The phagocytic activity of the neutrophilic granulocytes in patients with chronic candidiasis of the skin and mucous membranes]

24 patients with chronic candidiasis of the skin and mucous membranes have been examined. The following parameters have been evaluated: (1) ingestive capacity, (2) fungicidal capacity, (3) the state of the myeloperoxidase mechanism of respiratory explosion. In chronic candidiasis of the skin and mucous membranes the ingestive capacity of neutrophil granulocytes has been found to remain unchanged, constituting 70 +/- 3.5% in healthy persons and 60 +/- 4.2% in patients 60 minutes after interaction. The study has revealed the decrease of fungicidal activity in 50% of the patients which is probably linked with the constant activation of oxygen-dependent killing mechanisms (the index of the spontaneous nitro blue tetrazolium test has proved to be 8.9 +/- 0.8% in healthy persons and 15 +/- 3.4% in patients with candidiasis of the skin and mucous membranes) and the decreased reserve of the functional activity of neutrophil granulocytes. The activity of myeloperoxidase in patients with candidiasis of the skin and mucous membranes has been found to remain unchanged.     

Are Echinocandins Better Than Azoles for Invasive Candidiasis?

Antifungal therapy has advanced tremendously in the past decade, with multiple new agents for systemic fungal infections that have a broad spectrum of activity and are well-tolerated. There is usually more than one acceptable therapeutic option for many diseases, and this is true in particular of candidiasis. Fluconazole has been the drug of choice for most clinical syndromes of candidiasis, due to its tolerability, effectiveness, and ease of administration. However, the echinocandin class of antifungals, comprised of caspofungin, micafungin and anidulafingin, has emerged as the preferred choice in the therapy of invasive candidiasis and candidemia. Their potent fungicidal activity and minimal toxicity have made them first-line drugs for this indication. In certain clinical settings, they may even be agents of first choice. Nevertheless, recent trends in echinocandin resistance demonstrated with Candida glabrata mandate ongoing surveillance, and continued trends may impact upon future antifungal selection.     

Synthesis and antifungal activities of novel 1,3-beta-D-glucan synthase inhibitors. Part 1

Highly potent 1,3-beta-D-glucan synthase inhibitors 10, 11 and 13 have been identified by the chemical modification of the fungicidal macrocyclic lipopeptidolactone, RO-09-3655 (1), isolated from the cultured broth of Deuteromycotinia spp. D-Ornithine derivative (10) showed improved antifungal activity in the systemic candidiasis model in mice and reduced hepatotoxicity in vitro, as compared with 1.     

The role of anidulafungin therapy in solid organ transplant recipients

Anidulafungin is a new echinocandin recently approved for the treatment of esophageal candidiasis, candidemia and other forms of invasive candidiasis, such as peritonitis and intra-abdominal abscesses in non-neutropenic patients. It is fungicidal against Candida spp. and fungistatic against Aspergillus spp. It is active against Pneumocystis jirovecii. In contrast, anidulafungin does not have activity against Cryptococcus neoformans, Zygomycetes or molds, other than Aspergillus spp. The drug is well tolerated, even in patients with renal or hepatic impairment. In contrast to other echinocandins, it does not significantly interfere with the cytochrome P450 pathway and has a low drug-drug interaction profile, including calcineurinic agents and other drugs used in transplant recipients. So far, anidulafungin appears to have an excellent safety profile with few adverse events and it promises a special consideration in the management of fungal infections happening in transplant recipients.     

Inhibition of natural killer activity in emotional stress and elimination of this phenomenon by interferon inducer

The authors provide the data on the effect of emotional painful stress (EPS) of varying duration on the activity of natural killers (NK) of August rats' spleen 1 to 9 days after exposure to stress is discontinued. The activity of NK was tested against target cells K 562 labeled with 51Cr in a 14-hour test. The effect of stress was found to depend on the duration of the stressor reaction. 1 1/2- and 3-hour stress activated NK, while prolonged 6-hour stress suppressed the activity of natural killers within the first 2 days, followed by the recovery by day 7-9 of the activity of lymphocytes having natural cytotoxicity. Tiloron, a synthetic inducer of endogenous interferon, corrected the post-stressor depression of NK activity.     

