Differential effects of cyclosporin A and tacrolimus on magnesium influx in Caco2 cells.

Purpose: Hypomagnesemia with urinary magnesium (Mg) wasting is a well acknowledged side effect of cyclosporin A (CsA) and tacrolimus (FK506) treatments. TRPM6, TRPM7 and MagT1 are involved in the active transcellular Mg transport processes in intestine and kidney. Since Mg homeostasis is tightly controlled by the dynamic action of intestinal absorption of dietary Mg and renal excretion of Mg, we investigated whether CsA and FK506 in commercially available solutions for clinical use decrease the expression and the function of TRPM6, TRPM7 or MagT1 in the intestinal epithelial cell line Caco2.

A study of magnesium deficiency in human and experimental pulmonary hypertension.

Pulmonary hypertension (PH) is defined as an increase in mean pulmonary arterial pressure above 25 mmHg. Pulmonary vasoconstriction, cellular proliferation, inflammation, and oxidative stress are involved in the pathophysiology of PH. Since hypomagnesemia was reported to promote endothelial cell dysfunction leading to inflammation and oxidative stress, we investigated the potential involvement of magnesium (Mg) deficiency in experimental and human PH.

Magnesium-deficiency does not alter calcineurin inhibitors activity in mice.

Introduction: Tacrolimus (TAC) and cyclosporin (CsA) are commonly responsible for hypomagnesemia that predisposes in turn for hypertension, renal impairment and encephalopathy.

Objective: The effects of TAC on Mg(2+)-homeostasis and of pre-existing Mg(2+)-deficiency on TAC immunosuppressive activity were compared to CsA in mice.

Methods: Mg(2+) was quantified in plasma, erythrocytes, urine, feces, and femurs from mice treated with TAC 5mg/kg/day.

Biodistribution and anticancer activity of a new Vinca alkaloid encapsulated into long-circulating liposomes.

S12363 is a potent therapeutic agent with a strong in vitro activity against a variety of tumor types but also a high in vivo toxicity. Loading of this drug into long-circulating liposomes is expected to enhance its therapeutic index. Pharmacokinetics of liposomal S12363 showed that circulating S12363 was entrapped into liposomes until 24 hours after intravenous injection in mice.

Impact of cerebral malaria on brain distribution of mefloquine.

Cerebral malaria (CM) is the most severe complication of Plasmodium falciparum malaria. The aim of this study was to investigate the influence of CM on the cerebral uptake of mefloquine (MQ), in an experimental model of mice infected with Plasmodium berghei ANKA (PbA). Drug diffusion in brain is closely related to efflux pumps such as P-glycoprotein (P-gp/ABCB1/MDR1) and Breast Cancer Resistant Protein (BCRP/ABCG2), two major components of the blood-brain barrier (BBB) which can be modified by inflammation and/or infection.

Threshold to N-methyl-D-aspartate-induced seizures in mice undergoing chronic nutritional magnesium deprivation is lowered in a way partly responsive to acute magnesium and antioxidant administrations.

Magnesium deficiency may be induced by a diet impoverished in magnesium. This nutritional deficit promotes chronic inflammatory and oxidative stresses, hyperexcitability and, in mice, susceptibility to audiogenic seizures. Potentiation by low-magnesium concentrations of the opening of N-methyl-D-aspartate (NMDA) receptor/calcium channel in in vitro and ex vivo studies, and responsiveness to magnesium of in vivo brain injury states are now well established.

MDR1A (ABCB1)-deficient CF-1 mutant mice are susceptible to cerebral malaria induced by Plasmodium berghei ANKA.

Under experimental conditions, Plasmodium berghei infection causes cerebral malaria (CM) in susceptible strains of mice such as C57BL/6 and CBA/Ca, whereas BALB/c or DBA/2J strains serve as a model for CM-resistant mice. The aim of the present study was to investigate the susceptibility of the CF1 mouse strain, carrying a spontaneous mutation of the mdr1a gene, to infection with Plasmodium berghei ANKA (PbA). The mdr1a gene codes for P-glycoprotein (P-gp/ABCB1), an efflux pump that is one of the major components of the blood-brain barrier.

