The protective effect of solidagenone from Solidago chilensis Meyen in a mouse model of airway inflammation.

Solidagenone is the main active constituent present in Solidago chilensis Meyen which is used in folk medicine to treat pain and inflammatory diseases. This study aimed to evaluate the anti-inflammatory activity of solidagenone in vitro and in a model of allergic airway inflammation. In vitro studies were performed in activated macrophages and lymphocytes. BALB/c mice were sensitized and challenged with ovalbumin and treated with solidagenone orally (30 or 90 mg/kg body weight) or dexamethasone, as a positive control in our in vivo analysis. Supernatant concentrations of nitrite, TNF and IL-1ß, as well as gene expression of pro-inflammatory mediators in macrophages cultures, were reduced after solidagenone treatment, without affecting macrophages viability. Besides, solidagenone significantly decreased T cell proliferation and secretion of IFNγ and IL-2. Th2 cytokine concentrations and inflammatory cell counts, especially eosinophils, in bronchoalveolar lavage fluid were reduced in mice treated with solidagenone. Histopathological evaluation of lung tissue was performed, and morphometrical analyses demonstrated reduction of cellular infiltration and mucus hypersecretion. Altogether, solidagenone presented anti-inflammatory activity in vitro and in vivo in the OVA-induced airway inflammation model, suggesting its promising pharmacological use as an anti-inflammatory agent for allergic hypersensitivity.

Intoxication by a synthetic cannabinoid (JWH-018) causes cognitive and psychomotor impairment in recreational cannabis users.

BACKGROUND: Smoking mixtures containing synthetic cannabinoids (SCs) have become very popular over the last years but pose a serious risk for public health. Limited knowledge is, however, available regarding the acute effects of SCs on cognition and psychomotor performance. Earlier we demonstrated signs of impairment in healthy volunteers after administering one of the first SCs, JWH-018, even though subjective intoxication was low. In the current study, we aimed to investigate the acute effects of JWH-018 on several cognitive and psychomotor tasks in participants who are demonstrating representative levels of acute intoxication. METHODS: 24 healthy cannabis-experienced participants took part in this placebo-controlled, cross-over study. Participants inhaled the vapor of 75 µg JWH-018/kg body weight and were given a booster dose if needed to induce a minimum level of subjective high. They were subsequently monitored for 4 h, during which psychomotor and cognitive performance, vital signs, and subjective experience were measured, and serum concentrations were determined. RESULTS: Maximum subjective high (average 64%) was reached 30 min after administration of JWH-018, while the maximum blood concentration was shown after 5 min (8 ng/mL). JWH-018 impaired motor coordination (CTT), attention (DAT and SST), memory (SMT), it lowered speed-accuracy efficiency (MFFT) and slowed down response speed (DAT). CONCLUSION: In accordance with our previous studies, we demonstrated acute psychomotor and cognitive effects of a relatively low dose of JWH-018.

Effect of acute and subchronic administration of (R)-WIN55,212-2 induced neuroprotection and anti inflammatory actions in rat retina: CB1 and CB2 receptor involvement.

Cannabinoids have been shown to protect the retina from ischemic/excitotoxic insults. The aim of the present study was to investigate the neuroprotective and anti-inflammatory properties of the synthetic cannabinoid (R)-WIN55,212-2 (CB1/CB2 receptor agonist) when administered acutely or subchronically in control and AMPA treated retinas. Sprague-Dawley rats were intravitreally administered (acutely) with vehicle or AMPA, in the absence or presence of (R)-WIN55,212-2 (10-7-10-4M) alone or in combination with AM251 [CB1 receptor antagonist/inverse agonist,10-4M] and AM630 (CB2 receptor antagonist,10-4M). In addition, AMPA was co-administered with the racemic (R,S)-WIN55,212 (10-4Μ). (R)-WIN55,212-2 was also administered subchronically (25,100 µg/kg,i.p.,4d) in control and AMPA treated rats. Immunohistochemical studies were performed using antibodies against the CB1R, and retinal markers for retinal neurons (brain nitric oxide synthetase, bNOS) and microglia (ionized calcium binding adaptor molecule 1, Iba1). ELISA assay was employed to assess TNFα levels in AMPA treated retinas. Intravitreal administration of (R)-WIN55,212-2 reversed the AMPA induced loss of bNOS expressing amacrine cells, an effect that was blocked by both AM251 and AM630. (R,S)WIN55,212 had no effect. (R)-WIN55,212-2 also reduced a) the AMPA induced activation of microglia, by activating CB2 receptors that were shown to be colocalized with Iba1+ reactive microglial cells, and b) TNFα levels in retina. (R)-WIN55,212-2 administered subchronically led to the downregulation of CB1 receptors at the high dose of 100 µg/kg(i.p.), and to the attenuation of the WIN55,212-2 induced neuroprotection of amacrine cells. At the same dose, (R)-WIN55,212-2 did not attenuate the AMPA induced increase in the number of reactive microglia cells, suggesting CB2 receptor downregulation under subchronic conditions. This study provides new findings regarding the role of CB1 and CB2 receptor activation by the synthetic cannabinoid (R)-WIN55,212-2, administered acutely or sub-chronically, on neuron viability and microglia activation in healthy and diseased retina.

