Cyclosporine Interacts with Mycophenolic Acid by Inhibiting the Multidrug Resistance-Associated Protein 2

In mycophenolate mofetil (MMF)-treated organ transplant recipients, lower mycophenolic acid (MPA) plasma concentrations have been found in cyclosporine (CsA) compared with tacrolimus (Tac)-based immunosuppressive regimens. We previously demonstrated that CsA decreases exposure to MPA and increases exposure to its metabolite MPA-glucuronide (MPAG), possibly by interfering with the biliary excretion of MPAG. To elucidate the role of the multidrug resistance-associated protein (Mrp)-2 in the interaction between MMF and CsA, we treated three groups of 10 Mrp2-deficient rats (TR- rat) for 6 days with either vehicle, CsA (8 mg/kg) or Tac (4 mg/kg) by oral gavage. Hereafter, co-administration with MMF (20 mg/kg) was started in all groups and continued through day 14. The 24-h MPA/MPAG area under the concentration-time curve (AUC) was determined after single (day 7) and multiple MMF doses (day 14). On both study days, there were no significant differences in the mean MPA and MPAG AUC between CsA and Tac-treated animals. We conclude that the pharmacokinetics of MMF are comparable in Mrp2-deficient rats receiving either CsA or Tac as co-medication. This finding suggests that CsA-mediated inhibition of the biliary excretion of MPAG by the Mrp2 transporter is the mechanism responsible for the interaction between CsA and MMF.     

Subcutaneous cryptococcosis due to Cryptococcus diffluens in a patient with sporotrichoid lesions case report, features of the case isolate and in vitro antifungal susceptibilities.

Environmental fungi, in particular primary pathogens and Cryptococcus spp. can be responsible for skin lesions mimicking sporotrichosis. In this paper, we report a case of subcutaneous cryptococcosis in an apparently healthy, young male patient due to a non-C. neoformans Cryptococcus species, C. diffluens. The isolate showed in vitro phenotypic switching that may affect virulence and host inflammatory and immune responses, and in vitro resistance to amphotericin B and 5-flucytosin. This species shares several phenotypic traits with C. neoformans, and, therefore, decisive diagnosis should be based on biopsy and culturing results followed by molecular identification.     

DC-SIGN specifically recognizes Streptococcus pneumoniae serotypes 3 and 14

The Gram-positive bacterium Streptococcus pneumoniae is the leading causative pathogen in community-acquired pneumonia. The ever-increasing frequency of antibiotic-resistant S. pneumoniae strains severely hampers effective treatments. Thus, a better understanding of the mechanisms involved in the pathogenesis of pneumococcal disease is needed; in particular, of the initial interactions that take place between the host and the bacterium. Recognition of pathogens by dendritic cells is one of the most crucial steps in the induction of an immune response. For efficient pathogen recognition, dendritic cells express various kinds of receptors, including the DC-specific C-type lectin DC-SIGN. Pathogens such as Mycobacterium tuberculosis and HIV target DC-SIGN to escape immunity. Here the in vitro binding of DC-SIGN with S. pneumoniae was investigated. DC-SIGN specifically interacts with S. pneumoniae serotype 3 and 14 in contrast to other serotypes such as 19F. While the data described here suggest that DC-SIGN interacts with S. pneumoniae serotype 14 through a ligand expressed by the capsular polysaccharide, the binding to S. pneumoniae serotype 3 appears to depend on an as yet unidentified ligand. Despite the binding capacity of the capsular polysaccharide of S. pneumoniae 14 to DC-SIGN, no immunomodulatory effects on the dendritic cells were observed. The immunological consequences of the serotype-specific capacity to interact with DC-SIGN should be further explored and might result in new insights in the development of new and more potent vaccines.     

Dapsone therapy for malaria during pregnancy: maternal and fetal outcomes.

