Epidemiology, clinical manifestations and diagnosis of zoonotic cestode infections: an update.

This paper reviews the literature on zoonotic cestode infections with specific reference to the years 1999-2003. The sources and prevalence of various zoonotic tapeworm infections caused by adult and larval stages of the genera Taenia, Echinococcus, Diphyllobothrium, Hymenolepis and Dipylidium continue to be an important cause of morbidity and mortality, not only in most underdeveloped countries but also in industrialized countries, particularly in rural areas or among immigrant groups from endemic areas. The review gives a detailed report on recent molecular epidemiological studies on the taxonomy and phylogenetic variations in Echinococcus granulosus, immunological tests and imaging techniques used in epidemiological surveys and clinical investigations of important adult and larval tapeworm infections of animals and humans. Larval stages or metacestodes of Taenia solium, Echinococcus spp. and pseudophyllidean tapeworms (Spirometra syn. Diphyllobothrium spp.) may reside in various tissues of their intermediate hosts, including humans. In particular, Cysticercus cellulosae (T. solium) and the larvae of E. granulosus, and E. multilocularis, which are predominantly located in the liver, lungs and central nervous system forming various types of cysts, lead to a complex of systemic diseases such as cysticercosis, cystic echinococcosis and alveolar echinococcosis, respectively. Relatively rare clinical manifestations are seen in the muscles, subcutaneous tissue, spleen, kidneys, bones and body cavities.

Nitroheterocyclic drugs with broad spectrum activity.

The group of biologically active nitroheterocyclic compounds includes various 5- and 2-nitroimidazoles and 5-nitrofurans, which can be used as therapeutic agents against a variety of protozoan and bacterial (anaerobic) infections of humans and animals. The current status in the the treatment of giardiasis, trichomoniasis, balantidiasis, histomoniasis, and amebiasis (including infections due to opportunistic amebas) is presented. The most relevant drugs (benznidazole, furazolidone, metronidazole, misonidazole, nifurtimox, nimorazole, nitazoxanide, ornidazole, secnidazole, and tinidazole) are characterized with regard to their chemical, chemotherapeutic, toxicological, pharmacokinetic, and pharmacological properties, including the mechanism of action and resistance in certain parasitic protozoa.

Detection of a flow induced magnetic field eigenmode in the riga dynamo facility

In a closed volume of molten sodium an intense single-vortex-like helical flow has been produced by an outside powered propeller. At a flow rate of 0.67 m(3)/s a slowly growing magnetic field eigenmode was detected. For a slightly lower flow, additional measurements showed a slow decay of this mode. The measured results correspond satisfactorily with numerical predictions for the growth rates and frequencies.

New systematically active antimycotics from the beta-blocker category.

Candida albicans secretes phospholipases, which are considered to be one of the mediators of cell penetration. It is known that other phospholipases from mammalian cells can be inhibited by lipophilic beta-blocking structures. As the result of a synthesis programme of several years' duration, structures deriving from beta-hydroxyethylamines were introduced. In vitro and in vivo results with these compounds are presented in comparison with standard antimycotics. In combination with fluconazole, several of the compounds can prevent death in mice infected with lethal inocula of C. albicans. Histological examinations confirm the inhibitory effect of the beta-blocker-like structures on tissue penetration. The structures therefore constitute new antimycotics that are endowed with extensive in vitro effectiveness against fungi and also definite in vivo effects in the animal model.

Modification of cisplatin-induced renal p-aminohippurate uptake alteration and lipid peroxidation by thiols, Ginkgo biloba extract, deferoxamine and torbafylline.