Alterations in Rat Accumbens Dopamine, Endocannabinoids and GABA Content During WIN55,212-2 Treatment: The Role of Ghrelin.

The endocannabinoid/CB1R system as well as the central ghrelin signalling with its growth hormone secretagogoue receptors (GHS-R1A) are importantly involved in food intake and reward/reinforcement processing and show distinct overlaps in distribution within the relevant brain regions including the hypothalamus (food intake), the ventral tegmental area (VTA) and the nucleus accumbens (NAC) (reward/reinforcement). The significant mutual interaction between these systems in food intake has been documented; however, the possible role of ghrelin/GHS-R1A in the cannabinoid reinforcement effects and addiction remain unclear. Therefore, the principal aim of the present study was to investigate whether pretreatment with GHS-R1A antagonist/JMV2959 could reduce the CB1R agonist/WIN55,212-2-induced dopamine efflux in the nucleus accumbens shell (NACSh), which is considered a crucial trigger impulse of the addiction process. The synthetic aminoalklylindol cannabinoid WIN55,212-2 administration into the posterior VTA induced significant accumbens dopamine release, which was significantly reduced by the 3 mg/kg i.p. JMV2959 pretreatment. Simultaneously, the cannabinoid-increased accumbens dopamine metabolic turnover was significantly augmented by the JMV2959 pretreament. The intracerebral WIN55,212-2 administration also increased the endocannabinoid arachidonoylethanolamide/anandamide and the 2-arachidonoylglycerol/2-AG extracellular levels in the NACSh, which was moderately but significantly attenuated by the JMV2959 pretreatment. Moreover, the cannabinoid-induced decrease in accumbens γ-aminobutyric acid/gamma-aminobutyric acid levels was reversed by the JMV2959 pretreatment. The behavioural study in the LABORAS cage showed that 3 mg/kg JMV2959 pretreatment also significantly reduced the systemic WIN55,212-2-induced behavioural stimulation. Our results demonstrate that the ghrelin/GHS-R1A system significantly participates in the rewarding/reinforcing effects of the cannabinoid/CB1 agonist that are involved in cannabinoid addiction processing.

Δ9-tetrahydrocannabinol: Drug discrimination abuse liability testing in female Lister Hooded rats: Trials, tribulations and triumphs.

INTRODUCTION: The assessment of the abuse potential of CNS-active drugs is a regulatory requirement. Drug discrimination is one of the nonclinical tests that contribute to this assessment by providing information on a drug's potential to induce a discriminative stimulus comparable to that of a known drug of abuse. AIM: The objective was to validate drug discrimination in the rat for the purpose of supporting regulatory submissions for novel drugs with potential cannabinoid-like activity. METHODS: Ten female Lister hooded rats were trained to discriminate no-drug from Δ9-THC (1.5 mg/kg, IP) under a FR10 schedule of reinforcement. Once trained, a Δ9-THC dose-response curve was obtained using doses of 0.25, 0.75, 1.5, and 3 mg/kg, IP. This was followed by evaluation of amphetamine (0.3 mg/kg, SC); morphine (3 mg/kg, IP); midazolam (2.5 mg/kg, PO); and the synthetic cannabinoids WIN55,212-2 (0.75 to 2 mg/kg, IP), CP-47,497 (0.5 to 2 mg/kg, IP), and JWH-018 (1 mg/kg, IP) for their discriminative stimulus similarity to Δ9-THC. RESULTS: Pharmacological specificity was demonstrated by achieving the anticipated dose-response curve for Δ9-THC, and a vehicle-like response for the non-cannabinoid drugs. Although full generalisation was obtained for JWH-018, in contrast to published literature, WIN55,212-2 and CP-47,497 failed to generalise to Δ9-THC. DISCUSSION: Based on the literature review performed in light of the results obtained, contrasting and unpredictable behavioural responses produced by cannabinoids in animals and humans raises the question of the reliability and relevance of including drug discrimination and self-administration studies within an abuse potential assessment for novel cannabinoid-like drugs.

