Acute cocoa flavanols intake improves cerebral hemodynamics while maintaining brain activity and cognitive performance in moderate hypoxia.

INTRODUCTION: Acute cocoa flavanols (CF) intake has been suggested to modulate cognitive function and neurovascular coupling (NVC). Whether increased NVC is solely driven by improved vascular responsiveness or also by neuronal activity remains unknown. This study investigated the effects of acute CF intake on cognitive performance, NVC, and neuronal activity in healthy subjects in normoxia and hypoxia (4000 m simulated altitude; 12.7% O2). METHODS: Twenty healthy subjects (age 23.2 ± 4.3 years) performed four trials. Participants performed a Stroop task and "cognition" battery 2 h after acute CF (530 mg CF, 100 mg epicatechin) or placebo intake, and 30 min after initial exposure to hypoxia or normoxia. Electroencephalogram and functional near-infrared spectroscopy were used to analyze hemodynamic changes and neuronal activity. RESULTS: CF enhanced NVC in the right prefrontal cortex during several tasks (risk decision making, visual tracking, complex scanning, spatial orientation), while neuronal activity was not affected. CF improved abstract thinking in normoxia, but not in hypoxia and did not improve other cognitive performances. Hypoxia decreased accuracy on the Stroop task, but performance on other cognitive tasks was preserved. NVC and neuronal activity during cognitive tasks were similar in hypoxia vs. normoxia, with the exception of increased ß activity in the primary motor cortex during abstract thinking. CONCLUSIONS: Acute CF intake improved NVC, but did not affect neuronal activity and cognitive performance in both normoxia and hypoxia. Most cognitive functions, as well as NVC and neuronal activity, did not decline by acute exposure to moderate hypoxia in healthy subjects.

Electro-physiological changes in the brain induced by caffeine or glucose nasal spray.

OBJECTIVE: A direct link between the mouth cavity and the brain for glucose (GLUC) and caffeine (CAF) has been established. The aim of this study is to determine whether a direct link for both substrates also exist between the nasal cavity and the brain. METHODS: Ten healthy male subjects (age 22 ± 1 years) performed three experimental trials, separated by at least 2 days. Each trial included a 20-s nasal spray (NAS) period in which solutions placebo (PLAC), GLUC, or CAF were provided in a double-blind, randomized order. During each trial, four cognitive Stroop tasks were performed: two familiarization trials and one pre- and one post-NAS trial. Reaction times and accuracy for different stimuli (neutral, NEUTR; congruent, CON; incongruent INCON) were determined. Electroencephalography was continuously measured throughout the trials. During the Stroop tasks pre- and post-NAS, the P300 was assessed and during NAS, source localization was performed using standardized low-resolution brain electromagnetic tomography (sLORETA). RESULTS AND DISCUSSION: NAS activated the anterior cingulate cortex (ACC). CAF-NAS also increased θ and ß activity in frontal cortices. Furthermore, GLUC-NAS increased the ß activity within the insula. GLUC-NAS also increased the P300 amplitude with INCON (P = 0.046) and reduced P300 amplitude at F3-F4 and P300 latency at CP1-CP2-Cz with NEUTR (P = 0.001 and P = 0.016, respectively). The existence of nasal bitter and sweet taste receptors possibly induce these brain responses. CONCLUSION: Greater cognitive efficiency was observed with GLUC-NAS. CAF-NAS activated cingulate, insular, and sensorymotor cortices, whereas GLUC-NAS activated sensory, cingulate, and insular cortices. However, no effect on the Stroop task was found.

Itraconazole versus griseofulvin in the treatment of tinea capitis: a double-blind randomized study in children.