Synthesis and antifungal activities of novel 1,3-beta-D-glucan synthase inhibitors. Part 2

Highly potent 1,3-beta-D-glucan synthase inhibitors, 7b, 10a, 10b and 12, have been identified by the chemical modification of the ornithine residue of a fungicidal macrocyclic lipopeptidolactone, RO-09-3655 (1), isolated from the cultured broth of Deuteromycotinia spp. These compounds showed stronger antifungal activity against systemic candidiasis as well as pulmonary aspergillosis in mice, and less hepatotoxicity as compared with 1.     

Quantitative characteristics of nitroblue tetrazolium reduction by the neutrophils in experimental systemic candidiasis

The quantitative study of the reduction capacity of neutrophils with respect to nitro blue tetrazolium in experimental systemic candidiasis has revealed an increase in this capacity within 20 days of the infection. The reduction capacity has been found to depend not only on the degree of the contamination of the body with Candida cells, but also on the stage of the inflammatory process.     

Prevention of the stress-induced decrease in natural killer activity by using a beta-adrenergic blocker and vitamin E

The data are provided on the efficacy of the use of the beta-adrenoblocker inderal and the natural antioxidant vitamin E as agents that prevent the immobilization stress-induced depression of the activity of natural killers. The problems of the prevention of the action of excess catecholamines and activation of lipid peroxidation as pathogenetic component in the development of stressor depression of the activity of natural killers are discussed.     

Lymphocyte-mediated modulation of the functional activity of macrophages by individual antigenic complexes of Trichophyton cells

The capacity of antigenic complexes of the causative agent of zoo- and anthroponotic trichophytosis for inducing the factors, that modify the functional activity of macrophages, in mice and in spleen cell cultures has been studied. These complexes are capable of inducing the T-lymphocyte-mediated suppression and of stimulating the fungicidal activity (and oxygen-dependent metabolism) of phagocytes. The production of fungicidal activity suppressing lymphokines is linked with the presence of alkali-insoluble components of fungal cell walls and cytoplasmic antigens (the latter appear only in interactions of antigens with the lymphocytes of immunized animals) in the above-mentioned complexes.     

Anidulafungin: experimental therapy of fungal infections in animal models

We have reviewed the existing data on the efficacy of anidulafungin, which is the most recent echinocandin in the experimental treatment of fungal infections. The scarce published data practically only refers to disseminated and pulmonary aspergillosis and to disseminated candidiasis. Anidulafungin shows fungistatic activity against Aspergillus fumigatus, and fungicidal activity against Candida albicans and Candida glabrata.     

Increase in NK-activity using superlow doses of the immunomodulator cycloferon

A possibility of rising the antitumor activity of natural killers using various doses of the immunomodulator cycloferon was evaluated. A direct correlation has been revealed between the killer activity and the cycloferon dose. However, on a decrease in cycloferon concentrations by several orders, as compared with commonly accepted doses, this correlation changed for inverse. A possible mechanism of this effect is discussed in addition to practical significance of the obtained results.     

Activity of human natural killer cells against target cells possessing different sensitivity to interferon]

The cytotoxic activity of peripheral blood natural killers (NK) against target cells (TC) J-96 and L-929 with high sensitivity to interferon (IFN) action, J-41 and MCB resistant to IFN action and line K-562 labelled by H3-uridine was studied in 14 hrs cytotoxic test. It has been shown that human TC J-96 didn't differ from the J-41 in their sensitivity to NK cytotoxicity and they are strongly resistant to NK than TC K-562. The murine TC L-929 as the human TC didn't differ from the MCB in their sensitivity to NK lysis and had also the same sensitivity to NK as the K-562 cells.     