Pharmacodynamics of evocalcet for secondary hyperparathyroidism in Japanese hemodialysis patients.

BACKGROUND: This study investigated the pharmacokinetics, pharmacodynamics, and safety of multiple doses of evocalcet in Japanese secondary hyperparathyroidism (SHPT) patients receiving hemodialysis. METHODS: In this multicenter, open-label study, conducted between August 2013 and March 2014, 27 patients received multiple doses of 1 and 4 mg evocalcet for 14 days, followed by an extension period of multiple doses of 8 and 12 mg evocalcet for 7 days using an intra-patient dose escalation protocol. Pharmacodynamic parameters consisted of measurement of intact parathyroid hormone (PTH), serum-corrected calcium, serum phosphorus and intact fibroblast growth factor 23 concentrations. Safety was assessed by analysis of adverse events. RESULTS: Plasma evocalcet levels reached steady state 3 days after the first day of administration. Pharmacodynamic analyses showed that evocalcet effectively reduced intact PTH and serum-corrected calcium levels. Adverse events (AEs) occurred in 29.6 and 62.5% of patients receiving multiple doses of 1 or 4 mg, respectively. The AE 'blood calcium decreased' occurred in eight patients (33.0%) after multiple doses of 4 mg. All events were mild, except for one patient with a moderate AE (abnormal liver function) and one patient with a severe adverse drug reaction (blood calcium decreased). CONCLUSION: Multiple doses of evocalcet reduced intact PTH levels with a concomitant decrease in serum calcium levels. Evocalcet was well tolerated in SHPT patients receiving hemodialysis.

Involvement of spinal cannabinoid receptors in the antipruritic effects of WIN 55,212-2, a cannabinoid receptor agonist.

BACKGROUND: Cannabinoids have been used for their analgesic and euphoric effects for millennia, but recently the antipruritic effects of cannabis have been discovered. Considering the similarities between pain and itch sensations, we hypothesized that cannabinoid receptors may play a role in the antipruritic effects of cannabinoids. AIM: To analyse the role of the spinal cannabinoid receptors, CB1 and CB2, in the antipruritic effects of the cannabinoid agonist WIN 55,212-2. METHODS: Male Balb/c mice weighing 20-30 g were used. Scratching behaviour in the mice was produced by injection of serotonin 5 µg/50 µL intradermally into the nape of the neck. Scratching of the site of injection by the hind paws was video-recorded for 30 min. After testing different doses of WIN 55,212-2 [1, 3 and 10 mg/kg intraperitoneally (IP)], the effects of the CB1 receptor antagonist, AM-251 [1 µg/mouse administered intrathecally (IT)] and the CB2 receptor antagonist AM-630 (4 µg/mouse IT) on the antipruritic effects of WIN 55,212-2 were studied using a rotarod apparatus. RESULTS: WIN 55,212-2 (1, 3 or 10 mg/kg IP) dose-dependently decreased serotonin-induced scratches. The receptor antagonist CB1 partially reversed the effects of WIN 55,212-2 (P < 0.05); whereas CB2 had no statistically significant effect. WIN 55,212-2 impaired motor function only at the highest dose given (10 mg/kg, P < 0.05). CONCLUSIONS: Our findings support prior researches indicating that cannabinoids exert antipruritic effects. Moreover, our results show that the antipruritic effects of cannabinoids are partially mediated by spinal CB1 receptors.

Successful treatment of chromoblastomycosis of 10-year duration due to Fonsecaea nubica.

