entrapment efficiency, stability of formulations and in vitro skin permeation of MX. The transfersomes displayed a spherical structure. Their size, charge, and entrapment efficiency depended on the composition of cholesterol and cationic surfactants in the formulation. Transfersomes provided greater MX skin permeation than conventional liposomes and MX suspensions. The penetration-enhancing mechanism of skin permeation by the vesicles prepared in this study may be due to the vesicle adsorption to and/or fusion with the stratum corneum. Our results suggest that cationic transfersomes may be promising dermal delivery carriers of MX.     

Efficacy of anti-inflammatory therapy in a model of acute seizures and in a population of pediatric drug resistant epileptics

Targeting pro-inflammatory events to reduce seizures is gaining momentum. Experimentally, antagonism of inflammatory processes and of blood-brain barrier (BBB) damage has been demonstrated to be beneficial in reducing status epilepticus (SE). Clinically, a role of inflammation in the pathophysiology of drug resistant epilepsies is suspected. However, the use anti-inflammatory drug such as glucocorticosteroids (GCs) is limited to selected pediatric epileptic syndromes and spasms. Lack of animal data may be one of the reasons for the limited use of GCs in epilepsy. We evaluated the effect of the CG dexamethasone in reducing the onset and the severity of pilocarpine SE in rats. We assessed BBB integrity by measuring serum S100β and Evans Blue brain extravasation. Electrophysiological monitoring and hematologic measurements (WBCs and IL-1β) were performed. We reviewed the effect of add on dexamethasone treatment on a population of pediatric patients affected by drug resistant epilepsy. We excluded subjects affected by West, Landau-Kleffner or Lennox-Gastaut syndromes and Rasmussen encephalitis, known to respond to GCs or adrenocorticotropic hormone (ACTH). The effect of two additional GCs, methylprednisolone and hydrocortisone, was also reviewed in this population. When dexamethasone treatment preceded exposure to the convulsive agent pilocarpine, the number of rats developing status epilepticus (SE) was reduced. When SE developed, the time-to-onset was significantly delayed compared to pilocarpine alone and mortality associated with pilocarpine-SE was abolished. Dexamethasone significantly protected the BBB from damage. The clinical study included pediatric drug resistant epileptic subjects receiving add on GC treatments. Decreased seizure frequency (≥ 50%) or interruption of status epilepticus was observed in the majority of the subjects, regardless of the underlying pathology. Our experimental results point to a seizure-reducing effect of dexamethasone. The mechanism encompasses improvement of BBB integrity. Our results also suggest that add on GCs could be of efficacy in controlling pediatric drug resistant seizures.     

Glucocorticoids Increase Tyrosine Hydroxylase Activity in Cultured Murine Neuroblastoma

Cyclic AMP and glucocorticoids appear to have a role in regulating the activity of tyrosine hydroxylase (TH), as well as the expression of "morphological differentiation" in murine neuroblastoma. Monolayer cultures of C-1300 murine neuroblastoma (clone NBP2) were treated with the following compounds in ethanol: dexamethasone, triamcinolone acetonide, hydrocortisone, cortexolone, androstenedione, testosterone, estradiol-17 beta; or with the phosphodiesterase inhibitor Ro20-1724 [4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone]. Treatment with either 200 micrograms/ml Ro20-1724 or 50 micrograms/ml dexamethasone produced significant increases in TH activity compared to alcohol controls (1.44 vs. 0.82 nmol 14CO2/mg protein/hr compared to 0.095). Triamcinolone acetonide or hydrocortisone also produced smaller, but significant, increases in TH activity compared to dexamethasone. When steroid activities were compared at 25 microM concentration and after 60 min of incubation (to maximize TH activity), triamcinolone acetonide was not as effective (62%) as dexamethasone. The relatively inactive glucocorticoid cortexolone produced a slight but significant increase, while the androgens androstenedione and testosterone and the estrogen estradiol-17 beta were without effect.     