Peptides of the constant region of antibodies display fungicidal activity

Synthetic peptides with sequences identical to fragments of the constant region of different classes (IgG, IgM, IgA) of antibodies (Fc-peptides) exerted a fungicidal activity in vitro against pathogenic yeasts, such as Candida albicans, Candida glabrata, Cryptococcus neoformans, and Malassezia furfur, including caspofungin and triazole resistant strains. Alanine-substituted derivatives of fungicidal Fc-peptides, tested to evaluate the critical role of each residue, displayed unaltered, increased or decreased candidacidal activity in vitro. An Fc-peptide, included in all human IgGs, displayed a therapeutic effect against experimental mucosal and systemic candidiasis in mouse models. It is intriguing to hypothesize that some Fc-peptides may influence the antifungal immune response and constitute the basis for devising new antifungal agents.     

Delayed hypersensitivity and nonspecific cellular immunity. The cytotoxic activity of macrophages, natural and antibody-dependent killer cells

The experiment on (BALB/cXC57BL)F1 mice, showing a high level of delayed hypersensitivity (DH) when sensitized with BCG vaccine and Staphylococcus aureus strain B-243, has demonstrated the influence of such sensitization and DH reaction induced by the injection of a specific antigen (old tuberculin or staphylococcal phagolysate) into the sensitized animals on the cytotoxicity of macrophages, natural killers (NK) and antibody-dependent killers (ADK). Sensitization with BCG vaccine alone results in an insignificant rise in the activity of these effector cells, and sensitization with S. aureus produces no changes at all. The pronounced activation of the cytotoxicity of macrophages, NK and, to a lesser extent, ADK has been observed in DH reaction induced by the injection of a specific antigen into the sensitized mice. In the course of DH reaction a rise in the activity of NK and ADK not only against tumor target cells, but also against microbial ones (Candida albicans and S. aureus) has been found to occur.     

The synthesis and activity evaluation of N‐acylated analogs of echinocandin B with improved solubility and lower toxicity

Presently, echinocandins have been recommended as the first‐line drugs for the treatment of invasive candidiasis. However, low oral bioavailability and solubility limit their application. To improve this situation, this study chose amino acid and fatty acid as raw materials to modify the nucleus of echinocandin B. Six N‐acylated analogs were screened from the derivatives that possessed potent antifungal activity and good water solubility. Based on antifungal susceptibility and hemolytic toxicity, compound 5 as the candidate had good antifungal activity and no hemolytic effect. Moreover, compared with anidulafungin, compound 5 showed a comparable fungicidal effect, much higher solubility, and lower toxicity. In conclusion, compound 5 has the potential for further research and development on account of reserved antifungal activity, high solubility, and low toxicity.     

Candicidal action of resveratrol isolated from grapes on human pathogenic yeast C. albicans

Resveratrol (3,5,4'-trihydroxystilbene) is a naturally occurring, multi-biofunctional chemical existing in grapes and various other plants as a polyphenol type, and it is one of the best known natural anticancer and antiatherosclerosis reagents. In this study, we investigated the antifungal action by resveratrol in Candida albicans, which is a human infectious fungi as an agent of candidiasis. Resveratrol displayed potent fungicidal activity in an energy-dependent manner, without any hemolytic effects against human erythrocytes. It was found that the serum-induced mycelial forms, which play a crucial role in the pathogenesis of C. albicans during host tissue invasion, were disrupted by resveratrol. To understand the correlation between lethal effects and resveratrol action, we examined the physiological changes of C. albicans. A significant accumulation of intracellular trehalose was induced by stress responses to resveratrol action, and a remarkable arrest of cell-cycle processes at the S-phase in C. albicans occured. Therefore, the fungicidal effects of resveratrol demonstrate that this compound is a potential candidate as an antifungal agent in treating infectious diseases by candidal infections.     