BACKGROUND: Tinea capitis is a fungal infection in which topical therapy is often unsuccessful. Griseofulvin has been considered to be a first-line therapy. Other antifungal agents are the azole derivatives. Among these, itraconazole was compared with griseofulvin in children in a double-blind study. PATIENTS AND METHODS: Thirty-four children and one adult with clinical signs and symptoms of tinea capitis and with positive culture and microscopy for dermatophytes have been included in a double-blind comparison between itraconazole, 100 mg daily, and ultramicronized griseofulvin, 500 mg daily. Both drugs were given for 6 consecutive weeks. The final evaluation was made 8 weeks after the end of treatment to allow the hairs to regrow. Seventeen itraconazole- and 15 griseofulvin-treated patients received the complete 6-week treatment course. Fifteen of these 17 itraconazole patients and 14 of the 15 griseofulvin patients had infections caused by Microsporum canis. Fifteen of 17 patients were cured by itraconazole (88%) and 15 of 17 patients by griseofulvin (88%). One of the patients who discontinued griseofulvin therapy after 4 weeks was clinically and mycologically cured. Two of the original 17 griseofulvin patients discontinued therapy because of vomiting. None of the itraconazole-treated children experienced side effects. CONCLUSIONS: Itraconazole is the first azole derivate that matches griseofulvin for the treatment of tinea capitis in children. The drug also appears to be better tolerated than griseofulvin.

Prophylaxis of Candida and Aspergillus infections with oral administration of itraconazole.

The broad-spectrum oral triazole antifungal, itraconazole, has been shown to be effective in the treatment of superficial and systemic infections with fungi including Candida albicans, C. krusei and C. glabrata, Cryptococcus, Aspergillus, Histoplasma, Blastomyces and others. Its broad spectrum of activity, high and persistent tissue levels and favourable safety profile suggest that it may be appropriate for the prevention of opportunistic fungal infections in at-risk patients. In this study, itraconazole's prophylactic efficacy was tested against experimental models of Candida and Aspergillus infection. A single dose of 1.25 mg kg-1 or 2.5 mg kg-1, given 1 h before vaginal infection with C. albicans, protected 50% of treated rats. In systemic and disseminated candidosis, prophylaxis with itraconazole reduced both folliculitis and organ Candida content in guinea pigs. Amphotericin B was also used in this study and was found to be less efficacious than itraconazole. Itraconazole prolonged survival when administered to guinea pigs before experimental induction of systemic and invasive aspergillosis. In all cases, increasing the itraconazole dosage increased its prophylactic efficacy. Therefore, as the clinical efficacy of itraconazole is accurately reflected by the results of animal models, this study shows itraconazole to be a potential prophylactic therapy for patients at risk of opportunistic fungal infection.

Experimental aspergillosis in guinea pigs: influence of itraconazole on fungaemia and invasive fungal growth.

The guinea pig model of experimental aspergillosis was used to evaluate the efficacy of itraconazole 2.5 and 5 mg kg-1 in preventing the invasive phase of the disease when animals were already loaded with Aspergillus conidia. Evaluations were made by recording the survival rates, culturing fragments of nine organs, examining seven organs by means of histochemistry and immunohistochemistry (mAb EB-A1 to Aspergillus galactomannan) and by serological titration of galactomannan. The data indicate that itraconazole is highly effective in preventing true invasive aspergillosis. Serological evaluations of antigenaemia suggest that low titres may only reflect fungaemia, while titres of 1:8 and above are suggestive of invasive disease.

Deferoxamine augments growth and pathogenicity of Rhizopus, while hydroxypyridinone chelators have no effect.

Deferoxamine (DFO), when used in dialysis patients, is a well recognized risk factor for the development of mucormycosis caused by Rhizopus. This study compares, both in vivo and in vitro, the effects produced on Rhizopus by DFO and by two chelators of the hydroxypyridinone class, L1 and CP94. Experimental systemic mucormycosis was induced in the guinea pig by an i.v. injection of two different strains of Rhizopus: R. microsporus and R. arrhizus. Concomitant i.p. administration of DFO for four days shortened animal survival (P < 0.05), whereas concomitant administration of either L1 or CP94 did not. In vitro radioiron uptake by R. microsporus was 100-fold higher from the 55ferric complex of DFO than of L1 or CP94. In vitro fungal growth was stimulated sevenfold by the ferric complex of DFO (P < 0.0001) but not significantly by the ferric complex of either L1 or CP94. These results indicate that the ferric complex of DFO but not that of L1 or CP94 specifically stimulates both the iron uptake and the growth of Rhizopus. They suggest that the risk of developing mucormycosis should be minimal with L1 or CP94, as opposed to DFO.