Spatial and temporal variation in the provisioning behaviour of female rockhopper penguins Eudyptes chrysocome filholi

As seabirds are central place foragers during breeding, their provisioning behaviour and their ability to face variable energy demand from the chicks is expected to vary with environmental conditions. The provisioning behaviour of female rockhopper penguins Eudyptes chrysocome filholi was recorded over the chick‐rearing period at Kerguelen (KER) and Crozet (CRO) archipelagoes (two very distinct marine environments), using time‐depth recorders, or VHF transmitters coupled with an automatic recording station. No influences of the method have been found on the average foraging trip durations. Some previously undescribed short and multiple trips within a day were recorded using the automatic recording system. These multiple trips (6.8 h) were mostly performed with <5 days old chicks, a period during which feeding rates were the highest (1.1 meals per day), at both sites. During the brooding period, both KER and CRO females mainly performed daily trips of increasing duration (2 h longer at CRO) and at decreasing frequency. During the crèche compared to the brooding period, females from KER performed slightly fewer daily trips (0.6 per day) and more (<3 days) overnight trips, while females from CRO performed very few daily trips (0.1 per day) and more overnight trips, some of them being long trips lasting 5 to 29 days, mostly initiated during the transition between the brooding and the crèche periods. The result fit the hypothesis that long trips permit females to restore and/or maintain their body condition at more distant foraging places. It seemed that chick developement during the brooding period and environmental factors during the crèche period conditioned trip duration of females. Due to more long trips at CRO, the female feeding frequency was twice as high at KER than at CRO during the crèche period, while males participated in the feeding duties. Based on differences in female behaviour, we hypothesize that the male's contribution is likely to differ strongly from one site to another, and may buffer the possible decrease in female feeding frequency by feeding the chicks if food is less abundant.     

Effect of hydrocortisone on interleukin-6 production in human ,peripheral blood rnononuclear ceils

The effect of hydrocortisone on the production of interleukin-6 (IL-6) in human peripheral blood mononuclear cells was studied. Using our newly developed radioimmunoassay system for IL-6 of which specificity, reproducibility, sensitivity and usefulness have been demonstrated. IL-6 production in peripheral blood mononuclear cells of ten normal subjects revealed that in lipopolysaccharide (LPS, 10mug/ml)-stimulation, the mean +/- SD of IL-6 was 2.71 +/- 0.85 ng/ml. No detectable amount of IL-6 was observed in the absence of LPS and in the presence of hydrocortisone alone. Hydrocortisone (10(-10) M to 10(-3) M) inhibited LPS-stimulated IL-6 production in a dose-dependent manner. However, there was a wide variation in the response to hydrocortisone, namely, ranging from steroid-sensitive to steroid-resistant. Based on the concentration required to inhibit 50% of LPS-stimulated IL-6 production, three of ten subjects were at 10(-6) M, three at 10(-5) M and the rest at 10(-4) M, respectively. The dramatic anti-inflammatory and immunosuppressive effects of glucocorticosteroids can be life-saving in autoimmune diseases. The present findings suggested that there existed the differences in susceptibility to glucocorticosteroids even among normal subjects, providing some implications for the drug treatment, and also gave further evidence that there may exist an immunoregulatory feedback circuit between the immune and neuroendocrine systems.     

Pro-inflammatory effect in mice of CvL, a lectin from the marine sponge Cliona varians

CvL, a lectin from the marine sponge Cliona varians agglutinated type A papainized erythrocytes and was strongly inhibited by d-galactose and sucrose. Models of leukocyte migration in vivo were used to study the inflammatory activity of CvL through of mouse paw oedema and peritonitis. Effect of CvL on peritoneal macrophage activation was analysed. Effects of corticoids and NSAIDS drugs were also evaluated on peritonitis stimulated by CvL. Results showed that mouse hind-paw oedema induced by subplantar injections of CvL was dose dependent until 50 microg/cavity. This CvL dose when administered into mouse peritoneal cavities induced maxima cell migration (9283 cells/microL) at 24 h after injection. This effect was preferentially inhibited by incubation of CvL with the carbohydrates d-galactose followed by sucrose. Pre-treatment of mice with 3% thioglycolate increases the peritoneal macrophage population 2.3 times, and enhanced the neutrophil migration after 24 h CvL injection (75.8%, p<0.001) and no significant effect was observed in the presence of fMLP. Finally, pre-treatment of mice with dexamethasone (cytokine antagonist) decreased (65.6%, p<0.001), diclofenac (non-selective NSAID) decreased (34.5%, p<0.001) and Celecoxib (selective NSAID) had no effect on leukocyte migration after submission at peritonitis stimulated by CvL, respectively. Summarizing, data suggest that CvL shows pro-inflammatory activity, inducing neutrophil migration probably by pathway on resident macrophage activation and on chemotaxis mediated by cytokines.     