Effect of hypomagnesemia on allogeneic activation in mice.

Introduction: Magnesium (Mg) plays an essential role in a wide range of fundamental cellular reactions. It has been reported that in rodents Mg-deficient diet-induced hypomagnesemia results in an early inflammation. We have previously shown that chronic severe hypomagnesemia was associated neither with endothelial cell activation nor with an inflammatory process which are crucial in the allograft rejection process.

Impact of cyclosporine A on magnesium homeostasis: clinical observation in lung transplant recipients and experimental study in mice.

Background: Hypomagnesemia is a common finding in patients receiving cyclosporine A (CsA) therapy. The relationship between CsA-induced hypomagnesemia and nephrotoxicity and the effects of oral magnesium (Mg) supplementation remain unclear. After a retrospective analysis of the time-course of plasma Mg and creatinine levels in lung allograft recipients treated with both CsA and oral Mg supplementation, we investigated the effects of CsA treatment on Mg homeostasis in mice with normal or Mg-deficient diet and the effects of oral Mg supplementation on plasma Mg levels.

Neuroprotective gene profile in the brain of magnesium-deficient mice.

Background: Magnesium (Mg) deficiency may lead to serious metabolic, biological and organic dysfunctions, and cause various clinical disorders. In the current study, we explore endothelial cell activation, inflammation and cell death induced in the brain of adult mice by Mg-deficient diet.

Methods And Results: Neither TNFalpha, substance P, sTNFRI, sTNFRII proteins (ELISA), nor TNFalpha, adherence molecules and prolactin mRNAs, nor NK1R (immunohistochemistry on brain sections) were up-regulated.

Allogeneic activation is attenuated in a model of mouse lung perfused with magnesium-deficient blood.

Hypomagnesemia, which is frequently observed in patients treated with calcineurin inhibitors to prevent rejection after allogeneic transplantation, has been associated with a faster rate of decline in allograft function. The effect of hypomagnesemia on lung allograft has not been reported yet. In our model of isolated mouse lung, we have evaluated the early effects of allogeneic lung perfusion with blood from magnesium (Mg)-deficient mice for 3 h on lung activation and remodelling, compared to isogeneic perfusion.

Efavirenz does not interact with the ABCB1 transporter at the blood-brain barrier.

Purpose: This work characterizes the interactions between efavirenz (EFV) and P-glycoprotein (P-gp/ABCB1) at the blood-brain barrier (BBB) and predicts the possible consequences on the brain uptake of coadministered P-gp substrates.

Methods: The uptake of EFV was measured in whole brains of rat and mdr1a-/- and mdr1a+/+ mice, and in GPNT cells (rat brain endothelial cell line) with and without P-gp inhibitors (PSC833, S9788, Quinidine). The effect of a single dose or multiple doses of EFV on the P-gp functionality was evaluated in vivo and in vitro by measuring the brain and cell uptake of digoxin, completed by the analysis of the P-gp expression at the rat BBB after repeated administrations of EFV.

Role of E-selectin in cell apoptosis induced by allogeneic blood perfusion in isolated mouse lung.

Background: In a model of mouse isolated lung, we have recently demonstrated that E-selectin is involved in the activation of endothelial cells induced by allogeneic blood perfusion. In the present study, we explored the signaling pathway of apoptosis induced by E-selectin triggering.

Methods: Lungs were perfused for 3 hours with fresh blood in the absence or presence of an anti-E-selectin monoclonal antibody, or a protein kinase C (PKC), protein tyrosine phosphatase (PTP), or protein tyrosine kinase (PTK) inhibitor.

Influence of the pro-inflammatory cytokines on P-glycoprotein expression and functionality.

Purpose: P-glycoprotein (P-gp) is involved in the transport of many drugs at different barriers with consequence in terms of drug distribution and elimination. The expression and activity of P-gp can be modulated by different factors and pathologies. The present article reviews the knowledge regarding the effect of pro-inflammatory cytokines (TNFalpha, IL-1beta, IL-6, IL-2, IFNgamma) on the expression and the functionality of P-gp at three major sites of drug absorption and disposition: the liver, the blood-brain barrier, and the intestine.

