Activity of liposomal amphotericin B with prolonged circulation in blood versus those of AmBisome and fungizone against intracellular Candida albicans in murine peritoneal macrophages

Activity against intracellular Candida albicans was assessed in C. albicans-infected murine peritoneal macrophages exposed to long-circulating pegylated amphotericin B liposomes (PEG-AMB-LIP), AmBisome, or Fungizone. The level of antifungal activity of Fungizone is much higher than that of AmBisome or PEG-AMB-LIP, while PEG-AMB-LIP and AmBisome show equivalent activity levels. Previous exposure of uninfected macrophages to PEG-AMB-LIP or AmBisome is advantageous for intracellular antifungal activity.     

A case of skin cryptococcosis in systemic lupus erythematosus

Here is presented a case of woman treated by immunosuppressive preparations because of systemic lupus erythematosus with ski manifestations as tubercles and ulcerations on skin of trunk and extremities. On the basis of histological examination of tubercle skin specimens and mycological examinations of material obtained from skin ulcerations cryptococcosis was diagnosed. Disease was limited to skin that was an entry of infection. Patient was treated by Amphotericin B administered intravenously and Flucitosine per os. Amphotericin B was also applied topically. The results of cultures became gradually negative, up to total disappearance of fungus cells in direct specimens, prepared from examined material. After treatment continuing for 5 months only discoloured scars were observed on sick skin.     

Auricular fibrillation, systemic embolism and anticoagulant treatment

The risk of arterial embolism, specially cerebral, in patients with mitral stenosis associated atrial fibrillation is seventeen fold greater than that of the general population and five fold greater than that of non rheumatic atrial fibrillation. The usefulness of oral anticoagulant therapy in patients with atrial fibrillation and mitral stenosis is clear. In patients with non rheumatic atrial fibrillation, the controversy about its usefulness has been cleared with five recent reports showing a significant benefit or oral anticoagulation. We believe that these results may be applied to the routine management of these patients provided an adequate patient selection, consideration of contraindications and the use of a low anticoagulation range. Aspirin effectiveness in these patients is unsettled. One study showed benefits of 375 mg/day in patients younger than 75 years. The embolic risk in patients with atrial fibrillation must be stratified. High risk patients require the use of oral anticoagulation with an INR range between 3 and 4.5; those with medium risk require an INR between 2 and 3 and in some, aspirin use may be an alternative. When electrical cardioversion is indicated, oral anticoagulation must be used when atrial fibrillation has lasted for more than two days. In these cases, it is advisable to postpone cardioversion for three weeks after oral coagulation has started and to maintain this treatment for 3 or 4 additional weeks after cardioversion.     

Indicators of disease activity, prognosis, and treatment of systemic lupus erythematosus

Several instruments have been developed to assess disease activity in systemic lupus erythematosus. Any study of a new laboratory measure, any therapeutic trial, and any study of outcome and prognosis should include one of these validated measures of disease activity. The treatment of lupus is far from ideal. A controlled trial of plasmapheresis showed no benefit over standard regimens in lupus nephritis. A long course of pulse cyclophosphamide was shown to be better than pulse methylprednisolone or a short course of intravenous pulse cyclophosphamide. Despite the lack of ideal therapy, the prognosis of lupus, including 15-year survival rates, has improved over the past 4 decades. Specific organ damage continues to be an issue. Infection and vascular disease have emerged as important factors. With improved survival, other outcome measures, including specific organ function and health status, must be considered.     

New approaches for treatment of systemic lupus erythematosus

Each of the new approaches to treating SLE offers some hope in the ongoing effort to respond effectively to the challenges of this debilitating and often lethal condition. Research is extremely active and promises to accelerate as more is learned.     