The pharmacological profile of ovalbumin-induced paw oedema in rats

Rats are commonly used in anaphylaxis models, mainly in intestinal anaphylaxis. Hypersensitivity mechanisms are complex and they are not clearly defined. Ovalbumin (OVA) is commonly used for studies on the hypersensitivity mechanism. However, the potential pro-inflammatory mediators induced by this antigen in the model of paw oedema in immunized rats are still not completely understood. This work examines the pharmacological modulation of several mediators involved in rat hind paw immune oedema induced by OVA. Wistar rats were previously immunized (14-18 days) with OVA (30 microg, intraperitoneally) or sham-sensitized with aluminum hydroxide (control). The paw volumes were measured before the antigenic stimuli and 1, 2, 3 and 4 h after the intraplantar injection of OVA (10 microg/paw). Subcutaneous injection of dexamethasone, diphenhydramine, cyproheptadine, chlorpromazine or methysergide significantly inhibited (p < 0.05) the allergic paw oedema. The dual inhibitor of cyclooxygenase and lipoxygenase (NDGA), the cyclooxygenase inhibitor (indomethacin), the lipoxygenase inhibitor (MK-886), the PAF antagonist (WEB 2086), the mast cell stabilizer (ketotifen), and the anti-histamine (meclizine) did not inhibit the immune oedema. In addition, thalidomide and pentoxifylline (anti-tumour necrosis factor drugs) were ineffective against OVA-induced oedema. The fact that indomethacin, MK-886, NDGA and WEB 2086 are unable to inhibit this allergic oedema indicates that the dexamethasone action seems not to be via phospholipase A2, but possibly due to the synthesis and/or the inhibitory activity of cytokines. The paw oedema inhibition by diphenhydramine, but not by meclizine, may suggest a different mechanism, which is independent of the effect of histamine. These data indicate that allergic oedema is more sensitive to anti-serotonin drugs, mainly anti-5-HT2, suggesting that the principal mediator of this inflammatory response is serotonin.     

短期联合应用灰黄霉素、克霉唑和地塞米松对红色毛癣菌的影响

目的研究灰黄霉素、克霉唑及灰黄霉素、克霉唑与地塞米松组合成的联合药物对红色毛癣菌在体内、外活性影响。方法在体外分别应用灰黄霉素、地塞米松、克霉唑、灰黄霉素：克霉唑：地塞米松=5：5：1联合药物的不同药物浓度作用于红色毛癣菌,确立药物最小抑菌浓度（MIC）和联合药物的分数抑菌浓度（FIC）;制作由红色毛癣菌引起皮肤癣的豚鼠动物模型,根据豚鼠用药部位分成四组,对豚鼠皮疹进行疗效的评估。结果体外实验联合药物的MIC小于单药的MIC,且联合药物起协同和次协同作用;体内实验中联合用药组对动物受损局部皮肤给药后,对红色毛癣菌所致皮损积分为（1．89±0．68）,与对照组（3．33±0．69）比较,可明显减轻局部皮肤损伤病变程度,该药优于克霉唑组（2．33±0．69）、灰黄霉素组（2．11±0．58）。结论短期内灰黄霉素、克霉唑与地塞米松组合成的联合药物有较强的抗红色毛癣菌和抗炎作用,其抗菌活性强于单独药物的灰黄霉素和克霉唑。