E-selectin early overexpression induced by allogeneic activation in isolated mouse lung.

Background: The interaction between host lymphocytes and graft endothelial cells plays an important role in graft rejection.

Methods: Using our model of isolated ventilated lung from female mouse perfused with fresh blood from either isogeneic or allogeneic male mouse for 3 hours without noticeable ischemia, we have investigated the kinetics of the early events after endothelial cell triggering by E-selectin engagement.

Results: Isogeneic perfusion induced nonspecific endothelial cell activation, which was characterized by up-regulation of E-selectin, intercellular adhesion molecule (ICAM)-1, and of the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, and lymphotoxin-alpha (mRNAs by real-time polymerase chain reaction).

How to improve current therapeutic standards in upper respiratory infections: value of fusafungine.

Despite guidelines and educational programs, systemic antibiotics and anti-inflammatory drugs are often inappropriately prescribed in upper respiratory tract infections (URTIs), although they are most often of viral origin, generally benign, and self-limiting with spontaneous recovery in more than 80% of cases. Reduced use of systemic antibiotics is crucial in the current context of concern about emerging antibiotic resistance and reducing unnecessary costs associated both with drug over-consumption and with the management of the consequences of antibiotic resistance. Local bacterial or viral infection of the airways induces an early inflammatory reaction.

Effects of exogenous IL-2 administration on the homeostasis of CD4+ T lymphocytes.

IL-2 is currently used in HIV-infected patients to treat CD4+ T lymphopenia. In order to document a mechanism accounting for its capacity to restore immune function, we studied the effects of IL-2 administration in mice. IL-2 treatment of C57BL/6 mice for 4 days leads to a transient accumulation of CD4+ T lymphocytes.

Heterotopic en bloc tracheobronchial transplantation with direct revascularization in pigs.

Objective: This article describes the application of a novel aortic tube technique for directly revascularized tracheobronchial transplantation with dual blood supply in pigs.

Methods: Eleven adult Large White pigs underwent heterotopic tracheal transplantation with a dual revascularization technique (inferior thyroid artery and bronchial artery). Seven tracheobronchial grafts were perfused ex vivo, and hemodynamic data were collected.

Antibiotic prescribing patterns of French GPs for upper respiratory tract infections: impact of fusafungine on rates of prescription of systemic antibiotics.

Introduction: Despite attempts to limit their use, systemic antibiotics are extensively prescribed for respiratory infections in France. This survey analyzed data from the Thales database, which contains information from 1010 representative French general practitioners (GPs). The objective was to assess French GP prescribing patterns in upper respiratory tract infections (URTIs) including the rate of prescription of systemic antibiotics and anti-inflammatory drugs in the presence or absence of prescribing fusafungine (Locabiotal) an antibiotic with anti-inflammatory activity indicated for local use in URTIs.

[The impact of fusafungine on the prescription of antibiotics in the treatment of rhinopharyngitis].

Objective: The analysis in France, during the period 01/12/99 to 30/11/2000, of the prescription of systemic antibiotics in patients with rhinopharyngitis and of the variables statistically related to such prescriptions and the potential role of fusafungine in the form of a rhinopharyngeal spray.

Methods: A retrospective study, based on a panel of 1,010 general practitioners, in a cohort of 30,568 patients presenting with rhinopharyngitis. The fusafungine group consisted of 16,076 patients who had rhinopharyngitis and in whom fusafungine was prescribed.

Endothelial cell early activation induced by allogeneic lymphocytes in isolated perfused mouse lung.

Background: The early inflammatory response induced following vascularized organ allotransplantation is mediated by adhesin-ligand interactions between blood leukocytes and allogeneic endothelial cells. In the present study, we focused on the role of allogeneic blood lymphocytes in early immune alterations following lung reperfusion.

Methods: We developed an experimental model of isolated and ventilated lung in female C57BL/6 mouse perfused with either isogeneic (C57BL/6) or allogeneic (C3H/He) male mouse fresh blood for 3 hours.