The effect of electromagnetic radiation with extremely high frequency and low intensity on cytotoxic activity of human natural killer cells]

EHF electromagnetic radiation under short-time action suppresses the cytotoxical activity of the natural killer cells from granulocyte fraction and peripheral blood of healthy volunteers; the observed effect is non-linear. Under the long-time irradiation of the natural killer cells from the mononuclear fraction of blood, the suppressing effect gets a practically linear character after the 20-30 minutes action. Under the long-time irradiation of peripheral blood the insignificant stimulation of natural killers was observed. It is assumed that the radiation applied can suppress the cytotoxic activity of the natural killers, breaking the normal metabolic pathway of phosphatidylinositphosphate.     

Effect of Streptococcus salivarius K12 on the in vitro growth of Candida albicans and its protective effect in an oral candidiasis model

Oral candidiasis is often accompanied by severe inflammation, resulting in a decline in the quality of life of immunosuppressed individuals and elderly people. To develop a new oral therapeutic option for candidiasis, a nonpathogenic commensal oral probiotic microorganism, Streptococcus salivarius K12, was evaluated for its ability to modulate Candida albicans growth in vitro, and its therapeutic activity in an experimental oral candidiasis model was tested. In vitro inhibition of mycelial growth of C. albicans was determined by plate assay and fluorescence microscopy. Addition of S. salivarius K12 to modified RPMI 1640 culture medium inhibited the adherence of C. albicans to the plastic petri dish in a dose-dependent manner. Preculture of S. salivarius K12 potentiated its inhibitory activity for adherence of C. albicans. Interestingly, S. salivarius K12 was not directly fungicidal but appeared to inhibit Candida adhesion to the substratum by preferentially binding to hyphae rather than yeast. To determine the potentially anti-infective attributes of S. salivarius K12 in oral candidiasis, the probiotic was administered to mice with orally induced candidiasis. Oral treatment with S. salivarius K12 significantly protected the mice from severe candidiasis. These findings suggest that S. salivarius K12 may inhibit the process of invasion of C. albicans into mucous surfaces or its adhesion to denture acrylic resins by mechanisms not associated with the antimicrobial activity of the bacteriocin. S. salivarius K12 may be useful as a probiotic as a protective tool for oral care, especially with regard to candidiasis.     

Natural killers and interleukin-2 in mice of the strain MRL/MpJ-lpr/lpr

The functional activity of natural killers (NK) in the spleen and lymph nodes and interleukin-2 (IL-2) production have been studied in MPL-MpJ-lpr/lpr (H-2k) mice with genetically predetermined autoimmune diseases and CBA (H-2k) mice. In MPL/l mice it has been shown that NK activity in the spleen was markedly depressed already in the first month of life, whereas in lymph nodes there is a substantial NK activity on days 7-10, which reaches its maximum by the second month and by the 6th months is practically intractable. IL-2 production in MPL/l mice was depressed at all stages of investigation.     

INVESTIGATIONS ON FUNGICIDES. I. FUNGICIDAL AND SYSTEMIC FUNGICIDAL ACTIVITY IN CERTAIN ARYLOXYALKANECARBOXYLIC ACIDS

Fifty-four aryloxyalkanecarboxylic acids have been examined as systemic fungicides. Of these, four which produced negligible damage in broad-bean seedlings yet conferred systemic fungicidal protection to broad beans against Botrytis fabae and to tomatoes against Alternaria solanixvere studied in detail. The direct fungicidal activity of twenty compounds was assessed against B. fabae and Pythium ultimum. No correlation between fungicidal and systemic fungicidal action toward B. fabae was established. Other possibilities regarding their mode of action as systemic fungicides are discussed. The systemic fungicidal activity of a-phenoxyziobutyric and 2:4:6-trichlorophenoxyacetic acids in beans and of the latter compound in tomato plants was found to depend upon seasonal factors, but for 3-phenoxybutyric and 5-phenoxycaproic acids such variation was not observed. Results obtained in the bean test by two methods of assessment were found to correlate. The potato petiole test (van Raalte) for assessing systemic fungicidal activity was studied and modified. Evidence was obtained that the results might be unreliable owing to toxic effects produced by the compounds on the petiole tissue. Attempts were made to avoid this complication, but when phytotoxicity was eliminated, little fungicidal activity was shown.