To determine whether inhibition of lipid peroxidation modifies cisplatin-induced changes of renal p-aminohippurate (PAH) uptake, we examined the effects of various radical scavengers and torbafylline on cisplatin-induced lipid peroxidation and PAH accumulation changes in rat renal cortical slices. Renal cortical slices were incubated with different cisplatin concentrations (0.3, 0.6, 1.0 mg/ml) in the presence of either glutathione, N-acetylcysteine, the iron chelator deferoxamine, Ginkgo biloba extract or the xanthine derivate torbafylline. Lipid peroxidation monitored as the production of malondialdehyde (MDA) was stimulated by increasing cisplatin concentrations in a dose-related manner. At a cisplatin concentration of 1.0 mg/ml, MDA production was twofold compared to controls (0.69 +/- 0.06 vs. 1.36 +/- 0.07 nmol/mg; p < 0.05). In turn, cisplatin decreased PAH uptake of kidney slices dose-dependently from 13.3 +/- 1.3 to 2.6 +/- 0.2 (p < 0.01). All agents tested inhibited cisplatin-induced lipid peroxidation; however, at a cisplatin concentration of 1.0 mg/ml, none of them prevented the decline of cisplatin-induced PAH uptake. Of the agents tested, deferoxamine proved to be the most effective antioxidant, completely inhibiting cisplatin-induced lipid peroxidation but in contrast preventing the decrease in PAH uptake only at a cisplatin concentration of 0.3 mg/ml. No strict association between lipid peroxidation and decline of PAH uptake was found, suggesting that lipid peroxidation may only in part participate in cisplatin-induced alterations of PAH uptake.

Effects of rilopirox on rabbit blastocysts in a protein-free in vitro culture under different culture conditions.

The effect of rilopirox (Hoe 351, CAS 104153-37-9) on rabbit blastocysts in vitro was studied. Blastocysts of day 6 post coitum were cultured in Ham's F 10 medium supplemented with polyvinylpyrrolidone using different concentrations of rilopirox with and without serum proteins. In culture conditions without serum proteins there were no differences in the growth rates of the blastocysts after 24 h of culture in the presence of 1 microgram/ml of rilopirox. However, 5 micrograms/ml of rilopirox resulted in a significant reduction of the mean growth rate as well as in a serious morphological damage of the treated blastocysts. Purified human serum albumin could partly prevent this toxic effect, while complete human serum and foetal calf serum did not show this characteristic. Analyses of the protein synthesis of the blastocysts treated with rilopirox by two-dimensional gel electrophoresis and subsequent fluorography did not show any differences in comparison to the untreated controls, despite of obvious morphological alterations.

Ultrastructural investigations of Candida albicans after in vitro treatment with the new fungicidal agent rilopirox.

Candida albicans was maintained in various culture media and incubated with different concentrations of the antifungal agent rilopirox. After fixation, dehydration and embedding in Spurr's medium, the cells were analysed at the ultrastructural level to investigate morphological aspects of the antifungal mode of action of this new hydroxpyridone compound. All untreated or sham-treated control cells exhibited a normal ultrastructural appearance. The cells were surrounded by a multilayered cell wall of typical structure, and the plasmalemma was in close contact with the cell wall. Also, the cell organelles of the protoplast corresponded well with the findings of other authors. After treatment with rilopirox, a variety of ultrastructural changes were seen, and the extent of damage was dependent on the specific culture condition, drug concentration and incubation time. After only 6 h and 1-10 micrograms ml-1 rilopirox, the plasmalemma exhibited elongated invaginations, the number and size of the lipid droplets had increased and greatly enlarged mitochondria containing electron-dense deposits became visible. The vacuolar system was strongly expanded and occupied nearly the whole cell. Exposure to higher concentrations of the antifungal agent and prolonged incubation times resulted in complete cytoplasmic autolysis and membrane breakdown, while the fungal cell wall remained unaffected. After treatment with 0.5% rilopirox suspension gel on agar cultures, the extent of cellular damage was clearly enhanced and included all cell types of a treated yeast colony, i.e. single blastospores and pseudohyphae.

A modified method for experimental candidosis in mice avoiding lethality.

A model is presented which selected one out of 150 Candida albicans strains for the evaluation of antifungal agents. The mice were inoculated with 6 x 10(5) CFU of strain 352 into the tail vein. The strain has a moderate phospholipase B (PLB) activity in vitro and was originally isolated from a stool sample from a patient in an intensive care unit. This infection leads to very little suffering in the infected animals during the 6-day observation period. Kidney counts at day 5 after infection can give a first indication for a possible fungistatic mechanism. Possible interesting drugs can then be evaluated by a second set of experiments using a longer observation time to investigate the compounds for fungicidal properties. The model suggests that screening for systemic antifungals by avoiding lethality of mice in the first place can be done.

Pretreatment with pancuronium before suxamethonium administration in patients heterozygous for the usual and the atypical plasma cholinesterase gene.

