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.     

Comparison of ciclopirox olamine 1% cream with ciclopirox 1%-hydrocortisone acetate 1% cream in the treatment of inflamed superficial mycoses

The hydroxypyridone antifungal agent ciclopirox olamine cream 1% has been shown to be as effective in the treatment of inflamed, superficial fungal infections as a formulation in which ciclopirox 1% and hydrocortisone acetate 1% were combined. In a randomized, double-blind, parallel group comparison study, 138 patients with culture-confirmed superficial fungal diseases applied their assigned medication twice daily for 21 days. Clinical assessments were made at the baseline visit; at visits on days 4, 7, 14, and 21 during treatment; and on day 28 (one week posttreatment). Specimens for cultures were taken at baseline and on day 28. There were no differences for the 69 patients in either treatment group at any visit with respect to improvement in the signs/symptoms evaluated; mycological cures in the two treatment groups also were not significantly different.     

Multicentre double-blind clinical trials of ciclopirox olamine cream 1% in the treatment of tinea corporis and tinea cruris

In separate multicentre, randomized, double-blind clinical trials, 1% ciclopirox olamine cream was compared with its cream vehicle and with 1% clotrimazole cream as treatment for tinea corporis and tinea cruris. Patients who demonstrated clinical and mycological findings consistent with the diagnoses of tinea corporis or tinea cruris were included in the study. Clinical and mycological evaluations were made pretreatment, at the end of each of the four weeks of treatment, and weekly for the two weeks immediately following cessation of treatment. In both studies, use of ciclopirox olamine cream resulted in demonstrable improvements after the first week of therapy and in complete clinical and mycological clearing in two thirds of the patients at the end of the treatment period. These results were maintained through the two-week drug-free observation period that followed the end of treatment. Statistically, the results with ciclopirox olamine cream were significantly better than those with the vehicle and were equivalent to those with clotrimazole cream. All treatments were well tolerated.     

In vitro activity of ME1401, a new antifungal agent.

The in vitro antifungal activity of ME1401, a potential topical antifungal agent, was compared with that of haloprogin, clotrimazole, miconazole, tolnaftate, and ciclopirox olamine by using an agar dilution procedure. ME1401 showed a broad antifungal spectrum and inhibited all of the 428 strains of 52 species of pathogenic yeasts and filamentous fungi tested at concentrations ranging from 0.01 to 12.5 micrograms/ml. In general, the activity of ME1401 was comparable or superior to that of clotrimazole and was greater than that of haloprogin and the other reference drugs under the conditions used. Only tolnaftate was superior to ME1401 in its activity against clinical isolates of Trichophyton rubrum. ME1401 showed no cross-resistance with any of the reference drugs and exhibited potent fungicidal activity.     

Liraglutide: once-daily GLP-1 agonist for the treatment of type 2 diabetes

What is known and Objective: The prevalence of diabetes is increasing worldwide. Over the recent years, new discoveries have led to the development of new pharmacological agents targeting the incretin hormones gastric inhibitory peptide (GIP) and glucagon‐like peptide‐1 (GLP‐1). These agents, called incretin‐mimetics, are the newest agents added to the diabetes treatment options. The purpose of this article is to review the relevant literature on the chemistry, pharmacology, pharmacokinetics, metabolism, clinical trials, safety, drug interactions and place in therapy of liraglutide in the treatment of type 2 diabetes. Methods: An extensive search of the literature was performed with liraglutide and NN2211 as key terms. This article presents a review of the literature related to the chemistry, pharmacology, pharmacokinetics, drug interactions and safety and efficacy of liraglutide. Results and Discussion: Liraglutide, a subcutaneously administered GLP‐1 agonist, displays phamacodynamic and pharmacokinetic properties that allow for once‐daily administration. The agent has been shown to be efficacious as monotherapy, as well as in combination with glimperide, metformin and/or rosiglitazone, reducing glycoslyated haemoglobin (A1C) between 0·84% and 1·5%. The primary adverse event reported with liraglutide is transient nausea. What is new and conclusion: Liraglutide has been well studied in dual and triple combination therapies with sulfonylureas, metformin and rosiglitazone and appears safe and effective. For patients who cannot tolerate first‐line agents, metformin, insulin and sulfonylureas, liraglutide is a reasonable treatment option.     

