Impact of UGT1A9 polymorphism on mycophenolic acid pharmacokinetic parameters in stable renal transplant patients

There are wide individual differences in pharmacokinetic parameters of mycophenolate mofetil [MMF] among transplanted patients. Some studies have shown that single nucleotide polymorphisms [SNPs] of the Uridine Diphosphate Glucuronosyl Transferase1A9 [UGT1A9] are responsible for these differences in early days after transplantation. Therefore it was decided to evaluate the influence of UGT polymorphism on MMF pharmacokinetics among stable Iranian transplant patients. This was a cross sectional study from March 2008 through December 2008 in Imam Khomeini Hospital affiliated to the Tehran University of Medical Sciences in Iran. Blood samples were taken from 40 de novo stable Iranian renal transplant patients taking 2 g MMF daily with Sr[Cr]

Pharmacokinetics alterations of midazolam infusion versus bolus administration in mechanically ventilated critically ill patients

There is no randomized study carried out in order to compare their pharmacokinetic parameters although midazolam, as a sedative, has been widely administered via continuous infusion as well as intermittent bolus doses in mechanically ventilated critically ill patients. We prospectively investigated the effect of these two principal methods on pharmacokinetic parameters in 23 of mentioned patients [16 males, 7 females] with the mean [ +/- SD] age of 41.22 +/- 17.5. All patients received total dose of 72 mg throughout the test days, 9 of whom received 1 mg/h [continuous infusion] and the rest obtained 4 mg / 4 h [intermittent bolus doses]. Blood samples were collected at 8 and 4 h prior to the end time of drug administration [zero time], zero time and 4, 8, 12, 20 and 30 h after it. APACHE [Acute Physiology and Chronic Health Evaluation] II required data was recorded daily and the patients' mean score was 16.26 +/- 4.38. The mean [ +/- SD] value of pharmacokinetic parameters of Midazolam in continuous infusion and intermittent bolus doses methods were as follows: [t[1/2] = 17.88 +/- 14.65 h, Cl = 21.80 +/- 14.95 L/h] vs. [t[1/2] = 19.74 +/- 12.45 h, Cl = 29.43 +/- 19.45 L/h]. Volume of distribution [Vd] was measured in continuous infusion group which was 612.58 +/- 582.93 L. The calculated clearance and half-life were found not to be significantly different [p < 0.05]. The patients might be exposed to similar undesired effects due to the large volumes of distribution following the administration methods studied

PEGylation of octreotide using an alpha,beta-unsaturated-beta-mono-sulfone functionalized Peg reagent

PEGylation is a well-established technique utilized to overcome the problems related to the therapeutic applications of pep tides and proteins. Reasons for the PEGylation of these biological macromolecules include reducing immunogenicity, proteolytic degradation and rapid clearance from blood circulation. Octreotide is an octapeptide analogue of naturally-occurred somatostatin. This peptide has elimination half-life of less than 2 h that requires frequent daily subcutaneous or intravenous administration. To address this issue, octreotide modification was investigated using bis-thiol alkylating PEG reagent. The required bisthiol alkylating reagent [V] was prepared from commercially available 4-acetyl benzoic acid in five steps. Octreotide disulfide bond was mildly reduced to liberate the two cysteine sulfur atoms followed by bis-alkylation to form PEGylated peptide. The PEG modification process was monitored through the reverse phase HPLC and 'H-NMR analysis. According to the HPLC chromatograms of PEGylation reaction, the peak with 30 min retention time was identified to be PEG-octreotide. In addition, H-NMR analysis showed a 7.44% degree of PEG substitution

Introducing a full validated analyical procedure as an official compendial method for fentanyl transdermal patches

