Pomegranate extract affects fungal biofilm production: consumption of phenolic compounds and alteration of fungal autoinducers release

Candida albicans expresses numerous virulence factors that contribute to pathogenesis, including its dimorphic transition and even biofilm formation, through the release of specific quorum sensing molecules, such as the autoinducers (AI) tyrosol and farnesol. In particular, once organized as biofilm, Candida cells can elude conventional antifungal therapies and the host’s immune defenses as well. Accordingly, biofilm-associated infections become a major clinical challenge underlining the need of innovative antimicrobial approaches. The aim of this in vitro study was to assess the effects of pomegranate peel extract (PomeGr) on C. albicans growth and biofilm formation; in addition, the release of tyrosol and farnesol was investigated. The phenolic profile of PomeGr was assessed by high-performance liquid chromatography coupled to electrospray ionization mass spectrometry (HPLC-ESI-MS) analysis before and after exposure to C. albicans. Here, we showed that fungal growth, biofilm formation and AI release were altered by PomeGr treatment. Moreover, the phenolic content of PomeGr was substantially hampered upon exposure to fungal cells; particularly pedunculagin, punicalin, punicalagin, granatin, di-(HHDP-galloyl-hexoside)-pentoside and their isomers as well as ellagic acid–hexoside appeared highly consumed, suggesting their role as bioactive molecules against Candida. Overall, these new insights on the anti-Candida properties of PomeGr and its potential mechanisms of action may represent a relevant step in the design of novel therapeutic approaches against fungal infections

Effects of benzydamine and mouthwashes containing benzydamine on Candida albicans adhesion, biofilm formation, regrowth, and persistence

Objectives To assess the effects of benzydamine and mouthwashes (MoWs) containing benzydamine on different stages of Candida albicans biofilm: adhesion, formation, persistence, and regrowth (if perturbed). Materialsandmethods C.albicansCA1398,carryingthebioluminescenceACT1p-gLUC59fusionproduct,wasemployed. Fungal cells were exposed for 1\u2032, 5\u2032, or 15\u2032 to 4 different benzydamine concentrations (0.075 to 0.6%) to 2 mouthwashes (MoWs) containing benzydamine and to a placebo MoW (without benzydamine). Treated cells were tested for adhesion (90 min) and biofilm formation (24-h assay). Next, 24- and 48-h-old biofilms were exposed to benzydamine and MoWs to assess regrowth and persistence, respectively. The effects of benzydamine, MoWs containing benzydamine, and placebo on different biofilm stages were quantified by bioluminescence assay and by the production of quorum sensing (QS) molecules. Results Benzydamine and MoWs containing benzydamine impaired C. albicans ability to adhere and form biofilm, counter- acted C. albicans persistence and regrowth, and impaired a 48-h-old biofilm. Some of these effects paralleled with alterations in QS molecule secretion. Conclusions Our results show for the first time that benzydamine and MoWs containing benzydamine impair C. albicans capacity to form biofilm and counteract biofilm persistence and regrowth. Clinical relevance Benzydamine and MoWs containing benzydamine capacity to affect C. albicans biofilm provides an interesting tool to prevent and treat oral candidiasis. Likely, restraining C. albicans colonization through daily oral hygiene may counteract colonization and persistence by other critical oral pathogens, such as Streptococcus mutans, whose increased virulence has been linked to the presence of C. albicans biofilm

A family outbreak of tinea capitis due to Trichophyton violaceum in Michigan. Its control with griseofulvin

An outbreak of tinea capitis caused by Trichophyton violaceum in five siblings of a family of eight in Michigan and its control with griseofulvin are described.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43276/1/11046_2005_Article_BF02145740.pd

Plasma concentrations of glutamate in patients suffering from chronic migraine overusing acute medication, before and after withdrawal treatment