The object of this study was to investigate whether pretreatment with pancuronium before i.v. injection of suxamethonium could cause prolonged neuromuscular blockade in patients heterozygous for the usual and the atypical plasma cholinesterase gene (E1uE1a). Forty-three patients, 23 with genotype E1uE1a and 20 with normal genotype (E1uE1u), were pretreated with pancuronium 0.01 mg.kg-1 followed by suxamethonium 1.5 mg.kg-1, and received either neurolept anaesthesia or halothane anaesthesia. Seven patients (E1uE1a) were given suxamethonium 1.5 mg.kg-1 without pretreatment. The duration and type of neuromuscular block were evaluated using train-of-four (TOF) nerve stimulation. Type of anaesthesia did not significantly influence the results. The duration of block following pretreatment was significantly longer in heterozygous patients than in normal patients. Time to 90% twitch height recovery was 10.7 +/- 1.2 min (mean +/- s.d.) in genotypically normal patients, and 18.0 +/- 4.2 min in patients with genotype E1uE1a. Pretreatment with pancuronium caused a significantly slower recovery of the TOF ratio (phase II block). Thus, a TOF ratio of 0.7 was always reached within 13 min in genotypically normal patients. In genotypically abnormal patients, the same TOF ratio was reached within 20 min in all but three patients. In these three patients time to 90% twitch height recovery was prolonged (18-31 min), and TOF ratio did not return to normal, but stabilized at about 0.35, 0.50, and 0.65, respectively. Injection of edrophonium restored normal neuromuscular function in 10 min. It is concluded that in patients heterozygous for the usual and the atypical gene, pretreatment with pancuronium in combination with an increased dose of suxamethonium may cause a phase II block and thus a prolonged neuromuscular block.

[Therapy of seborrheic eczema with an antifungal agent with an antiphlogistic effect]. / Therapie des seborrhoischen Ekzems mit einem antiphlogistisch wirksamen Antimykotikum.

Numerous AIDS patients show the typical seborrheic eczema in a very prominent way. For this is an inflammatory disease, combination preparations were taken frequently which contain antimycotics and corticosteroids. We investigated 7 antimycotic compounds in 3 inflammatory models: amorolfin, ciclopiroxolamine (cic), fluconazole, ketoconazole, miconazole, naftifine, and rilopirox. In an in vitro model the inflammatory activity towards the 5-lipoxygenase was investigated. 1,000 mumol naftifine, 100 mumol ketoconazole, 50 mumol cic, and 10 mumol rilopirox inhibited 5-HETE by 90%. In a cell culture model only cic had a significant activity towards cyclo-oxygenase. In this model the inhibition of the prostaglandin E2 liberation by 1 mumol cic was 40%. In an in vivo model the anti-inflammatory activity on a mouse ear was investigated (arachidonic acid induced). In this model only cic showed a significant inhibition of inflammation (50%) at 1 mg/ear. These investigations show, that cic has a strong antiphlogistic activity. In an open clinical trial with 20 patients suffering from seborrheic eczema after 4 weeks on cic cream a strong inhibition of infiltration and flakiness had been observed. The antimycotic compound cic offers a possibility to treat inflammatory mycoses without using corticosteroid combinations. In a double blind clinical trial (tinea) where cic was compared with a cic/hydrocortisone combination no statistical differences were found.

Studies for the elucidation of the mode of action of the antimycotic hydroxypyridone compound, rilopirox.

Rilopirox is a synthetic, fungicidal antimycotic agent with hydrophobic characteristics. Its chemical name is 6-[4-(4-chlorophenoxy)-phenoxy-methyl]-1-hydroxy-4-methyl-2-pyridone and it has a molecular weight of 357.79. Rilopirox is very soluble in dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) but poorly soluble in water. The amount of antimycotic agent remaining in the solution is dependent on the final concentration of the solvent and the amount of rilopirox used. Complexometric studies show that rilopirox has a high affinity for iron ions [unpubl. data]. Catalase, an iron-containing enzyme, is inhibited by the chelating agent rilopirox. Studies on yeast mitochondria and submitochondrial particles show that rilopirox inhibits the respiratory chain. Complex I (NADH-ubiquinone oxidoreductase) contains iron-sulfur proteins and is the main system which is inhibited.

Ciclopiroxolamine cream 1%: in vitro and in vivo penetration into the stratum corneum.