Therapy of experimental meningeal and disseminated cryptococcosis.

This study evaluated the efficacy of itraconazole, a broad-spectrum triazole antifungal drug, which has previously been demonstrated to exhibit activity against Candida albicans C. krusei, C. glabrata, Aspergillus, Histoplasma and Blastomyces as a potential treatment for cryptococcosis. The susceptibility of 62 strains of Cryptococcus neoformans was tested in vitro. All strains were inhibited by itraconazole 0.1 microgram ml-1. Itraconazole was fungicidal after replenishment at a concentration that can easily be achieved in vivo. When mice were infected intracerebrally with Cr. neoformans all control animals died, whereas only 11% and 26% of itraconazole-treated animals died. In a group treated with ketoconazole, 67% died. After intravenous infection, 30% of control guinea pigs died, while other animals treated with itraconazole (5 or 10 mg kg-1) or amphotericin B (1.25 or 2.5 mg kg-1) all survived. Itraconazole 10 mg kg-1 produced the best results, with brain and meningeal cultures becoming negative in 55-64% of animals. In addition, intravenously infected guinea pigs received oral or intraperitoneal treatment with itraconazole or fluconazole (each 5 or 10 mg kg-1) as monotherapy or in combination. Although both treatments were active, itraconazole 10 mg kg-1 was the most effective. In two out of six immunosuppressed guinea pigs infected with Cr. neoformans oral itraconazole was effective, resulting in negative brain and meningeal cultures. A combination of itraconazole (5 mg kg-1) with flucytosine or amphotericin B was more efficacious than monotherapy. Therefore, itraconazole is a potentially effective therapy for the treatment of Cryptococcus infection when administered either alone or in combination with other antifungal drugs. It may also be effective in immunocompromised patients.

[A severe Aspergillus flavus infection in slaughtering chicks and the effect of disinfection with enilconazole: a case study]. / Een ernstige Aspergillus flavus-infectie bij slachtkuikens en het effect van desinfectie met enilconazole: een case study.

In a flock of chicks, the number of birds dying per day from infection with especially Aspergillus flavus increased up to 1% during the second half of the fattening period. Levels of Aspergillus flavus were measured before and after cleaning of the chicken house with the anti-mycotic agent eniconazole (Clinafarm, Janssen Pharmaceutical Company, BV). The cleaning and disinfection schedule followed reduced levels if Aspergillus flavus to zero.

Mucormycosis during deferoxamine therapy is a siderophore-mediated infection. In vitro and in vivo animal studies.

This study investigates the pathophysiology of mucormycosis caused by Rhizopus, which has been reported in 46 dialysis patients, while treated with deferoxamine (DFO). This drug aggravates mucormycosis, which we experimentally induced in guinea pigs and which lead to a shortened animal survival (P < or = 0.01). The drug's effect on Rhizopus is not mediated through the polymorphonuclear cells. Fe.DFO, the iron chelate of DFO, abolishes the fungistatic effect of serum on Rhizopus and increases the in vitro growth of the fungus (P < or = 0.0001). This effect is present at Fe.DFO concentrations > or = 0.01 microM, at which fungal uptake of radioiron from 55Fe.DFO is observed. A 1,000-fold higher concentration of iron citrate is required to achieve a similar rate of radioiron uptake and of in vitro growth stimulation as observed with Fe.DFO. These in vitro effects of Fe.DFO (1 microM) in serum on radioiron uptake and on growth stimulation are more striking for Rhizopus than for Aspergillus fumigatus and are practically absent for Candida albicans. For these three fungal species, the rates of radioiron uptake from 55Fe.DFO and of growth stimulation in the presence of Fe.DFO in serum are directly related (r = 0.886). These results underscore the major role of Fe.DFO in the pathogenesis of DFO-related mucormycosis. Pharmacokinetic changes in uremia lead to a prolonged accumulation of Fe.DFO after DFO administration, which helps explain the increased sensitivity of dialysis patients to DFO-related mucormycosis.