We report a case of chromoblastomycosis due to the presence of large plaque and verrucous hyperplasia lesions on the left upper limb, with elbow abnormal activities, in a 56-year-old male. The diagnosis of chromoblastomycosis was based on gross and microscopic morphologies, histopathological examination and clinical manifestation. Molecular tools were applied to identifying the causative agent Fonsecaea nubica, which is rarely reported to be associated with chromoblastomycosis. The patient was initially treated orally with terbinafine (250 mg/day) and itraconazole (200 mg/day), subsequently patient received thermotherapy (45-50°C, 3 h/day) for 1 month. The patient was successfully cured. A literature review was performed to assess general features, treatment and outcome of chromoblastomycosis due to F.  nubica. All the 5 reviewed patients were male, over 30 years old and their lesions occurred after traumatic inoculation.

Terbinafine is a novel and selective activator of the two-pore domain potassium channel TASK3.

Two-pore domain potassium channels (K2Ps) are characterized by their four transmembrane domain and two-pore topology. They carry background (or leak) potassium current in a variety of cell types. Despite a number of important roles there is currently a lack of pharmacological tools with which to further probe K2P function. We have developed a cell-based thallium flux assay, using baculovirus delivered TASK3 (TWIK-related acid-sensitive K+ channel 3, KCNK9, K2P9.1) with the aim of identifying novel, selective TASK3 activators. After screening a library of 1000 compounds, including drug-like and FDA approved molecules, we identified Terbinafine as an activator of TASK3. In a thallium flux assay a pEC50 of 6.2 ( ±0.12) was observed. When Terbinafine was screened against TASK2, TREK2, THIK1, TWIK1 and TRESK no activation was observed in thallium flux assays. Several analogues of Terbinafine were also purchased and structure activity relationships examined. To confirm Terbinafine's activation of TASK3 whole cell patch clamp electrophysiology was carried out and clear potentiation observed in both the wild type channel and the pathophysiological, Birk-Barel syndrome associated, G236R TASK3 mutant. No activity at TASK1 was observed in electrophysiology studies. In conclusion, we have identified the first selective activator of the two-pore domain potassium channel TASK3.

The efficacy of fractional carbon dioxide (CO2) laser combined with terbinafine hydrochloride 1% cream for the treatment of onychomycosis.

BACKGROUND: Although systemic and topical antifungal agents are widely used to treat onychomycosis, oral medications can cause adverse effects and the efficacy of topical agents is not satisfying. Currently, laser treatment has been studied for its efficacy in the treatment of onychomycosis. Our study was aimed to evaluate the efficacy of fractional carbon dioxide (CO2) laser treatment combined with terbinafine cream for 6 months in the treatment of onychomycosis and to analyze the influencing factors. METHODS: A total of 30 participants (124 nails) with clinical and mycological diagnosis of onychomycosis received fractional CO2 laser treatment at 2-week interval combined with terbinafine cream once daily for 6 months. The clinical efficacy rate (CER) was assessed from the percentage of fully normal-appearing nails or nails with ≤5% abnormal appearance, and the mycological clearance rate (MCR) was assessed from the percentage of nails with negative fungal microscopy. RESULTS: The CER was evaluated at 3 time points: at the end of treatment (58.9%), at 1 month after the last treatment (63.5%), and at 3 months after the last treatment (68.5%). The MCRs at 1 month and 3 months after the last treatment were 77.4 and 74.2%, respectively. The evaluation of influencing factors showed significantly higher CER (p < 0.05) in nails of participants with age <50 years, distal lateral subungual onychomycosis (DLSO), superficial white onychomycosis (SWO), nail thickness <2 mm, affected first-to-fourth finger/toenails, Trichophyton rubrum, and Trichophyton mentagrophytes. All participants experienced tolerable mild burning sensation during laser treatment, but there were no other adverse reactions reported. CONCLUSIONS: Fractional CO2 laser treatment combined with terbinafine cream for 6 months was an effective and safe method for the treatment of onychomycosis. There were 5 factors that positively influenced the treatment outcome: age, clinical type of onychomycosis, nail thickness, involved nail, and species of fungus.

Targeting of CYP17A1 Lyase by VT-464 Inhibits Adrenal and Intratumoral Androgen Biosynthesis and Tumor Growth of Castration Resistant Prostate Cancer.

Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) is a validated treatment target for the treatment of metastatic castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) inhibits both 17α-hydroxylase (hydroxylase) and 17,20-lyase (lyase) reactions catalyzed by CYP17A1 and thus depletes androgen biosynthesis. However, coadministration of prednisone is required to suppress the mineralocorticoid excess and cortisol depletion that result from hydroxylase inhibition. VT-464, a nonsteroidal small molecule, selectively inhibits CYP17A1 lyase and therefore does not require prednisone supplementation. Administration of VT-464 in a metastatic CRPC patient presenting with high tumoral expression of both androgen receptor (AR) and CYP17A1, showed significant reduction in the level of both dehydroepiandrosterone (DHEA) and serum PSA. Treatment of a CRPC patient-derived xenograft, MDA-PCa-133 expressing H874Y AR mutant with VT-464, reduced the increase in tumor volume in castrate male mice more than twice as much as the vehicle (P < 0.05). Mass spectrometry analysis of post-treatment xenograft tumor tissues showed that VT-464 significantly decreased intratumoral androgens but not cortisol. VT-464 also reduced AR signaling more effectively than abiraterone in cultured PCa cells expressing T877A AR mutant. Collectively, this study suggests that VT-464 therapy can effectively treat CRPC and be used in precision medicine based on androgen receptor mutation status.

Behavioral evidence for the interaction between cannabinoids and Catha edulis F. (Khat) in mice.

Several studies have shown the existence of an interaction between the endocannabinoid system and some drugs of abuse, such as opioids, nicotine, alcohol, and cocaine. For instance, the endocannabinoid system has long been known to play a role in the underlying mechanisms of drug reward and dependence. The aim of this study was to evaluate the possible existence of an interaction between the endocannabinoid system and khat after acute administration. Behavioral interactions of khat extract with cannabinoids were assessed. To this effect, mice were randomly divided into different groups (vehicle, khat extract, khat and WIN55,212-2, a cannabinoid agonist, khat extract and cannabinoid antagonists, AM251 & AM630) and their behavioral responses were evaluated in activity monitor, elevated plus maze and Y-maze tests. These tests were used to determine changes in locomotor activity, anxiety-like behavior, and working memory. Khat and WIN55,212-2 demonstrated differential responses in these tests, but co-administration of these agents invariably increased the measured parameters, which were reversed by the cannabinoid receptor antagonists used. The data collectively indicate that there is an interaction between khat and the endocannabinoid system, which most likely involves the cannabinoid receptors or a common mechanism separately activated by the two agents.

[Complex use of naphthalane and nonselective chromotherapy in gonarthrosis treatment in rolling stock workers].

Complex treatment using naphthalane applications with nonselective chromotherapy covered 64 engine operators of locomotive crews, aged 40-69 years, having 1-3 stage knee osteoarthrosis. Findings are that optimized treatment schedules effectively reduce intensity of pain, improve functional state of the joints involved, increase life quality of the patients, have no side effects. Comparative analysis of the treatment results showed that efficiency of combined naphthalane and nonselective chromotherapy exceeds isolated naphthalane effects.

Herb-drug interaction of Epimedium extract on the pharmacokinetic of dapoxetine in rats.

The aim of study is to develop a high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method to investigate the pharmacokinetic interaction of Epimedium extract on the dapoxetine in rats. Experimental rats were divided into the following four parallel groups: (1) dapoxetine alone (10mg/kg, i.v.); (2) oral administration of Epimedium extract (2g/kg) for 3 consecutive days and on the fourth day dapoxetine was administered (10mg/kg, i.v.); (3) dapoxetine alone (10mg/kg, p.o.); (4) oral administration of Epimedium extract (2g/kg) for 3 consecutive days and on the fourth day dapoxetine was administered (10mg/kg, p.o.). The calibration curves of dapoxetine were acquired over a concentration ranges from 1 to 500ng/mL with the R(2)=0.999. The mean matrix effects and extraction recoveries of dapoxetine at three different concentrations (1, 10, 500ng/mL) ranged from 107.3 to 110.9% and from 25.5 to 28.2% respectively. The interday and intraday relative standard deviation were both <6% while the bias were both <14%. The pharmacokinetic results demonstrated that pretreated with/without Epimedium extract for three consecutive days did not significant alter the pharmacokinetics of dapoxetine in rats. The oral bioavailability of dapoxetine was about 75% in rats.

Terbinafine hydrochloride loaded liposome film formulation for treatment of onychomycosis: in vitro and in vivo evaluation.