MRI tumor characterization using Gd‐GlyMe‐DOTA‐perfluorooctyl‐mannose‐conjugate (Gadofluorine M™), a protein‐avid contrast agent

The rationale and objectives were to define the MRI tumor‐characterizing potential of a new protein‐avid contrast agent, Gd‐GlyMe‐DOTA‐perfluorooctyl‐mannose‐conjugate (Gadofluorine M?; Schering AG, Berlin, Germany) in a chemically induced tumor model of varying malignancy. Because of the tendency for this agent to form large micelles in water and to bind strongly to hydrophobic sites on proteins, it was hypothesized that patterns of dynamic tumor enhancement could be used to differentiate benign from malignant lesions, to grade the severity of malignancies and to define areas of tumor necrosis. Gadofluorine M, 0.05 mmol Gd kg^?1, was administered intravenously to 28 anesthetized rats that had developed over 10 months mammary tumors of varying degrees of malignancy as a consequence of intraperitoneal administration of N‐ethyl‐N‐nitrosourea (ENU), 45–250 mg kg^?1. These tumors ranged histologically from benign fibroadenomas to highly undifferentiated adenocarcinomas. Dynamic enhancement data were analyzed kinetically using a two‐compartment tumor model to generate estimates of fractional plasma volume (fPV), apparent fractional extracellular volume (fEV*) and an endothelial transfer coefficient (K^PS) for this contrast agent. Tumors were examined microscopically for tumor type, degree of malignancy (Scarff–Bloom–Richardson score) and location of necrosis. Eighteen tumor‐bearing rats were successfully imaged. MRI data showed an immediate strong and gradually increasing tumor enhancement. K^PS and fEV*, but not fPV obtained from tumors correlated significantly (p < 0.05) with the SBR tumor grade, r = 0.65 and 0.56, respectively. Estimates for K^PS and fEV* but not fPV were significantly lower in a group consisting of benign and low‐grade malignant tumors compared with the group of less‐differentiated high‐grade tumors (1.61 ± 0.64 vs 3.37 ± 1.49, p < 0.01; 0.45 ± 0.17 vs 0.78 ± 0.24, p < 0.01; and 0.076 ± 0.048 vs 0.121 ± 0.088, p = 0.24, respectively). It is concluded that the protein‐avid MRI contrast agent Gadofluorine M enhances tumors of varying malignancy depending on the tumor grade, higher contrast agent accumulation for more malignant lesions. The results show potential utility for differentiating benign and low‐grade malignant lesions from high‐grade cancers. Copyright © 2006 John Wiley & Sons, Ltd.     

Yet another ten stories on antiviral drug discovery (part D): Paradigms,paradoxes, and paraductions

This review article presents the fourth part (part D) in the series of stories on antiviral drug discovery. The stories told in part D focus on: (i) the cyclotriazadisulfonamide compounds; (ii) the {5‐[(4‐bromophenylmethyl]‐2‐phenyl‐5H‐imidazo[4,5‐c]pyridine} compounds; (iii) (1H,3H‐thiazolo[3,4‐a]benzimidazole) derivatives; (iv) T‐705 (6‐fluoro‐3‐hydroxy‐2‐pyrazinecarboxamide) and (v) its structurally closely related analogue pyrazine 2‐carboxamide (pyrazinamide); (vi) new strategies for the treatment of hemorrhagic fever virus infections, including, as the most imminent, (vii) dengue fever, (viii) the veterinary use of acyclic nucleoside phosphonates; (ix) the potential (off‐label) use of cidofovir in the treatment of papillomatosis, particularly RRP (recurrent respiratory papillomatosis); and (x) finally, the prophylactic use of tenofovir to prevent HIV infections. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 4, 667–707, 2010     