Studies were conducted to assess the penetration of 1% ciclopiroxolamine cream, establishing the concentrations of the antimycotic compound in different layers of the stratum corneum with two skin models. Results of in vitro studies using skin from domestic pigs indicate that ciclopiroxolamine has the ability to penetrate fast into the epidermis, by inhibiting and killing inoculated Trichophyton mentagrophytes. In vivo investigation of the stratum corneum has been performed in healthy human volunteers by 20 strippings collected in four layers. Fungicidal concentrations of ciclopiroxolamine were determined after extraction from the strippings. These studies demonstrate that the concentrations reached levels which are sufficient to inhibit and kill pathogenic fungi.

Quantification of keratinolytic activity from Dermatophilus congolensis.

The bacterium Dermatophilus congolensis is the causative agent of pitted keratolysis, a skin disease. Infection occurs mainly in keratinized tissues and it is necessary for the organism to produce and excrete exoenzymes which are able to degrade keratin. We investigated the amount of keratinase liberated using Keratinazure as substrate and the fungal protease XI as standard. When compared with uninoculated samples, D. congolensis liberated significant amounts of keratinase during a 12-day incubation period with this substrate. An equivalent of 15 units of protease (keratinase) was produced by 10(7) colony-forming units of D. congolensis during a 12-day period at 37 degrees C. We consider the extracellular proteolytic activity of this bacterium to be responsible for keratinized tissues being the main sites of infection.

Ciclopirox nail lacquer 8%: in vivo penetration into and through nails and in vitro effect on pig skin.

This report presents original methods to assess the bioavailability of an antifungal drug from a varnish preparation in finger nails. For the studies with human volunteers a ciclopirox 8% nail lacquer was used to determine its efficacy in the treatment of onychomycoses. In vivo studies were performed on the fingernails of healthy volunteers by determining the total amount of ciclopirox penetrated per milligram of nail and the partition of the drug in the plate of the nails (technically divided into four layers). Ciclopirox concentrations were evaluated by measuring the inhibition of Candida pseudotropicalis growth in vitro. The ciclopirox concentration after 30 days treatment was determined as 3.35 +/- 0.82 micrograms/mg nail material. This is a sufficient amount to kill the fungal pathogens. In addition, in vitro penetration experiments were carried out with excised pig skin. Lacquer formulations from 0.5 to 8% were used to inhibit the growth of Trichophyton mentagrophytes. Formulations from 2 to 8% led to a strong to total inhibition of the dermatophyte after 30 min treatment time.

Experimental dermatophytosis in nude guinea pigs compared with infections in Pirbright White animals.

With this investigation we wanted to compare the suitability of two different strains of guinea pigs to evaluate topical antifungals after experimental Trichophyton mentagrophytes infection. The "hairless"-strain was compared with the hairy Pirbright White strain. The infection areas were treated with a skin retention test (application before infection) and two sets of therapy tests (application after infection). In the retention test the different antimycotic compounds led to better gradations. Also, in the two sets of therapy tests the gradations among the compounds were more clearly and more comparable to published results of clinical trials. In the histological investigations the infections in the "hairless" animals developed in a way which is known from dermatophytoses in human skin. In the Pirbright White strain, however, due to the adjacent hair roots, a marked inflammatory reaction of the tissue persisted for 3 weeks which is not observed on human skin of the trunk and extremities. We, therefore, consider the "hairless" strain of guinea pigs to be more suitable than hairy animals for the comparison of topical antimycotics.

Rilopirox--a new hydroxypyridone antifungal with fungicidal properties.

Rilopirox, 6-[[p-chlorophenoxy)phenoxy]methyl]-1hydroxy-4-methyl-2(1H)-pyrido ne, is a new fungicidal antimycotic with very low water solubility. It was designed to meet the demand for an intravaginal antifungal with a long skin retention time and a strong killing effect on pathogenic yeasts. In addition, it inhibits all common fungal pathogens in the range 0.98 to 15.6 micrograms/ml. Fungicidal rates vis-à-vis Trichophyton mentagrophytes and Candida albicans under proliferative and non-proliferative conditions are higher than those achieved with common azole and allylamine antifungals. Rilopirox is affected by Fe3+ ions and high concentrations of human serum owing to its chelating activity. The peptone source is of utmost importance to the inhibitory activity of rilopirox whereas the pH value seems to be unimportant so long as it is within the range 5-8.5. Rilopirox appears to meet the demand for an intravaginal antifungal as a result of its very low water solubility of 50 ng/ml and its immediate fungicidal action even under non-proliferative conditions.