Onychomycosis is a fungal infection of nail unit that is caused by dermatophytes. Oral Terbinafine hydrochloride (TBF-HCl) is being used for the treatment of onychomycosis since 24 years. The side effects caused by the systemic application and limitations of topical administration of this drug regarding the diffusion through nail lead to the development of a new formulation based on, TBF-HCl-loaded liposome. The newly obtained film formulations were prepared and characterized via several parameters, such as physical appearance, drug content, thickness, bioadhesive properties and tensile strength. In vitro and ex vivo permeation studies were performed to select an optimum film formulation for antifungal activity to show the efficiency of formulations regarding the treatment of onychomycosis. The in vitro release percentages of drug were found 71.6 ± 3.28, 54.4 ± 4.26, 56.1 ± 7.48 and 46.0 ± 2.43 for liposome loaded pullulan films (LI-P, LII-P) and liposome loaded Eudragit films (LI-E, LII-E), respectively. The accumulated drug in the nail plates were found 31.16 ± 4.22, 24.81 ± 5.35, 8.17 ± 1.81 and 8.92 ± 3.37 for LI-P, LII-P, LI-E and LII-E, respectively, which within therapeutic range for all film formulations. The accumulated drug in the nail plate was found within therapeutic range for all film formulations. The efficacy of the selected TBF-HCl-loaded liposome film formulation was compared with TBF-HCl-loaded liposome, ethosome, liposome poloxamer gel and ethosome chitosan gel formulations. It was found that TBF-HCl-loaded liposome film formulation had better antifungal activity on fungal nails which make this liposome film formulation promising for ungual therapy of fungal nail infection.

Determining canine skin concentrations of terbinafine to guide the treatment of Malassezia dermatitis.

BACKGROUND: Terbinafine (TBF) is known to concentrate and persist in human skin. Its use is increasing in veterinary medicine, but there are limited data concerning its tissue concentration and efficacy in dogs. HYPOTHESIS/OBJECTIVES: (i) Describe TBF accumulation in canine skin; (ii) Integrate pharmacokinetic data with historical minimum inhibitory concentration (MIC) results for Malassezia pachydermatis to verify the currently used dosage of TBF for the treatment of Malassezia dermatitis. ANIMALS: Ten healthy, client-owned dogs. METHODS: Dogs were given TBF (generic preparation, 250 mg tablets) 30 mg/kg per os (p.o.) once daily for 21 days. Serum, sebum and stratum corneum (SC) samples were collected on days 1, 5, 7, 11, 14, 21, 28 and 35. High-pressure liquid chromatography was used to determine drug concentrations in samples. RESULTS: Relevant (mean ± standard deviation) parameters for TBF in serum, paw SC, thorax SC and sebum, respectively, were: maximum concentration (Cmax , µg/mL) 23.59 ± 10.41, 0.31 ± 0.26, 0.30 ± 0.32 and 0.48 ± 0.25; half-life (t1/2 , d) 4.49 ± 2.24, 6.34 ± 5.33, 4.64 ± 3.27 and 5.12 ± 3.33; time to maximum concentration (Tmax , d) 10.40 ± 6.98, 13.20 ± 5.16, 11.90 ± 8.62 and 10.60 ± 3.69. CONCLUSIONS AND CLINICAL IMPORTANCE: These results suggest that TBF does not achieve high concentrations in canine SC or sebum compared to serum. The mean Cmax of all skin tissues (paw SC, thorax SC and sebum) barely exceeded the reported Malassezia MIC90, of 0.25 µg/mL, which indicates that doses higher than 30 mg/kg p.o. once daily may be necessary.

Should patients with CKD stage 5D and biochemical evidence of secondary hyperparathyroidism be prescribed calcimimetic therapy? An ERA-EDTA position statement.

This paper reflects the position of the CKD-MBD workgroup, an official working group of ERA-EDTA and of the ERBP advisory board, the official guideline-producing body of ERA-EDTA, on the topic of the use of calcimimetics in patients with CKD stage 5D, as based on two recent meta-analysis.

Evaluation of antifungal combinations of nystatin-intralipid against Aspergillus terreus using checkerboard and disk diffusion methods.