A dysfunction of the glutamatergic system would have an essential role in the pathogenetic mechanism of the migraine. Glutamate is implicated in cortical spreading depression, trigeminovascular activation, and central sensitization [1]. Higher glutamate levels than those of healthy controls have been reported in migraine patients’ plasma and platelets [2] and in chronic migraine patients’ cerebrospinal fluid [3]. Our aim was verifying if there were differences in the plasma levels of glutamate between patients with chronic migraine overusing acute medications and control subjects, and if plasma levels of glutamate in chronic migraine patients modified after withdrawal from the overused medication. Methods. We studied 12 patients (F=10, M=2; mean age 50.3±9.8 years) with diagnosis of chronic migraine, according to ICHD-II criteria, overusing acute medications, and 15 healthy subjects as controls (F=2, M=3; mean age 48.2±7.3 years). Patients were studied twice, before and after 15 days of standardized inpatient withdrawal treatment. Venous blood samples for the assay of glutamate concentrations were taken in the morning, after overnight fasting. Glutamate concentrations were measured by means of a fluorimetric detector high pressure liquid chromatographic (HPLC/FD) method. Results. Plasma concentrations of glutamate were significantly higher in chronic migraine patients either before (62.5±5.1 µmol/L) or after treatment (27.7±11.3 µmol/L) than in control subjects (7.3±2.9 µmol/L) (P<0.05, ANOVA followed by Student-Newman-Keuls’ test). However, after 15 days of inpatient withdrawal treatment, once overuse was interrupted, and the frequency of headache reduced, plasma glutamate concentrations were significantly lower in the same patient with respect to the prior level (P<0.0001, Student’s t-test for paired data), without any differences depending on the kind of medication overused. Conclusions. Elevated plasma levels of glutamate in chronic migraine sufferers could support the role of this excitatory aminoacid in the process of central sensitization. The decline in glutamate plasma concentrations is associated with medication-overuse discontinuation and reduced headache frequency; thus, plasma glutamate levels monitoring in chronic migraine might serve as a biomarker of clinical improvement. [1] Ramadan NM. The link between glutamate and migraine. CNS Spectr 2003; 8(6):446-9 [2] Alam Z, Coombes N, Waring RH, Williams AC, Steventon GB. Plasma levels of neuroexcitatory amino acids in patients with migraine or tension headache. J Neurol Sci 1998; 156(1):102-6 [3] Peres MF, Zukerman E, Senne Soares CA, Alonso EO, Santos BF, Faulhaber MH. Cerebrospinal fluid glutamate levels in chronic migraine. Cephalalgia 2004; 24(9):735-

Limits of medication-overuse headache classification (code 8.2 according to ICHD-II)”

The major chamges that we propose are: 1. classifying the drugs inducing MOH into 2 groups: drugs with psychotropic effects that produce tolerance, dependence, repetition of intake and, sometimes, abstinence symptoms after withdarawal; drugs related to non-dependence-producing substances; 2 including in the first group also the combinations of analgesics and drugs with psychotropic effects, since we consider the latter as the most important component to maintain overuse