Immunomodulation by the new synthetic thiazole derivative tiprotimod. 3rd communication: influence on host resistance to microorganisms, tumors and on experimental immune disorders.

To evaluate the influence of [2-(3-carboxy-1-probylthio)-4-methyl-1,3-thiazole]acetic acid (tiprotimod, HBW 538) on the host defense mechanisms, a number of experimental studies in different animal models were performed. The prophylactic treatment of NMRI mice with tiprotimod significantly prolonged the mean survival time of the animals after intravenous infection with Candida albicans 200/175 and increased the resistance to the fungal infection to 180% in comparison to controls. In vitro the drug showed no direct fungistatic or fungicidal activity. In an experimental model of persistent systemic candidiasis Balb/c mice infected intravenously with Candida albicans were treated with the immunomodulator tiprotimod after the fungal colonization of kidney was manifested (3 days post infection). The treatment of the mice after the infection resulted in a reduction of the infectious load and the abscess formation in kidney as well as in a decrease of numbers of yeasts in the urine. In the syngeneic B16 melanoma tumor model tiprotimod significantly prolonged the medium survival time and reduced the number of visuable metastases in the lungs even when applied after resection of the primary tumor graft. Tiprotimod also beneficially influenced the course of the disease in two murine graft-vs-host models (hemolytic anemia and immune complex glomerulonephritis) which lead to a B cell mediated autoimmune disease with fatal outcome. The application of the drug in the induction phase mitigated the development of the diseases and prevented animals from dying.(ABSTRACT TRUNCATED AT 250 WORDS)

[The significance of yeasts in seborrheic eczema]. / Zur Bedeutung der Hefen beim seborrhoischen Ekzem.

The high prevalence of seborrheic dermatitis in HIV-infected subjects has led to intensified the discussion of the etiopathogenesis of this dermatological disease. There is increasing controversy about the significance of Pityrosporum in seborrheic dermatitis. On the other hand, recent clinical and experimental data favor the role of intestinal candidiasis in seborrheic dermatitis: a high quantity of Candida in the feces of the affected patients, elevated phospholipase activity of the Candida sp. with special pathogenic relevance for mucosal adhesion and fast and long-lasting regression of seborrheic dermatitis after vigorous therapy with oral nystatin. Similar findings have been recorded in the seborrheic forms of psoriasis.

Ciclopirox olamine lotion 1%: bioequivalence to ciclopirox olamine cream 1% and clinical efficacy in tinea pedis.

Studies were conducted to assess the bioequivalence of a new antimycotic formulation, ciclopirox olamine lotion 1%, to an established compound, ciclopirox olamine cream 1%. Results of in vitro studies, using skin samples from human cadavers and domestic pigs, demonstrated that the two formulations equally penetrate all layers of the stratum corneum and inhibit the growth of Trichophyton mentagrophytes and Candida albicans. In vivo studies in guinea pigs and in human volunteers demonstrated the comparable therapeutic efficacy of the lotion and the cream in experimental trichophytosis. In addition, a multicenter, double-blind clinical trial was undertaken to compare ciclopirox olamine lotion 1% with the vehicle alone in the treatment of patients with tinea pedis. Patients with plantar, interdigital, or vesicular tinea pedis were enrolled in the studies. Patients were treated for 28 days. Clinical and mycological responses were determined during treatment and two weeks posttreatment. Ciclopirox olamine lotion 1% was found to be significantly more effective than its vehicle in the treatment of patients with common tinea pedis. Minor localized side effects (pruritus, burning sensation) were reported in 2% of 89 patients treated with ciclopirox olamine lotion 1%. The results demonstrate the bioequivalence of ciclopirox olamine lotion 1% and ciclopirox olamine cream 1% and confirm the clinical effectiveness and safety of the lotion in the treatment of tinea pedis, a generally recalcitrant fungal infection. It is concluded that ciclopirox olamine lotion 1% can be used as an alternative to ciclopirox olamine cream 1% for treatment of tinea pedis, tinea versicolor, tinea cruris, tinea corporis, and cutaneous candidiasis when the convenience and/or cosmetic elegance of a lotion is desired.