Identification of a potential cardiac antifibrotic mechanism of torasemide in patients with chronic heart failure.

OBJECTIVES: This study sought to investigate whether torasemide inhibits the enzyme involved in the myocardial extracellular generation of collagen type I molecules (i.e., procollagen type I carboxy-terminal proteinase [PCP]). BACKGROUND: Torasemide has been reported to reduce myocardial fibrosis in patients with chronic heart failure (HF). METHODS: Chronic HF patients received either 10 to 20 mg/day oral torasemide (n = 11) or 20 to 40 mg/day oral furosemide (n = 11) in addition to their standard HF therapy. At baseline and after 8 months from randomization, right septal endomyocardial biopsies were obtained to analyze the expression of PCP by Western blot and the deposition of collagen fibers (collagen volume fraction [CVF]) with an automated image analysis system. The carboxy-terminal propeptide of procollagen type I (PICP) released as a result of the action of PCP on procollagen type I was measured in serum by radioimmunoassay. RESULTS: The ratio of PCP active form to PCP zymogen, an index of PCP activation, decreased (p < 0.05) in torasemide-treated patients and remained unchanged in furosemide-treated patients. A reduction (p < 0.01) in both CVF and PICP was observed in torasemide-treated but not in furosemide-treated patients. Changes in PCP activation were positively correlated (p < 0.001) with changes in CVF and changes in PICP in patients receiving torasemide. CONCLUSIONS: These findings suggest the hypothesis that the ability of torasemide to reduce myocardial fibrosis in chronic HF patients is related to a decreased PCP activation. Further studies are required to ascertain whether PCP may represent a new target for antifibrotic strategies in chronic HF.     

Anatomical and functional connectivity of the transected ulnar nerve after accessory nerve neurotization in the cat

AIM: The objective of this experimental study was to test the capacity of accessory nerve motoneurons to innervate muscles of the ulnar nerve territory after direct anastomosis. METHODS: This study used 22 cats in two groups: experimental group (15 cats) and control group (7 cats). The first one was followed during twelve months using electromyographic records every two months postsurgery; muscle and nerve histological assessment and counting horseradish peroxidase-labeled motoneurons. RESULTS: Our results showed that reinnervation was achieved in 12/15 nerves. The number of HRP labelled medullar motoneurons after anastomosis showed a significant statistic difference with a simple ulnar nerve transection; there was no significant statistic difference in labelling between the group with an anastomosis and the one with a simple accessory nerve transection. CONCLUSIONS: Direct anastomosis between the spinal accessory nerve and the ulnar nerve is achievable and thus, the accessory spinal nerve is another possible choice for correcting the motor deficit arising from lower brachial plexus avulsion, but the limited number of motoneurons would only allow partial reinnervation..     

Plasmacytoma of the thyroid

Three cases of plasmacytoma of the thyroid are described and their clinical and histological features recorded. Two were considered to be true extramedullary plasmacytomas, the third the initial manifestation of a disseminated myelomatous process. Plasmacytomas of the thyroid are shown to have many features in common with malignant lymphomas in this site, including an association with Hashimoto thyroiditis in more than half the reported cases. No certain method of assessing the prognosis in any individual case has yet been described.     

Pharmacokinetic/pharmacodynamic evaluation of antimicrobial treatments of orofacial odontogenic infections

OBJECTIVE: To evaluate the efficacy of antimicrobial therapy in oral odontogenic infections using estimated pharmacokinetic/pharmacodynamic parameters or efficacy indices, and to compare pharmacokinetic/pharmacodynamic breakpoints with National Committee for Clinical Laboratory Standards' (NCCLS) breakpoints. STUDY DESIGN: Retrospective literature search to obtain minimum inhibitory concentration (MIC) values, pharmacokinetic parameters of antimicrobials and NCCLS breakpoints. Pharmacokinetic simulations were carried out using WinNonlin software (Pharsight Corporation, Mountain View, CA, USA). METHODS: For antimicrobials with time-dependent activity, the time that the plasma drug concentration exceeds the MIC as the percentage of dose interval at steady state was calculated. For antimicrobials with concentration-dependent activity, the total area under the plasma concentration-time curve over 24 hours at steady state divided by the MIC was calculated. Pharmacokinetic/pharmacodynamic breakpoints were calculated according to these parameters. RESULTS: Only amoxicillin/clavulanic acid and clindamycin showed adequate efficacy indices against the most commonly isolated bacteria in odontogenic infections. Metronidazole reached good indices against anaerobes only. Pharmacokinetic/pharmacodynamic susceptibility breakpoints do not coincide exactly with NCCLS breakpoints. CONCLUSION: Owing to the scarcity of double-blind, clinical trials on the use of antimicrobials in endodontics, this study may be useful in determining the best antimicrobial treatment in these infections. However, as we have not used concentration data in infected tissue to determine pharmacokinetic/pharmacodynamic indices, it would be necessary to design clinical trials in order to confirm these results.     

Determination of ceftazidime and cefepime in plasma and dialysate-ultrafiltrate from patients undergoing continuous veno-venous hemodiafiltration by HPLC

We have developed and validated a new, rapid and reproducible HPLC method for the determination of cefepime and ceftazidime in plasma and dialysate-ultrafiltrate samples obtained from intensive care unit (ICU) patients undergoing continuous veno-venous hemodiafiltration (CVVHDF). The method for plasma samples involved protein precipitation with acetonitrile, followed by washing with dichloromethane to remove apolar lipophilic compounds. Dialysate-ultrafiltrate samples did not require any preparation. Separation was performed on a μBondapak C18 (30 cm × 3.9 mm × 10 μm) with UV detection. The mobile phase contained acetate buffer: ACN and was delivered at 2 ml/min. The coefficients of determination of the calibration curves were always ≥0.998 and R.S.D.% of the response factors <10%. The intra and inter-assay precision and accuracy of the quality controls (QC) and limit of quantification (LOQ) were satisfactory in all cases. Plasma and dialysate-ultrafiltrate samples were stable at −20 and −80 °C for 2 months and also after three freeze/thaw cycles. Dialysate-ultrafiltrate samples were stable in the chromatographic rack for 24 h at room temperature, but we recommend storing processed plasma samples at 4 °C until the analysis. The described method has proved to be useful to give accurate measurements of ceftazidime and cefepime in samples obtained from patients undergoing CVVHDF.     

Elimination of piperacillin and tazobactam by renal replacement therapies with AN69 and polysulfone hemofilters: evaluation of the sieving coefficient

BACKGROUND/AIM: Piperacillin-tazobactam is commonly used to treat infections in ICU patients. Controversial data have been published about the sieving/saturation coefficient (Sc/Sa) of piperacillin during continuous renal replacement therapies (CRRT). The objective was to evaluate the Sc/Sa of piperacillin-tazobactam during continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD) using AN69 and polysulfone. METHODS: Ringer lactate, BSA-containing Ringer lactate and plasma were circulated at 150 ml/min. The ultrafiltrate/dialysis flow was kept at 1,500 ml/min. A bolus was injected and samples were taken. Drugs were measured using HPLC. Sc/Sa was calculated according to standard formula. RESULTS: Free passage of drugs through the membranes was reported with protein free solutions. In the presence of proteins the Sc/Sa lowered and correlated to protein free fraction. Polysulfone had a significantly higher permeability than AN69 during CVVH. CONCLUSION: Drug binding to albumin contributes to the decrease of the Sc/Sa of piperacillin but it does not completely justify the in vivo value obtained by some authors.