Extended spectrum of antibiotic susceptibility for tuberculosis,Djibouti

In the Horn of Africa, there is a high prevalence of tuberculosis that is reported to be partly driven by multidrug-resistant (MDR) Mycobacterium tuberculosis strictu sensu strains. We conducted a prospective study to investigate M. tuberculosis complex species causing tuberculosis in Djibouti, and their in vitro susceptibility to standard anti-tuberculous antibiotics in addition to clofazimine, minocycline, chloramphenicol and sulfadiazine. Among the 118 mycobacteria isolates from 118 successive patients with suspected pulmonary tuberculosis, 111 strains of M. tuberculosis, five Mycobacterium canettii, one ‘Mycobacterium simulans’ and one Mycobacterium kansasii were identified. Drug-susceptibility tests performed on the first 78 isolates yielded nine MDR M. tuberculosis isolates. All isolates were fully susceptible to clofazimine, minocycline and chloramphenicol, and 75 of 78 isolates were susceptible to sulfadiazine. In the Horn of Africa, patients with confirmed pulmonary tuberculosis caused by an in vitro susceptible strain may benefit from anti-leprosy drugs, sulfamides and phenicol antibiotics.     

Distribution of calcineurin activity in blood cell fractions and impact of tacrolimus inhibition

The aim of this study was to investigate calcineurin (PP2B) activity in different blood cell fractions and its inhibition by tacrolimus. Basal PP2B activity was measured in each blood cellular fraction collected from healthy volunteers. The inhibition profile of PP2B activity was explored in isolated peripheral blood mononuclear cells (PBMC) and platelets exposed directly to tacrolimus and in PBMC and platelets isolated from whole blood previously exposed to tacrolimus. Contrasting with red blood cells (30%) and platelets (25%), PBMC represented only 8.7% of PP2B activity of unfractionated whole blood. After tacrolimus exposure of isolated PBMC and platelets, the concentration of tacrolimus required to inhibit 50% of PP2B activity (EC(50)) in PBMC was significantly lower than in platelets (0.26 ng/mL vs. 0.83 ng/mL, P < 0.001). EC(50) values were similar in PBMC and platelets isolated from whole blood previously exposed to tacrolimus (7.69 ng/mL vs. 7.42 ng/mL, respectively). These results suggest PBMC is a very suitable matrix for PP2B measurement in monitoring transplant recipients but clinical studies are necessary to solve clearly this issue.     

Vitamin D3 Supplementation Alleviates Left Ventricular Dysfunction in a Mouse Model of Diet-Induced Type 2 Diabetes: Potential Involvement of Cardiac Lipotoxicity Modulation

Cardiovascular Drugs and Therapy - To evaluate the effectiveness of vitamin D3 supplementation, in secondary prevention, on cardiac remodeling and function, as well as lipid profile, in a mouse...     

Arsthinol nanosuspensions: pharmacokinetics and anti‐leukaemic activity on NB4 promyelocytic leukaemia cells

Objectives The organoarsenical arsthinol was used in the 1950s in the treatment of amoebiasis and yaws and was considered as ‘highly tolerated’. The aim of this work was to study its anti‐leukaemic activity and to develop nanosuspensions of the drug, thereby limiting brain concentrations and the risk of encephalopathy. Methods Arsthinol nanosuspensions were produced by high‐pressure homogenization. The anti‐leukaemic activity was assessed on NB4 acute promyelocytic leukaemia cells (vs solutions of arsthinol, As₂O₃ and melarsoprol). In addition, a pharmacokinetics study was performed to compare the nanosuspensions and the solution of arsthinol. Key findings Arsthinol induced growth inhibition of NB4 cells at lower concentration (IC50 (concentration inhibiting growth by 50%) = 0.78 ± 0.08 μmol/l after 24 h) than As₂O₃ (IC50 = 1.60 ± 0.23 μmol/l after 24 h) or melarsoprol (IC50 = 1.44 ± 0.08 μmol/l after 24 h). When formulated as nanosuspension, arsthinol remained cytotoxic (IC50 = 1.33 ± 0.30 μmol/l after 24 h). This formulation also reduced the drug's access to the brain (C_max = 0.03 μmol/g) whereas bone marrow concentrations remained very high (C_max = 2 μmol/g). Conclusions Nanosuspensions of arsthinol could be proposed for further studies in the treatment of acute promyelocytic leukaemia.     

No effect of CYP450 and P-glycoprotein on hydroxyurea in vitro metabolism

Our objectives were (1) to study the HU metabolism via human cytochromes and (2) to test if HU is a substrate of P-gp. HU metabolism was investigated by determining the appearance of urea and HU decreasing upon incubation with human liver microsomes. Quantification was determined using HPLC coupled with UV-detection at 449 nm. Our method was linear between 5 and 1000 μ m , precise (coefficients of variation ranging from 1.7 to 9.9%), accurate (97.7–103.9%). The limit of quantification was 7 μ m . The ATPase activity of human P-gp membranes was determined by measuring inorganic phosphate liberation. HU and urea measurements in microsomes were not different between 0 and 60 min whatever HU concentration used from 30 to 300 μ m . The presence of NADPH in the medium has no effect on HU and urea measurements. In the absence of verapamil, the ATPase activity was unaffected by HU at concentrations of 10, 30, 100 and 300 μ m . HU is unlikely to cause clinically relevant drug interactions with the substrates of these enzymes/transporters. However, it will be necessary to validate these in vitro data in patients with sickle cell anemia to evaluate the impact of genetic polymorphisms of these enzymes in a black population.     

Arthropathies following the administration of pefloxacin to an adolescent with mucoviscidosis

We report the occurrence of knee joint effusion with prolonged functional impairment in a 17-year old boy with cystic fibrosis treated with pefloxacin for recurrent lower respiratory tract infections caused by Pseudomonas aeruginosa. Because the quinolone pefloxacin fairly often induces joint disease in pediatric age groups, we advocate restricting its use to those patients whose growth is completed. In growing individuals, it seems reasonable to use second generation quinolones only in infections caused by resistant organisms and to avoid exerting the joints during treatment.     

Processing of thyrotropin-releasing hormone prohormone (pro-TRH) generates a biologically active peptide, prepro-TRH-(160-169), which regulates TRH-induced thyrotropin secretion.

Rat thyrotropin-releasing hormone (TRH) prohormone contains five copies of the TRH progenitor sequence Gln-His-Pro-Gly linked together by connecting sequences whose biological activity is unknown. Both the predicted connecting peptide prepro-TRH-(160-169) (Ps4) and TRH are predominant storage forms of TRH precursor-related peptides in the hypothalamus. To determine whether Ps4 is co-released with TRH, rat median eminence slices were perifused in vitro. Infusion of depolarizing concentrations of KCl induced stimulation of release of Ps4- and TRH-like immunoreactivity. The possible effect of Ps4 on thyrotropin release was investigated in vitro using quartered anterior pituitaries. Infusion of Ps4 alone had no effect on thyrotropin secretion but potentiated TRH-induced thyrotropin release in a dose-dependent manner. In addition, the occurrence of specific binding sites for 125I-labeled Tyr-Ps4 in the distal lobe of the pituitary was demonstrated by binding analysis and autoradiographic localization. These findings indicate that these two peptides that arise from a single multifunctional precursor, the TRH prohormone, act in a coordinate manner on the same target cells to promote hormonal secretion. These data suggest that differential processing of the TRH prohormone may have the potential to modulate the biological activity of TRH.