Predictive Modeling of Tacrolimus Dose Requirement Based on High‐Throughput Genetic Screening

Any biochemical reaction underlying drug metabolism depends on individual gene–drug interactions and on groups of genes interacting together. Based on a high‐throughput genetic approach, we sought to identify a set of covariant single‐nucleotide polymorphisms predictive of interindividual tacrolimus (Tac) dose requirement variability. Tac blood concentrations (Tac C₀) of 229 kidney transplant recipients were repeatedly monitored after transplantation over 3 mo. Given the high dimension of the genomic data in comparison to the low number of observations and the high multicolinearity among the variables (gene variants), we developed an original predictive approach that integrates an ensemble variable‐selection strategy to reinforce the stability of the variable‐selection process and multivariate modeling. Our predictive models explained up to 70% of total variability in Tac C₀ per dose with a maximum of 44 gene variants (p‐value <0.001 with a permutation test). These models included molecular networks of drug metabolism with oxidoreductase activities and the multidrug‐resistant ABCC8 transporter, which was found in the most stringent model. Finally, we identified an intronic variant of the gene encoding SLC28A3, a drug transporter, as a key gene involved in Tac metabolism, and we confirmed it in an independent validation cohort.     

Formulation optimization and <Emphasis Type="Italic">in vivo</Emphasis> evaluation of mucoadhesive xyloglucan microspheres

Mucoadhesive microspheres of the novel polymer, xyloglucan, have been formulated and their performance characteristics have been systematically evaluated in vitro and in vivo. The mucoadhesive microspheres were obtained by incorporating glipizide as model drug in xyloglucan as a mucoadhesive polymer and sodium alginate as a gel-forming polymer by the orifice-ionic gelation method. A3² factorial design was employed to study the effect of independent variables, xyloglucan concentration (X ₁ ) and calcium chloride (CaCl₂) concentration (X ₂ ), on the dependent variables including drug entrapment efficiency, release time (t ₈₀), and percentage mucoadhesion in 1h. The best batch exhibited high drug entrapment efficiency (92.98%) and percentage mucoadhesion (78% after 1h). The drug release was also controlled for more than 8 hours. In vivo testing of the mucoadhesive microspheres revealed significant hypoglycemic effect of glipizide.     

Persistence and Dissipation of Flubendiamide and Des-iodo Flubendiamide in Cabbage (Brassica oleracea Linne) and Soil

Flubendiamide belongs to a novel class of insecticide which controls lepidopteran pest complex of cabbage such as diamondback moth, cabbage white butterfly, cluster caterpillar etc. Being a newly introduced insecticide no information is available on its residue persistence in cabbage. A study was undertaken to evaluate the residue persistence of flubendiamide in cabbage and soil following 2 applications of flubendiamide 480 SC at the recommended and double the recommended dose of 24 and 48 g a.i. ha⁻¹. Initial residue deposits of flubendiamide in cabbage were 0.33 and 0.49 mg kg⁻¹ respectively. The residues persisted for 10 days from the both the treatments and dissipated with the half-life of 3.9 and 4.45 days, respectively. Des-iodo flubendiamide, a metabolite of flubendiamide, was not detected in cabbage at any time during the study period. Soil sample collected from the treated field after 15 days was free from any residue of flubendiamide or its metabolite.     

Pharmacokinetic study of tempo carboxylic acid, a nitroxyl MRI contrast media, in control and streptozocin diabetic rats

The pharmacokinetics of tempo carboxylic acid (TCA), a nitroxyl contrast medium have been evaluated in control and streptozocin-diabetic rats. Previous magnetic resonance imaging (MRI) studies in diabetic rats showed prolongation of contrast visualization in the renal cavities after injection of TCA. Diabetes induced only slight alterations to the pharmacokinetic parameters. Rate constants and half lives were unchanged after four months of diabetes. A significant decrease of the apparent total body clearance and volume of distribution was observed while the area under the curve was increased. These alterations are not sufficient to explain MRI abnormalities which have to be elucidated.     

Primary Amenorrhoea in a Triple X Female

The incidence of trisomy X in the newborn population is estimated to be 1 in 1,000 liveborn females. Most of them have normal physical appearance and puberty. Therefore, the reported number of triple X females in the literature is low. We herein report one patient with triple X chromosomes, primary amenorrhoea and normal intelligence. Steroid hormonal levels, clinical and ultrasound findings were suggestive of ovarian failure/gonadal dysgenesis. This case emphasizes the need for chromosomal analysis in women presenting with premature ovarian failure leading to primary or secondary amenorrhoea.     

Effect of storage and sodium chloride on excision of CTXФ or pre-CTXФ and CTXФ from Vibrio cholerae O139 strains

We examined the effect of storage and sodium chloride on excision of CTXФ or pre-CTXФ and CTXФ from Vibrio cholerae O139 strains. We found that one strain of V. cholerae O139 VO146P showed loss of the complete phage array, and other strain VO170P showed partial loss of the phage array giving rise to altered strains designated as VO146N and VO170N. Results of PCR and RFLP analysis revealed that both strains (VO146P and VO170P) possessed a single copy of pre-CTX^ETΦ and two copies of CTXΦ comprising CTX^ClassΦ and CTX^CalcΦ arranged in tandem, and integrated in the large chromosome. The presence of classical ctxB was detected in CTX^CalcΦ of both V. cholerae O139 strains. Nucleotide sequencing of three housekeeping genes showed no difference between parent and altered strains of V. cholerae O139.     

Motion artifact suppression technique (MAST) for MR imaging

A technique has been developed that significantly improves the image resolution and reduces motion artifacts in conventional two-dimensional Fourier transform and three-dimensional Fourier transform magnetic resonance imaging sequences. Modifications on the gradient waveforms completely refocus the transverse magnetization at the echo time, regardless of the motion occurring between the time of the 90 degrees radiofrequency excitation and the echo time (within-view). This accomplishes suppression of motion artifacts and regains the signal from flowing blood and CSF. Images of the head, abdomen, chest, and spine are reproduced which show the increase in signal and anatomical detail that would otherwise be degraded and lost in artifact noise. This technique has reduced the practical difficulty of obtaining clinically diagnostic T2-weighted abdominal images. It also has allowed diagnostic quality T1- and T2-weighted images to be obtained with one acquisition per view, thus reducing the total scan time.     

Prospective observational study of drug-induced hyperkalemia in hospitalized non dialized adult patients

OBJECTIVE: To study the incidence and risk factors of drug-induced hyperkalemia in adult, hospitalized patients. METHODOLOGY: A three months prospective observational study was used including all hospitalized, non dialyzed, patients older than 17 years who presented with a hyperkalemia egal or over 6 mmol/L. The studied variables were demographic, clinical, biological and therapeutic. RESULTS: Forty patients, among 112 included, had a hyperkalemia promoted by drug(s) (3.5 cases for 1000 hospitalized patients). They were 73 +/- 15 years old and 72.5% had a past medical history of chronic renal failure. The hyperkalemia (6.42 +/- 0.48 mmol/L) was associated with an increase in creatininemia in 67.5% of patients. The most frequent treatment observed were renin angiotensin system drugs in 62.5% of patients, spironolactone in 37.5% or both drugs in 25%. CONCLUSION: A better use of these drugs would be able to prevent some cases of hyperkalemia.