The need to consider using dapsone in pregnant women for its antimalarial activity is becoming greater in areas where Plasmodium falciparum resistance to chloroquine and pyrimethamine-sulfadoxine is rapidly increasing. Dapsone in combination with other antimalarials might provide a valuable alternative for both treatment and prophylaxis. This review assesses the clinical pharmacology of dapsone and its adverse drug reactions in relation to haemolysis, glucose-6-phosphate dehydrogenase (G6PD) deficiency, blood dyscrasias and methaemoglobinaemia. Studies are summarised reporting its use in leprosy, dermatological and other conditions, and malaria, in relation to maternal and infant outcomes. A total of 924 pregnancies were identified during which dapsone therapy was taken. Only limited data are available and this precludes a meaningful quantitative benefit-risk analysis.Mild degrees of haemolysis consistently occur with continued therapy, although adverse effects may be less likely with intermittent treatment, as most reported adverse effects have occurred with long-term use of dapsone. There are a number of gaps in knowledge where more data are needed. These include no data on pharmacokinetics in pregnancy and whether these are altered with co-administration of chlorproguanil. Potential complications in women with severe anaemia are unknown and there is no information on haemolytic effects in women or the fetus with G6PD deficiency. The use of dapsone in HIV-infected women in malarious areas could carry increased risks because of the immunosuppressive actions of the drug. Trials of dapsone therapy in pregnancy should be considered in malarious areas where there is good reason for its deployment. Controlled trials have provided data on maternal tolerance, and dapsone in combination with other antimalarial drugs can offer clear benefit in terms of improved birthweight. The use of dapsone combinations should be considered when no good alternative is available and the threat of malaria is the greater risk.     

Pharmacokinetic profile of nomegestrol acetate and 17β-estradiol after multiple and single dosing in healthy women

BackgroundThe pharmacokinetics of the monophasic oral contraceptive nomegestrol acetate (NOMAC) plus 17β-estradiol (E₂) were investigated after a single dose and multiple dosing.Study designNOMAC/E₂ (2.5 mg/1.5 mg) was administered daily to healthy women (18–50 years, n= 23) for 24 days; blood samples for pharmacokinetic analysis were obtained on Day 24 and again, after a 10-day pill-free interval, on Day 35 after a single dose.ResultsNOMAC reached steady state after 5 days with mean ± standard deviation (SD) trough NOMAC concentration (C_av) of 4.4±1.4 ng/mL. On Day 24, mean±SD peak NOMAC concentration (C_max, 12.3±3.5 ng/mL) was reached in mean 1.5 h (t_max); the mean±SD elimination half-life (t_½) was 45.9±15.3 h. After a single dose, NOMAC mean±SD C_max was 7.2±2.0 ng/mL and mean±SD t_½ was 41.9±16.2 h. On Day 24, E₂ mean±SD C_av was 50.3±25.7 pg/mL; mean±SD C_max was 86.0±51.3 pg/mL. After a single dose, mean±SD E₂ C_max was 253±179 pg/mL.ConclusionsThese data demonstrate that NOMAC/E₂ has a pharmacokinetic profile consistent with once-daily dosing.     

Antidiuretic hormone release during laparoscopic donor nephrectomy

BACKGROUND: During laparoscopic procedures, increased intra-abdominal pressure may cause transient renal dysfunction due to impaired renal blood flow and induction of neurohormones. However, the relationship between antidiuretic hormone (ADH) secretion and increased intra-abdominal pressure is poorly understood. HYPOTHESIS: Laparoscopic donor nephrectomy (LDN) is associated with an increase in plasma ADH concentration, which influences renal function in both the donor and transplanted graft. OBJECTIVES: To evaluate plasma ADH levels during LDN and to correlate ADH levels with graft function. DESIGN AND INTERVENTIONS: In 30 patients who underwent LDN, plasma ADH levels were collected before insufflation, during surgery, after desufflation, and 24 hours after the procedure. In 6 patients who had open donor nephrectomy, blood samples were obtained as controls. Furthermore, graft function, operative characteristics, and clinical outcome were compared. SETTING: University hospital. RESULTS: In the LDN group, mean ADH levels during pneumoperitoneum and 30 minutes postinsufflation were significantly higher compared with preinsufflation values (P<.001). Twenty-four hours after LDN, mean ADH levels had returned to normal values. There were no significant differences in ADH levels in the open donor nephrectomy group. No significant differences in either intraoperative diuresis, blood pressure readings, or postoperative graft function were documented among the 2 groups. CONCLUSIONS: In this study, LDN was associated with an increase in plasma ADH that appeared to be related to increased intra-abdominal pressure. We conclude that the increased ADH concentrations during LDN are not associated with clinically significant changes in either the kidney donor or the transplanted graft.