Oral itraconazole versus topical bifonazole treatment in experimental dermatophytosis.

Guinea pigs, infected with either Trichophyton mentagrophytes or Microsporum canis, were treated orally or topically with azole antifungals daily for two weeks. Fungi located in the stratum corneum were affected similarly by both treatment schedules, showing typical cell wall changes after azole exposure and necrosis of internal organelles. Fungi located in the hair sheaths were affected only by the oral treatment, which not only prevented invasion of the inner hair structures and inflammatory responses but also led to a complete clearance of the infection within 7 days. Topically applied azole treatment was not able to injure fungi in the hair sheaths and did not suppress invasion into the hair shafts. These observations are in favour of oral antifungal medication with azoles for the treatment of dermatophyte infections involving hairy skin.

Itraconazole in the treatment of chromoblastomycosis due to Fonsecaea pedrosoi.

The efficacy and tolerability of itraconazole in chromoblastomycosis due to Fonsecaea pedrosoi were evaluated in a non-comparative open clinical trial in 19 Brazilian patients with histopathologically and mycologically proven active chromoblastomycosis. Patients were classified in terms of severity and received itraconazole at the dosage of 200 to 400 mg per day until previously described criteria of cure have been reached. Clinical, mycologic, histopathologic, and laboratory evaluations were performed before, during, and after therapy. The plasma levels of itraconazole and the in vitro susceptibility of the isolates were determined in 15 cases. Clinical and biologic cure were achieved by eight patients (42%) having mild to moderate disease, after a mean duration of therapy of 7.2 months (3.2-29.6 months). Sterile scarred lesions were observed in a post-therapy follow-up lasting on average 9.6 months that was carried out in this subgroup. Clinical cure alone occurred after a mean period of 25.1 months of treatment (16-30.5 months) in seven patients (36%) with moderate to severe disease. Finally, clinical improvement was obtained in four patients (21%) with severe lesions after a mean treatment time of 17.6 months (10.7-22.5 months). All patients responded favorably to itraconazole therapy. No significant side effects nor biochemical alteration during this trial were important enough to interrupt the treatment. Our results support those of previous trials, suggesting that itraconazole is an effective compound against chromoblastomycosis due to Fonsecaea pedrosoi.

Immunohistochemical identification of Penicillium marneffei by monoclonal antibody.

We present an experimental study on the immunohistochemical identification of Penicillium marneffei in paraffin-embedded, formalin-fixed tissue. The monoclonal antibody EB-A1 detects a specific galactomannan that appears to have at least one epitope identical in P. marneffei and Aspergillus sp. This immunohistochemical approach could be useful in the diagnosis of a rare diseae, penicilliosis marneffei, which proves to be difficult to identify by conventional microscopy.

Posttreatment itraconazole levels in the nail. New implications for treatment in onychomycosis.

BACKGROUND: A problem in the treatment of onychomycosis is the lengthy duration of therapy. The pharmacokinetics of itraconazole suggest a potential for briefer treatment. OBJECTIVE: This study was designed to investigate itraconazole nail kinetics in 39 patients with onychomycosis in relation to their therapeutic outcome. METHODS: All patients received itraconazole for 3 months at a dose of 100 or 200 mg daily. Itraconazole levels of distal nail clippings were determined during a 6-month posttherapy period. RESULTS: Therapeutic itraconazole concentrations were found in the nail plates of fingernails and toenails for up to 6 months after treatment. Cure of the toenails was observed in 79% of the patients treated with the 200 mg dosage and in 26% of those treated with 100 mg at 6 months after therapy. CONCLUSION: The data suggest that the drug reaches the nail via incorporation into the matrix and by diffusion from the nail bed and is eliminated with regrowth of the nail after discontinuation of treatment.