OBJECTIVE: The objective of this study was to evaluate the efficacy of combinations of nystatin-intralipid, found previously to be more active than nystatin, with antifungals of different mode of activity, against Aspergillus terreus. METHODS: Antifungal activity of combinations of nystatin-intralipid with voriconazole, caspofungin, terbinafine or 5-fluorocytosine were evaluated by the checkerboard and disk diffusion methods. The results were compared to those obtained with nystatin. RESULTS: The combination of nystatin-intralipid with caspofungin exhibited better antifungal activity than each drug alone and resulted in a synergistic interaction in three out of six tested strains of A. terreus. No such effect was obtained with Nystatin and caspofungin. Nystatin-intralipid or nystatin with voriconazole yielded indifferent interactions. When nystatin-intralipid was combined with terbinafine, a strong antagonism was produced in all six A. terreus strains. This effect was observed both by checkerboard and disk diffusion methods. In contrast no interaction or only slight antagonism was observed in the combination of nystatin with terbinafine. Disk diffusion method revealed similar inhibition zones when disks impregnated with 5-fluorocytosine were placed on plain, nystatin-intralipid or nystatin containing agar plates. CONCLUSIONS: Among four tested combinations, only combination of nytatin-intralipid with caspofungin, a representative of the echinocandin class of antifungals, resulted in synergistic interaction. Antagonism obtained by combining nystatin-intralipid with terbinafine can be explained by existence of hydrophobic interaction between these two compounds interfering with their antifungal action. The fact that nystatin-intralipid and nystatin interact differently with other antifungals, may indicate differences in their mechanisms of activity.

Cinacalcet in pediatric and adolescent chronic kidney disease: a single-center experience.

Cinacalcet, a calcimimetic drug, has been shown to be efficacious in adult chronic kidney disease (CKD) patients; however, it was not fully studied in pediatric CKD patients. We aimed at assessing the effect of cinacalcet on intact parathyroid hormone (iPTH) secretion in children with CKD-4/5 with iPTH consistently ≥ 300 pg/mL refractory to conventional treatment. This is a prospective cohort analysis of 28 children with uncontrolled hyper-parathyroidism secondary to stage 4 and 5 CKD admitted to a tertiary center during the period from April 2012 to April 2014. Twenty-eight patients with CKD-4/5 were assessed prospectively regarding bone biochemistry, renal ultrasonography, serum iPTH level, and medications. Patients were classified into 3 groups: group 1, 6 patients with CKD-4 on supplemental and supportive therapy; group 2, 6 patients with CKD-5 on hemodialysis and; group 3, 16 patients with CKD-5 on automated peritoneal dialysis. Patients were between the ages of 9 months and 18 years on commencing cinacalcet at doses of 0.5 to 1.5 mg/kg. All patients showed at least a 60% reduction in iPTH (60%-97%). Highly significant reduction in iPTH and serum alkaline phosphatase levels was detected post-cinacalcet. The serum calcium (Ca), phosphate (P), and Ca × P product were unaffected. Treatment was well tolerated with no hypophosphatemia, hypocalcemia, or other adverse effects almost in all patients. Cinacalcet use was proven safe for all pediatric and adolescent patients with CKD-4/5 during the study period, and at the same time most of the patients reached the suggested iPTH target values.

A retrospective chart review of the clinical efficacy of Nd:YAG 1064-nm laser for toenail onychomycosis.

Cosmetic improvement in nail appearance is a great concern to patients with onychomycosis. Although oral and topical treatments for onychomycosis can potentially eradicate the infection, unsightly nails may remain despite negative mycology. Laser-based devices have been approved for the temporary clearance of nails with onychomycosis, thus providing a means of improving the aesthetic appearance of the nails. A retrospective chart review of patients treated with a Nd:YAG 1064-nm laser and debridement for onychomycosis, and terbinafine 1% cream for associated tinea pedis, between July 2012 and February 2014 was performed to ascertain the proportion of patients who achieved clinical outcomes. A temporary improvement in the appearance of the target nail was observed in 78% of patients and the affected area of the nail plate was reduced by at least 50% from baseline in 46% of patients. It appears that patients whose great toenails are potentially infected with non-dermatophyte molds may particularly benefit from laser therapy. Higher clinical outcome rates were observed with administration of four or more treatments, but additional observations and/or studies are needed to optimize the regimen of laser therapy to improve the cosmetic appearance of infected nails.