Involvement of AMPA Receptors in CSD‐Induced Impairment of LTP in the Hippocampus

Objective.— To investigate the alteration of hippocampal long‐term plasticity and basal synaptic transmission induced by repetitive cortical spreading depressions (CSDs). Background.— There is a relationship between migraine aura and amnesia attack. CSD, a state underlying migraine attacks, may be responsible for hippocampus‐related symptoms. However, the precise role of CSD on hippocampal activity has not been investigated. Methods.— Male Wistar rats were divided into CSD and control groups. Repetitive CSDs were induced in vivo by topical application of solid KCl. Forty‐five minutes later, the ipsilateral hippocampus was removed, and hippocampal slices were prepared for a series of electrophysiological studies. Results.— Repetitive CSDs led to a decrease in the magnitude of long‐term potentiation in the hippocampus. CSD also reduced hippocampal synaptic efficacy, as shown by a reduction in post‐synaptic α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor responses. In contrast, the post‐synaptic N‐methyl‐d ‐aspartate receptor responses remained unchanged. In addition, there were no changes in paired‐pulse profiles between the groups, indicating that CSD did not induce any presynaptic alterations. Conclusion.— These findings suggest that a reduction of post‐synaptic α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor responses is the mechanism responsible for impaired hippocampal long‐term potentiation induced by CSD.     

Anti‐C1q antibodies: association with nephritis and disease activity in systemic lupus erythematosus

Background: Anti‐C1q antibodies have been described in systemic lupus erythematosus (SLE) as well as in other connective tissue diseases. They have been considered as a marker for disease activity and presence of nephritis. Objective: The aim of this study was to determine the prevalence of anti‐C1q antibodies in Brazilian lupus patients as well as analyze their association with different clinical and serologic parameters. Methods: Sera from 81 SLE patients, based on the American College of Rheumatology (ACR) criteria, were collected from a lupus referral outpatient clinic in Salvador, Brazil. Antibodies to C1q were detected by an enzyme‐linked immunoassay (ELISA) kit and antibodies to other cellular antigens identified by indirect immunofluorescence on HEp‐2 cell substrate (ANA), or Crithidia luciliae (dsDNA), and to nucleosome by ELISA. A cutoff of 20 U wasestablished for anti‐C1q and antinucleosome assays. Results: Anti‐C1q antibodies were detected in 39.5% (32/81) of SLE sera. The presence of anti‐C1q antibodies was associated with proteinuria (P=0.028) but not with other laboratory or clinical features, such as antinucleosome or anti‐dsDNA antibodies, hematuria, urinary casts or renal failure, leukopenia, pericarditis, pleuritis, malar rash, seizures, and psychosis. There was a positive correlation between the titers of anti‐C1q antibodies and the systemic lupuis erythematosus disease activity index (SLEDAI) score (r=0.370; P=0.001). Conclusion: This study in Brazilian SLE patients confirms previous findings of the association of anti‐C1q antibodies with nephritis and disease activity. J. Clin. Lab. Anal. 23:19–23, 2009. © 2009 Wiley‐Liss, Inc.     

Analysis of the Drosophila melanogaster anti‐ovarian response to honey bee queen mandibular pheromone

Queen mandibular pheromone (QMP) is a potent reproductive signal to which honey bee workers respond by suppressing their ovaries and adopting alloparental roles within the colony. This anti‐ovarian effect of QMP on workers can, surprisingly, be induced in other insects, including fruit flies, in which females exposed to synthetic QMP develop smaller ovaries with fewer eggs. In this study, we use the Drosophila melanogaster model to identify the components of synthetic QMP required for the anti‐ovarian effect. We found that virgin females respond strongly to 9‐oxo‐2‐decenoic acid and 10‐hydroxy‐2‐decenoic acid (10HDA), suggesting that the decenoic acid components of QMP are essential for the anti‐ovarian response. Further, a nuclear factor of activated T‐cells reporter system revealed neurones expressing the olfactory receptors Or‐56a, Or‐49b and Or‐98a are activated by QMP in the antenna. In addition, we used olfactory receptor GAL4 drivers and a neuronal activator (a neuronal activating bacterial sodium channel) to test whether the candidate neurones are potential labelled lines for a decenoic acid response. We identified Or‐49b as a potential candidate receiver of the 10HDA signal. Finally, the anti‐ovarian response to synthetic QMP is not mediated by decreasing the titre of the reproductive hormones ecdysone and juvenile hormone.     