In vitro antifungal spectrum of itraconazole and treatment of systemic mycoses with old and new antimycotic agents.

Itraconazole is a lipophilic triazole with potent in vitro activity. It is also effective after topical, oral and parenteral administration. The antifungal activity of itraconazole has been evaluated against more than 6,500 different strains, belonging to more than 260 fungal species, using the serial decimal dilution test in fluid broth medium (brain-heart infusion broth). Candida spp., Torulopsis spp., Cryptococcus neoformans, Pityrosporum spp. (Dixon broth), various other yeasts, dermatophytes, Aspergillus spp., Penicillium spp., Sporothrix schenckii, dimorphic fungi (mycelium phase and yeast phase), Phaeohyphomycetes, Entomophthorales and various Hyalohyphomycetes are sensitive. Most strains of Fusarium and Zygomycetes are poorly sensitive. Itraconazole was administered orally and parenterally in normal and immunocompromised guinea-pigs infected with C. albicans, Cr. neoformans, Histoplasma duboisii, S. schenckii, P. marneffei and A. fumigatus. It was effective in terms of both survival of the animals and elimination of the fungi from the various tissues. Itraconazole was superior to fluconazole in candidosis, cryptococcosis, sporotrichosis and aspergillosis, and to amphotericin B and to flucytosine in candidosis, cryptococcosis and aspergillosis. No comparative studies have yet been undertaken for other deep mycoses. The results of combination therapy with itraconazole and fluconazole in cryptococcosis were indifferent; with flucytosine or amphotericin B, additive or synergistic effects were seen in systemic candidosis, cryptococcosis and aspergillosis. No drug-related side-effects were observed after oral or parenteral administration of itraconazole.

[In-vitro and in-vivo activity of itraconazole]. / In-vitro- und In-vivo-Aktivität von Itraconazol.

Itraconazole is a lipophilic triazole with potent in vitro activity. It is also highly efficacious after topical, oral and parenteral administration. The antifungal activity of itraconazole has been evaluated against more than 6500 different strains, belonging to more than 260 fungal species using the serial decimal dilution test in fluid media (BHI broth). Candida, Torulopsis, Cryptococcus, Pityrosporum (Dixon broth), various other yeasts, dermatophytes, Aspergillus, Penicillium, Sporothrix, dimorphic fungi (MP and YP), Phaeohyphomycetes, Entomophthorales and various Hyalohyphomycetes are sensitive. Most strains of Fusarium and Zygomycetes are poorly sensitive. Itraconazole was administered orally and parenterally in normal and in immunocompromised guinea-pigs, infected with C. albicans, Cr. neoformans, H. duboisii, Sp. schenckii, P. marneffei and A. fumigatus. It was efficacious both in survival of the animals and in eliminating the fungi from the various tissues. Itraconazole was superior to fluconazole in candidosis, cryptococcosis, sporotrichosis and aspergillosis, to amphotericin B and to flucytosine in candidosis, cryptococcosis and aspergillosis. No comparative studies were done up to now for the other deep mycoses. The results of combination therapy of itraconazole with fluconazole in cryptococcosis were indifferent, with 5-flucytosine or amphotericin B, additive or synergistic in systemic candidosis, cryptococcosis and aspergillosis. No drug-related side-effects were observed after oral or parenteral administration of itraconazole.

Ketoconazole 2% emulsion in the treatment of seborrheic dermatitis.

Fifty patients (42 men, 8 women) with seborrheic dermatitis were included in the trial. Ketoconazole 2% emulsion or the same emulsion without active drug was applied b.i.d. for 4 weeks. Two patients dropped out in the ketoconazole group and nine in the placebo group. Pityrosporum ovale was cultured from all patients at the start and from six out of 23 in the ketoconazole group versus nine out of 16 in the placebo group at week 4. The overall assessment showed a significantly better response to treatment for the ketoconazole emulsion (72%) than for the placebo (32%).