Pharmacodynamics of fluconazole in a murine model of systemic candidiasis

In this study we defined the pharmacodynamic parameter that optimizes outcome in deep-seated Candida albicans infections treated with fluconazole. Using a murine model of systemic candidiasis, we conducted single-dose dose-ranging studies with fluconazole to determine the dosage of this drug that resulted in a 50% reduction in fungal densities (50% effective dose [ED50]) in kidneys versus the fungal densities in the kidneys of untreated controls. We found that the ED50 of fluconazole given intraperitoneally was 4.56 mg/kg of body weight/day (95% confidence interval, 3.60 to 5.53 mg/kg/day), and the dose-response relationship was best described by an inhibitory sigmoid maximal effect (Emax) curve. To define the pharmacodynamics of fluconazole, we gave dosages lower than, approximating, and higher than the ED50 of fluconazole (range, 3.5 to 5.5 mg/kg/day, equivalent to the ED16 to the ED75) to various groups of infected animals using three dose-fractionation schedules. For each total dose of fluconazole examined, the dose-fractionation schedules optimized the ratio of the area under the concentration-time curve (AUC) to the MIC (the AUC/MIC ratio), the ratio of the maximum concentration of drug in serum (Cmax) to the MIC, and the time that the drug remained above the MIC for the infecting C. albicans isolate. Similar reductions in fungal densities in kidneys were seen between groups that received the same total dose of fluconazole in one, two, or four equally divided doses. Thus, dose-fractionation studies demonstrated that the pharmacodynamic parameter of fluconazole that best predicted outcome was the AUC/MIC ratio.     

Onychomycosis: diagnosis and systemic treatment

Onychomycosis, a persistent fungal infection affecting the toenails and fingernails, can interfere with standing, walking, and exercising. Associated physical impairments can result in paresthesia, pain, discomfort, and loss of manual dexterity. Patients may also suffer from loss of self-esteem and social interaction. A definitive diagnosis is crucial for effective treatment, because many other skin and nail disorders mimic onychomycosis. Diagnosis involves microscopic potassium hydroxide preparation, cultures, nail biopsy, and histologic analysis. Treatment can include topical and systemic antifungal therapies as well as nonpharmaceutical methods. This paper discusses pathophysiology, diagnosis, and treatment options for this common nail dystrophy, including the newer antifungal medications now available.     

Importance of beta2-microglobulin in murine resistance to mucosal and systemic candidiasis

beta2-Microglobulin knockout (beta2m-/-) mice, which lack major histocompatibility complex class I expression and are deficient in CD8alpha/beta T-cell receptor alpha/beta (TcRalpha/beta) T cells, were as resistant to systemic (intravenous) challenge with Candida albicans as immunocompetent controls. Conversely, the beta2m-/- mutant mice were susceptible to systemic candidiasis of endogenous origin despite the induction of C. albicans-specific antibody and cell-mediated immune responses after colonization with a pure culture of C. albicans. Despite some superficial and transient infections of tongues and esophagi (detected by histology) at 1 to 2 weeks after oral colonization and gastric infections (cardia-antrum section) which were observed at 10 to 12 weeks after oral challenge, C. albicans-colonized beta2m-/- mice showed an overall resistance to candidiasis in other mucosal and cutaneous tissues. These data suggest that immune defects that accompany the loss of beta2-microglobulin play an important role in murine resistance to gastric and disseminated candidiasis of endogenous (intestinal tract) origin and that innate immunity and CD4 TcRalpha/beta as well as CD8alpha/alpha TcRalpha/beta (or -gamma/delta) T cells play an important role in resistance to systemic, cutaneous, and nongastric mucosal tissues.     

Safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) in neutropenic patients

The safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) administered for empirical antifungal therapy were evaluated for 36 persistently febrile neutropenic adults receiving cancer chemotherapy and bone marrow transplantation. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study which enrolled a total of 8 to 12 patients in each of the four dosage cohorts. Each cohort received daily doses of either 1.0, 2.5, 5.0, or 7.5 mg of amphotericin B in the form of AmBisome/kg of body weight. The study population consisted of patients between the ages of 13 and 80 years with neutropenia (absolute neutrophil count, <500/mm3) who were eligible to receive empirical antifungal therapy. Patients were monitored for safety and tolerance by frequent laboratory examinations and the monitoring of infusion-related reactions. Efficacy was assessed by monitoring for the development of invasive fungal infection. The pharmacokinetic parameters of AmBisome were measured as those of amphotericin B by high-performance liquid chromatography. Noncompartmental methods were used to calculate pharmacokinetic parameters. AmBisome administered as a 1-h infusion in this population was well tolerated and was seldom associated with infusion-related toxicity. Infusion-related side effects occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication. Serum creatinine, potassium, and magnesium levels were not significantly changed from baseline in any of the dosage cohorts, and there was no net increase in serum transaminase levels. AmBisome followed a nonlinear dosage relationship that was consistent with reticuloendothelial uptake and redistribution. There were no breakthrough fungal infections during empirical therapy with AmBisome. AmBisome administered to febrile neutropenic patients in this study was well tolerated, was seldom associated with infusion-related toxicity, was characterized by nonlinear saturation kinetics, and was effective in preventing breakthrough fungal infections.     