Liposomal amphotericin B in critically ill paediatric patients

What is known and Objective: Literature provides much evidence regarding liposomal amphotericin B treatment for fungal infections in neonates and infants. Relevant data regarding critically ill paediatric patients of older age are scarce. We aimed to present our experience regarding liposomal amphotericin B use in critically ill paediatric patients from a tertiary‐care paediatric hospital in Athens, Greece. Methods: We prospectively identified all paediatric patients who received treatment with liposomal amphotericin B in the intensive care unit of a tertiary‐care paediatric hospital during a 3‐year period (2005–2008). Data were retrieved from the evaluation of the available medical records. Results and Discussion: Twenty‐three (nine females, mean age: 26·4 months, range: 5–39 months) critically ill paediatric patients were included; 12 had malignancy. In 16 of the 23 included children, liposomal amphotericin B was administered for the treatment of confirmed fungal infections (all but one were invasive), whereas in seven patients, it was used as pre‐emptive treatment. One patient received voriconazole concomitantly. Eleven of the 16 children with documented infections were cured; five improved. Six of the seven children who received pre‐emptive treatment also showed clinical improvement. Nine deaths were noted, all attributed to underlying diseases. Two cases of hepatotoxicity and one case of nephrotoxicity (all leading to drug‐discontinuation) occurred. Seven and five cases of mild reversible hypokalaemia and hyponatraemia, respectively, were also noted. What is new and Conclusion: According to the findings of our small case series, liposomal amphotericin B may provide a useful treatment option for fungal infections of vulnerable critically ill paediatric patients with considerable comorbidity.     

Mucormycosis-associated fungal infections in patients with haematologic malignancies

Among patients with haematologic disorders, mucormycosis most commonly occurs in those with acute leukaemia or lymphoma who have developed neutropenia due to malignancy or to chemotherapy, and in transplanted patients receiving immunosuppressive treatment. Here, we aim to present a retrospective study conducted over a 5-year period (2001-2005). The study included 20 patients with haematologic malignancies with a proven mucormycosis admitted in Medical Oncology Divisions in Cukurova University Hospital. The most frequent sites of infection were paranasal sinuses (95%) and lung (5%). Antifungal treatment was empirically administered in 18 (90%) patients; 18 patients underwent radical surgical debridement (90%). The therapy was successful for only eight patients (40%). Eleven patients died within 1 months of the diagnosis of fungal infection: the cause of death was only by mucormycosis in four patients (36.6%), mucormucosis and systematic inflamatuar response syndrome (SIRS) in two patients (18.2%) and progression of haematologic disease in five patients (45.5%). At univariate analysis, the factors that correlated with a positive outcome from infection were the following: amphotericin B treatment, neutrophil recovery from postchemotherapy aplasia. At multivariate analysis, the factors that significantly correlated with recovery from infection were the liposomal amphotericin B treatment (p = 0.026), doses of L-AmB (p = 0.008) and the length of the treatment (p = 0.01), respectively. It seems to have increased in recent years. Although a reduction of mortality has been observed recently, the mortality rate still remains high. Extensive and aggressive diagnostic and therapeutic procedures are essential to improve the prognosis in these patients.     