A simple, sensitive and specific HPLC method and also a simple and fast extraction procedure were developed for quantitative analysis of fentanyl transdermal patches. Chloroform, methanol and ethanol were used as extracting solvents with recovery percent of 92.1, 94.3 and 99.4% respectively. Fentanyl was extracted with ethanol and the eluted fentanyl through the C18 column was monitored by UV detection at 230 nm. The linearity was at the range of 0.5-10 microg/mL with correlation coefficient [r[2]] of 0.9992. Both intra and inter-day accuracy and precision were within acceptable limits. The detection limit [DL] and quantitation limit [QL] were 0.15 and 0.5 microg/mL, respectively. Other validation characteristics such as selectivity, robustness and ruggedness were evaluated. Following method validation, a system suitability test [SST] including capacity factor [k'], plate number [N], tailing factor [T], and RSD was defined for routine test

evaluation of the possible effect of positive end expiratory pressure [PEEP] on pharmacokinetics of phenytoin in patients with acute brain injury under mechanical ventilation

Positive ventilation has shown to have an influence on pharmacokinetic and disposition of some drugs.Beacause phenytoin with a narrow therapautic range, is the most commonly used drug for prophylaxis and treatment of early seizures after acute brain injuries, in the present study the effect of short term PEEP [5-10 cm H2O for at least 8 hours] on phenytoin serum concentration and pharmacokinetic parameters such as Vmax and clearance in brain injured patients under mechanical ventilation was examined. Ten patients with moderate to severe acute brain injury who were placed on mechanical ventilation with an initial PEEP level of 0-5 cm H2O were included in the study. Patients received phenytoin loading dose of 15 mg/kg followed by a maintenance daily dose of 3-7 mg/kg initiated within 12 hours of loading dose. Sampels were taken on two different occasions before and after PEEP elevation. Total phenytoin serum concentrations were determined by HPLC method. A time invarient Michaelis-Menten pharmacokinetic model was used to calculate Vmax and clearance for each patient.Derrived variables were calculated as follows: Vmax, 3.5-6.8 and 3.7-8.2 mg/kg/day; Clearance, 0.1-0.7 and 0.1-1.2 l/kg/day [before and after PEEP elevation, respectively]. Our data have shown a wide range of variability [2.6-32.5 mg/l] in phenytoin serum concentrations. There were no statistically significant differences in the measured total concentrations [p=0.721] and calculated Vmax and clearance [p=0.285]before and after PEEP elevation. Administration of fluid and inotropic agents, limitation in application of higher levels of PEEP and drug interactions, shall be considered as possible explanations for these findings

Assessment of different bioequivalence metrics in rifampin bioequivalence study

The use of secondary metrics has become special interest in bioequivalency studies. The applicability of partial area method, truncated AUC and Cmax/AUC has been argued by many authors. This study aims to evaluate the possible superiority of these metrics to primary metrics [i.e. AUCinf, Cmax and Tmax]. The suitability of truncated AUC for assessment of absorption extent as well as Cmax/AUC and partial AUC for the evaluation of absorption rate in bioequivalency determination was investigated following administration of same product as test and reference to 7 healthy volunteers. Among the pharmacokinetic parameters obtained, Cmax/AUCinf was a better indicator or absorption rate and the AUCinf was more sensitive than truncated AUC in evaluation of absorption extent

comparative study of bolus administration and continuous infusion of ranitidine on gastric PH with intragastric PH-probe

The high mortality rate associated with significant bleeding from stress ulceration has promoted efforts to prevent this complication in critically ill patients. Gastric pH is a key factor in the pathogenesis of stress ulceration and maintaining a pH of 4 or greater reduces the risk for development of the gastric ulceration. Our aim was to compare effects of intravenous bolus administration and continuous intravenous infusion of ranitidine on gastric pH in critically ill patients at the intensive care unit [ICU]. Twenty patients who met the inclusion criteria were entered this prospective, randomized, cross over study. A total of 1500 gastric pH measurement was obtained for each phase of the study. Continuous infusion of ranitidine maintained a gastric pH greater than 4 over a longer period than that of bolus administration [22.1 hrs vs. 14.2 hrs, respectively; P<0.001]. The pH-monitoring device which was made locally, was comparable to a standard international device. This study showed that continuous infusion of ranitidine was more effective than administration of an equivalent dose of the drug by bolus in maintaining the appropriate gastric pH required for the prevention of stress ulceration