Serological diagnosis for cryptococcosis by the detection of beta-glucan and capsular polysaccharide

Cryptococcosis is definitely diagnosed microbiologically or pathologically. As adjunctive diagnosis, serological and genetic diagnosis could be a promising method for rapid diagnosis of cryptococcosis. Capsular polysaccharides such as glucuronoxylomannan were used as antigens for serodiagnosis and very high sensitivity and specificity were obtained in pulmonar cryptococcosis. Polymerase chain reaction for URA5 gene was examined but the sensitivity was not high enough for clinical use.     

SCH56592 treatment of murine invasive aspergillosis

We analyzed the clinical presentation of 800 severe malaria cases six months to 15 years of age (mean +/- SD = 4.3 +/- 3.0) recruited at the pediatric ward of the Ouagadougou University Hospital, and at the Sourou and Nayala District Hospitals in Burkina Faso. Inclusion criteria followed the World Health Organization (WHO) definition of severe and complicated malaria. The children were treated according to WHO guidelines with a complete regimen of drugs that were provided free of charge as part of the study. The case fatality rate of each sign and symptom of severe malaria was calculated on the 686 children whose outcomes were known. A total of 95 patients (13.8%) died while in the hospital; the mean +/- SD age of these children was 3.2 +/- 2.1 years. The age distribution and the clinical patterns of severe malaria was compared in patients from the urban areas of Ouagadougou characterized by relatively low transmission, and from rural areas where the mean inoculation rates are at least 20-fold higher. The mean +/- SD age of the urban and rural patients was 4.8 +/- 3.0 and 2.2 +/- 1.9 years, respectively (P < 0.001). The prevalence of coma was higher in the urban subsample (53.6% versus 28.9%; P < 0.001) while that of severe anemia (hemoglobin < 5 g/dL) was higher in rural patients (47.4% versus 14.8%; P < 0.001). Our data, in line with previous results obtained comparing rural areas characterized by different inoculation rates, show that the epidemiologic context influences the clinical presentation of severe malaria.     

Comparison of treatment utilization and outcome for Hispanics and non-Hispanic whites

Ketoprofen is a chiral non-steroidal anti-inflammatory drug (NSAID) available as a racemic (rac) mixture of S-(+)- and R-(-)-isomers. Its inhibitory effect on prostaglandin biosynthesis resides virtually in the S-form. Interestingly, R-ketoprofen does not undergo substantial metabolic inversion in humans. Though contraindicated during the last trimester of pregnancy, NSAIDs, including ketoprofen, are used as tocolytic agents in some cases. The S/R plasma concentration ratio was reported to average 2.3 in premature neonates whose mothers were given rac-ketoprofen and to be close to 1 in the maternal plasma. Thus, we investigated the placental transfer of rac-ketoprofen in vitro using Schneider's perfused human cotyledon model. Glucosed Earle solutions with and without human serum albumin (HSA) were used. Several maternal perfusates were tested with different rac-ketoprofen concentrations together with 20 mg L-1 of antipyrine as a reference substance. Ketoprofen enantiomers were assayed by a specific HPLC method with derivatization procedure. HSA concentrations in maternal perfusate influenced the placental transfer of ketoprofen enantiomers. In the absence of HSA in the maternal perfusate, the S-(+)/R-(-) concentration ratio was close to 1 in the fetal perfusate. By contrast, this ratio averaged 1.44 after addition of HSA 10 g L-1 on the maternal side. Similar results were found for dialysis experiments using an inert Spectrapor 2 membrane suggesting that the S-(+)-free concentration is superior to the R-(-)-free concentration in the presence of HSA. Direct measurements of the free concentrations by centrifugal ultrafiltration confirmed this hypothesis. Accordingly, the data observed in vivo may result, at least in part, from the stereoselective protein binding of ketoprofen.     

