Midodrine in patients with spinal cord injury and anejaculation: A double-blind randomized placebo-controlled pilot study.

OBJECTIVE: The objective of this study is to evaluate the efficacy of midodrine in the treatment of anejaculation in men with spinal cord injury (SCI). STUDY DESIGN: Prospective, double-blind, randomized, placebo-controlled pilot study. METHOD: Men with anejaculation associated with SCI (level of injury above T10) of more than 1 year in duration were approached. Those with no ejaculatory response to one penile vibratory stimulation (PVS) trial were assigned in a double-blind manner to one of the two following interventions once a week for a maximum of 3 weeks or until ejaculation occurred: oral administration of flexible midodrine (7.5-22.5 mg max) followed by PVS (group M), or oral administration of flexible sham-midodrine (placebo) followed by PVS (group P). Sociodemographic data, medical characteristics, and plasma desglymidodrine concentration were collected for all participants. OUTCOME MEASURE: Ejaculation success rate in each group. RESULTS: Among the 78 men approached, 23 participants (level of SCI: C4-T9) were randomized. Three participants abandoned the study and 20 completed the study; 10 were assigned to group M, 10 to group P. Ejaculation was reached for one participant of group M and for two participants of group P. Autonomic dysreflexia associated to PVS occurred in three patients. CONCLUSION: In this small sample study, treatment of anejaculation after SCI with midodrine and PVS did not result in a better rate of antegrade ejaculation in 10 men than in 10 men treated with a placebo and PVS.

Successful and cost-efficient replacement of immunoassays by tandem mass spectrometry for the quantification of immunosuppressants in the clinical laboratory.

The purpose of this paper is to describe the implantation of mass spectrometry in replacement of immunoassays for the measurement of immunosuppressant drugs in the clinical setting, from scientific and financial perspectives. A straightforward, rapid, and economical method was developed for the simultaneous quantification of tacrolimus, sirolimus, and cyclosporine. Following a simple protein precipitation step, supernatants are injected on a small C(18) guard cartridge and gradient elution of the immunosuppressants is performed in a total chromatographic run time of 2.25 min. Sodium adducts of the compounds and internal standards are quantified by electrospray tandem mass spectrometry. The method shows inter-assay impression of less than 10-15% for all compounds with good extraction efficiency (89-104%) and minimal matrix effects, except for sirolimus where ion suppression is more pronounced. The method correlates well with chemiluminescent microparticle immunoassays (on the Abbott Architect analyzer), although the immunoassay results are significantly higher than those obtained by HPLC-MS/MS. The transition from immunoassays to mass spectrometry was well received by the laboratory staff, and significant reductions in reagent costs have been realized (>$250,000 CAD per year). With these savings, the purchase and installation of two complete HPLC-MS/MS systems was completely financed in less than three years.

Development and validation of a rapid liquid chromatography isotope dilution tandem mass spectrometry (LC-IDMS/MS) method for serum creatinine.

OBJECTIVES: To develop an isotope dilution liquid chromatography tandem mass spectrometry (LC-IDMS/MS) method for the standardization of serum creatinine. DESIGN AND METHODS: Supernatants obtained by protein precipitation were injected into a LC-MS/MS. Chromatography was performed on a cation exchanger pre-column in normal phase isocratic mode. Creatinine and creatinine-D(3) were quantified using ion transitions of m/z 114-->44 and 117-->47, respectively. RESULTS: The method was calibrated with the NIST Standard Reference Material 914a and was found to be exact in analyzing the certified reference material SRM 967 from NIST (97.1+/-0.9% and 102.1+/-0.9% of target value for levels 1 and 2, respectively) and by calculating recuperation of spiked creatinine in 10 different patient samples (103.6+/-4.1%). Intra-assay imprecision was 0.9% at both 64.6 and 354 micromol/L creatinine, while inter-assay imprecisions were 1.9% and 1.8%. Absence of ion suppression was confirmed by spiking experiments. The method was shown to be free of carryover. A good correlation was obtained between the LC-MS/MS method and a Jaffe method run on an automated analyzer (r=0.999). CONCLUSIONS: We have developed a fast and simple method for the quantification of serum creatinine by isotope dilution tandem mass spectrometry (IDMS/MS) and we propose that this method can be used as a reference method by laboratories that wish to validate their serum creatinine automated assay.

Cyp3A4, Cyp3A5, and MDR-1 genetic influences on tacrolimus pharmacokinetics in renal transplant recipients.

OBJECTIVE: The immunosuppressive drug tacrolimus requires strict therapeutic monitoring due to its narrow therapeutic index and great inter-individual variability. Cytochrome P450 3A4 (Cyp3A4) and Cyp3A5 are the most important contributors to tacrolimus metabolism while the P-glycoprotein pump (MDR-1) modulates its bioavailability. The objective was to investigate the association between Cyp3A4, Cyp3A5, and MDR-1 polymorphisms and tacrolimus pharmacokinetics in the early period after renal transplantation. METHODS: Forty-four renal transplant recipients were genotyped for 8 Cyp3A4, 7 Cyp3A5, and 5 MDR-1 genetic variants affecting the proteins' expression and/or function. Dose-adjusted tacrolimus though levels were determined during the first week after transplantation and correlated with corresponding genotype. RESULTS: We found no correlation between Cyp3A4 polymorphism and tacrolimus pharmacokinetics. Patients who do not carry both Cyp3A5*3 alleles achieved lower mean dose-adjusted tacrolimus blood concentrations (p<0.001) and needed a longer time to reach the target concentration (10-12 ng/ml; p<0.001) compared to Cyp3A5*3 homozygotes. Patients with less than three copies of MDR-1 (T-129C, C3435T and G2677T) polymorphisms, associated with reduced expression of P-glycoprotein, had also lower dose-adjusted tacrolimus blood concentrations compared to patients having equal to or greater than three copies of MDR-1 genetic variants (P=0.003). There was no difference in the rate of biopsy-confirmed acute rejection among groups during the first 3 months after transplantation. CONCLUSION: The complete absence of Cyp3A5*3 allele and the accumulation of less than three copies of MDR-1 (T-129C, C3435T and G2677T) polymorphisms are associated with lower tacrolimus blood levels identifying these genotypes as markers for patients requiring higher tacrolimus doses.

Correlations between surface and interface energies with respect to crystal nucleation.

The energetic chemical and structural properties of interfaces between solid and liquid metals are of great interest in numerous applications. However, solid-liquid interfacial energies of metals are often determined by nucleation experiments, requiring particular attention to the measurements so obtained. The purpose of this paper is to conduct an analysis of the level of liquid undercooling of 3d-, 4d-, and 5d-transition metals, as well as of other common undercooled elements, through a critical survey of thermophysical data and experimental results. As already pointed out for the liquid-vapor surface energy sigma(LV), the solid-liquid interface energy sigma(LS) determined from the maximum amount of liquid undercooling is well connected to the position of the element in the periodic table, leading to the individualization of each behavior, including the size of the critical nucleus. The beta ratio of sigma(LS)/sigma(LV) is demonstrated to be an interesting dimensionless number by which to classify the elements into distinctive groups. No significant unexplained anomaly is identified, except for Co, supporting the belief that Turnbull's classical theory furnishes a robust support to describe the crystal nucleation in pure elements.