Itraconazole oral solution for primary prophylaxis of fungal infections in patients with hematological malignancy and profound neutropenia: a randomized, double-blind, double-placebo, multicenter trial comparing itraconazole and amphotericin B

Systemic and superficial fungal infections are a major problem among immunocompromised patients with hematological malignancy. A double-blind, double-placebo, randomized, multicenter trial was performed to compare the efficacy and safety of itraconazole oral solution (2.5 mg/kg of body weight twice a day) with amphotericin B capsules (500 mg orally four times a day) for prophylaxis of systemic and superficial fungal infection. Prophylactic treatment was initiated on the first day of chemotherapy and was continued until the end of the neutropenic period (>0.5 x 10(9) neutrophils/liter) or up to a maximum of 3 days following the end of neutropenia, unless a systemic fungal infection was documented or suspected. The maximum treatment duration was 56 days. In the intent-to-treat population, invasive aspergillosis was noted in 5 (1.8%) of the 281 patients assigned to itraconazole oral solution and in 9 (3.3%) of the 276 patients assigned to oral amphotericin B; of these, 1 and 4 patients died, respectively. Proven systemic fungal infection (including invasive aspergillosis) occurred in 8 patients (2.8%) who received itraconazole, compared with 13 (4.7%) who received oral amphotericin B. Itraconazole significantly reduced the incidence of superficial fungal infections as compared to oral amphotericin B (2 [1%] versus 13 [5%]; P = 0.004). Although the incidences of suspected fungal infection (including fever of unknown origin) were not different between the groups, fewer patients were administered intravenous systemic antifungals (mainly intravenous amphotericin B) in the group receiving itraconazole than in the group receiving oral amphotericin B (114 [41%] versus 132 [48%]; P = 0.066). Adequate plasma itraconazole levels were achieved in about 80% of the patients from 1 week after the start of treatment. In both groups, the trial medication was safe and well tolerated. Prophylactic administration of itraconazole oral solution significantly reduces superficial fungal infection in patients with hematological malignancies and neutropenia. The incidence of proven systemic fungal infections, the number of deaths due to deep fungal infections, and the use of systemic antifungals tended to be lower in the itraconazole-treated group than in the amphotericin B-treated group, without statistical significance. Itraconazole oral solution is a broad-spectrum systemic antifungal agent with prophylactic activity in neutropenic patients, especially for those at high risk of prolonged neutropenia.     

Invasive fungal infections: epidemiology and analysis of antifungal prescriptions in onco-haematology

What is known and Objective: Invasive fungal infections (IFI) are associated with high rates of morbidity and mortality, particularly in onco‐haematology patients. We aimed to study the epidemiology of IFI in neutropenic patients and estimate the economic impact of treatment of those infections. Methods: All patients hospitalized in onco‐haematology, and treated with antifungal agents, in 2005 were investigated. Four features were studied: the diagnosis for each patient, the antifungal drugs used, the thoracic densitometry reports and the sero‐mycological data. Infectious episodes were stratified according to the EORTC 2008 classification criteria (10). Results and Discussion: Of the 1130 patients surveyed, 192 patients received systemic antifungal agents. Of these 46% had acute leukaemia, 29% bone‐marrow allografts, 7% lymphoma and 18% other malignant haemopathies. Using the EORTC 2008 criteria (10), there were 8 proved IFI (3 aspergillosis, 3 candidosis and 2 other IFI), 17 probable IFI (11 aspergillosis, 6 candidosis) and 16 possible aspergillosis. The incidence of IFI was 2·1%. Eighty patients (41·7%) had received prophylaxis: 56 with fluconazole and 24 with voriconazole. Treatment was most often empirical (n = 127, 66·1%). Combination of two antifungals was used in 17 cases. The mean duration of prophylactic, empirical, proved/probable aspergillosis‐directed, candidaemia‐directed and combination treatment was 19, 19, 46, 32 and 27 days, respectively. The cost of antifungal treatment in 2005 reached almost 2 000 000€, including 427 000€ for documented infections (proved and probable), 1 246 000€ for empirical treatment and 58 300€ for prophylaxis. What is new and Conclusion: The incidence of IFI is low but the pharmacoeconomic impact is extremely high. Improved strategies are required to reduce the frequency and duration of empirical treatment without compromising beneficial outcome.