Allium sativum (garlic) treatment for murine transitional cell carcinoma

BACKGROUND: Currently, immunotherapy with Bacillus Calmette-Guerin (BCG) is the most effective treatment for superficial bladder carcinoma, but treatment-related toxicity may limit its use in some patients. Alternative treatments are needed for patients who fail to respond to BCG immunotherapy. Allium sativum (AS), or garlic, is known to have a broad range of biologic activities, including immune stimulation and reported antitumor activity. For these reasons, the authors conducted a series of experiments designed to explore the possible therapeutic effects of AS in the MBT2 murine bladder carcinoma model. METHODS: C3H/HeN mice were randomized prior to initiation of each experimental protocol. Mice received 1 x 10(3) MBT2 cells in 0.1 mL RPMI-1640, administered subcutaneously into the right thigh, on Day 0 of the experiment. AS was injected at the site of tumor transplantation on Day 1 and at 2- to 7-day intervals up to Day 28. To evaluate the effects of oral AS in this model, treatment was initiated 30 days prior to tumor inoculation and continued for 30 days after tumor inoculation. Animals in all experiments were followed for tumor incidence, tumor growth, and survival. RESULTS: In the initial experiments, subcutaneous AS significantly reduced tumor volume compared with the saline control (P < 0.05). Unfortunately, treatment-related death was also observed, requiring reduction in the total dose of AS. Animals that received 5 weekly immunizations of AS (5 mg, 5 mg, 1 mg, 1 mg, and 1 mg; cumulative dose = 13 mg) had significantly reduced tumor incidence, tumor growth, and increased survival when compared with animals that received the saline control. No treatment-related deaths were observed with this treatment schedule. To determine whether systemic AS administration might be effective, orally administered AS was tested at doses of 5 mg, 50 mg, and 500 mg per 100 mL of drinking water. Mice that received 50 mg oral AS had significant reductions in tumor volume (P < 0.05) when compared with animals that received the saline control, and mice that received 500 mg oral AS had significant reductions in both tumor volume and mortality (P < 0.05). CONCLUSIONS: The significant antitumor efficacy of subcutaneous and oral AS warrants further investigation and suggests that AS may provide a new and effective form of therapy for transitional cell carcinoma of the bladder.     

New aspects in treatment of systemic mycoses

The incidence of systemic fungal infection has been increasing during the last two decades. Candida and Aspergillus spp. are the classical opportunistic pathogens. Rare fungi, such as Mucor, Rhizopus, Fusarium, Trichosporon, Paecilomyces, Alternaria, Cladosporium and Pseudoallescheria, are emerging as cause of systemic fungal infection in the immunocompromised host. For more than 40 years Amphotericin B has been the gold standard of antifungal treatment because of its broad spectrum comprising yeasts, dimorphic fungi and moulds. Its nephrotoxicity has led to the development of lipid-associated preparations of amphotericin B: liposomal amphotericin B, amphotericin B colloidal dispersion and amphotericin B lipid complex. These preparations are less nephrotoxic, but higher doses than those of conventional amphotericin B are needed to achieve the same effect. The triazole fluconazole is the treatment of choice in infections caused by Candida albicans. New antifungal compounds are voriconazole and the candins, the pradimicin/benanomycin family, nikkomycin Z and a liposomal preparation of nystatin.     

Epidemiology, diagnosis and treatment of systemic Candida infection in surgical patients under intensive care

In a career of many searching conceptual insights, Kenneth Bowers drew an important distinction between 2 different dissociative theories of hypnosis: dissociated experience and dissociated control. We contrast these 2 views and discuss how a dissociated control theory can be integrated with current conceptions of frontal executive function. Then we use this frontal elaboration of the dissociated control theory to sketch out a provisional understanding of memory function associated with hypnosis and hypnotic suggestibility, with particular emphasis on unsuggested effects.     

Combination of antiviral immunotoxin and ganciclovir or cidofovir for the treatment of murine cytomegalovirus infections

The effects of two anti-murine cytomegalovirus (MCMV) immunotoxins used in combination with ganciclovir (GCV) or cidofovir (HPMPC) against MCMV were determined in vitro and in mice. The inhibitors were added to cell cultures 24 or 48 h after MCMV adsorption so as to not affect the initial infection rate. The immunotoxins (0.63, 1.25 and 2.5 micrograms/ml) combined with GCV (1.25, 2.5 and 5 microM) or HPMPC (0.03, 0.06 and 0.12 microM) caused synergistic inhibition of virus yield in C127I cells at most of the combinations tested. No toxic effect on cell growth in culture was observed at these immunotoxin/drug combinations. The effects of immunotoxin and GCV treatment were studied further in MCMV-infected severe combined immunodeficient (SCID) mice. Immunotoxin (1 mg/kg per day) given by intraperitoneal (i.p.) injection on days 1, 4 and 7 of the infection did not extend the mean day to death compared with the placebo group. Once daily i.p. treatment with GCV (50 mg/kg per day) for days starting at 24 h after virus inoculation extended survival time almost 11 days. The combination of immunotoxin plus GCV was better than GCV alone, extending the mean day to death an additional 2 to 3 days, which is suggestive of a synergistic effect.