Variability of oral sumatriptan pharmacokinetics in migraine patients

Sumatriptan was the first selective serotonin (5-HT) 1B/1D agonist for the acute treatment of migraine attacks. It is thought to relieve migraine attacks by several mechanisms including cranial vasoconstriction and peripheral and central neural inhibition. Sumatriptan has proved to be effective and generally well tolerated in the absence of cardiovascular disease . Nevertheless, its use by migraine sufferers is still limited, approximately 40% of patients using only one prescription of this drug. Reason for terminating use after only one prescription is inefficacy and/or side effects in the majority (78%) of patients . Objectives: To evaluate oral bioavailability and pharmacokinetic profiles of sumatriptan in migraine patients. Methods: We studied 10 migraine patients (8 F, 3 M; mean age 45.3+8.1 years, range 34-60 years) twice, after oral (100 mg) and after subcutaneous (6 mg) administration of sumatriptan. A 1-week washout period was allowed between the administration of the two formulations. Patients were studied in headache free intervals. Blood samples were taken at baseline, at 15, 30, 45, 60, 90, 120, 180, 240, 300 and 360 min. after oral administration, and at baseline, at 5, 10, 15, 20, 25, 30, 60, 90, 120 and 180 min. after subcutaneous injection. Sumatriptan concentrations were determined by HPLC with electrochemical detection. Pharmacokinetic parameters were calculated by means of the P K Solutions 2.0 program. The value of AUC obtained after subcutaneous administration was assumed correspond to 100% of bioavailability and relative oral bioavailability was calculated referred to this value. Results: Following administration of an oral dose of 100 mg, plasma concentrations of sumatriptan showed large differences among patients and two subjects had multiple peaks. In particular (Fig. 1), 5 patients (these subjects will be referred to as group A hereinafter) absorbed the drug faster (Tmax &lt;120 min.), and achieved plasma levels significantly higher (soon after 45 minutes and up to 90 minutes) than the other 5 patients (hence forth, these last patients with Tmax &gt;180 min will be referred to as group B). Notably, the systemic exposure to sumatriptan in the first 2 hours (which are the most important for rapid onset of action and for the antimigraine efficacy) was significantly greater in group A than in group B, as shown by AUC0-2 value in group A (3.174.2+1186 ng/min/ml) which is double the value in group B (1530.9+256 ng/min/ml). On the other hand, after subcutaneous administration of 6 mg of sumatriptan, the profile of the curves was similar in all patients, and there were no differences in pharmacokinetics between group A and group B. Conclusions: Since Tmax is a key variable in migraine response, and migraine relief is related to the systemic exposure to the drug in the first 2 hours after dosing, patients with slow rate and low extent of absorption of the drug in this interval of time could have poor benefit after oral sumatriptan administration. These patients could instead obtain more migraine relief using injection formulation of the drug, since there are no significant differences in pharmacokinetics after subcutaneous administration of sumatriptan. Our findings have the limitation of having been obtained in a small number of patients; however, they could explain the variability of outcomes observed with the different formulations of sumatriptan. Indeed, almost one third of patients in clinical trials fail to have headache relief after oral administration, while only one sixth of patients fail to have headache relief after subcutaneous administration. It is precisely the marked variability in the rate and extent of sumatriptan absorption after oral administration that we observed in clinical practice which could have an impact on sumatriptan response and, as a consequence, in some patients’ disaffection with this drug

Pharmacokinetics of indomethacin in chronic migraine patients after withdrawal of the overused combination of indomethacin, prochlorperazine, and caffeine

The combination of indomethacin, prochlorperazine and caffeine (IPC) is often overused by migraine patients who develop medication-overuse headache (MOH), a secondary chronic headache that resolves after withdrawal of the overused medication. In a previous study (1) we showed that indomethacin clearance was lower in chronic migraine patients overusing IPC combination than in migraine patients only occasionally taking this combination. Objective: To verify if the reduced clearance of indomethacin reverts to normal after withdrawal of the overused IPC. Methods: We repeated the study of indomethacin pharmacokinetics in 9 female headache patients after 6 months from inpatient withdrawal of the IPC combination. In each patients indomethacin pharmacokinetics had been already studied before withdrawal treatment. The IPC combination (indomethacin 50 mg, prochlorperazine 8 mg, caffeine150 mg) habitually taken was administered by rectal route to each patient. Blood samples were drawn before dosing and at the following post-dose times: 0.5, 1, 2, 3, 4, and 6 h. Indomethacin concentrations were measured by HPLC method. Pharmacokinetic parameters were calculated by means of the P K Solutions 2.0 program. Results: The pharmacokinetic parameters of indomethacin in 4 patients (group A) who relapsed in IPC overuse were similar to those observed before withdrawal treatment; instead (Table 1) in 5 patients (group B) who steadily discontinued IPC combination, indomethacin disposition was significantly different from that observed before withdrawal treatment. Table 1. Pharmacokinetic parameters of indomethacin in group B. Parameter Before withdrawal After withdrawalHalf life (h) 2.74+0.98 1.45+0.34 *AUC0-t (mg/h/ml) 13.02+6.62 5.36+2.36 *Cl (ml/h/Kg) 64.05+30.16 123.98+39.91 * *P <0.05 (paired Student\u2019 t-test)Conclusions: In headache patients who discontinued IPC overuse, indomethacin clearance increased and reverted to values previously obtained in occasional IPC users (1).1. Ferrari A., Savino G., Gallesi D., Pinetti D., Bertolini A., Sances G., et al. (2006) Pharmacol Res. 542: 142-149